Treatment of Ischemic Stroke

**Chapter 5**

**Abstract**

evidence-based data are scarce.

**1.1 The diagnosis of stroke**

vision disorders.

**85**

to both ischemic stroke and intracranial hemorrhage.

Acute stroke suggests the following signs:

complications

**1. Introduction**

The Treatment of Acute Stroke

*Irina Alexandrovna Savvina and Anna Olegovna Petrova*

causes in cerebral ischemia, or vascular malformations, cerebral amyloid

angiopathies, small-vessel diseases, rare vasculopathies and undetermined causes in parenchymal hemorrhages. This chapter will focus only on acute cerebral ischemia and parenchymal hemorrhage. We will cover the general assessment of stroke patients, the complications that can occur in the acute stage, the treatment of acute stroke, and finally a few situations that require specific managements and where

**Keywords:** cerebral ischemia, parenchymal hemorrhages, thrombolytic therapy,

This chapter focuses on the treatment of acute cerebral ischemia and intracranial hemorrhage, which are two types of stroke. Stroke is characterized by a sudden loss of brain function with no established cause other than vascular origin. This applies

• Sudden onset of symptoms and development of the clinical picture in a few

• Focal neurological symptoms associated with damage to certain parts of the brain: motor deficits (weakness or immobility of the limbs on one side of the body (hemiplegia or hemiparesis) or an isolated limb), loss of sensitivity (decreased sensitivity in various parts of the body), aphasia, agnosia, and

seconds or minutes with further stabilization or improvement.

Stroke is a major public health issue, because of its high incidence rate, high case fatality rate, risk of residual physical and neuropsychological disabilities, and direct and indirect costs. Many strokes are preventable and treatable in the acute stage, provided that patients are admitted soon enough. The term stroke covers a wide range of heterogeneous disorders, depending on the severity of the clinical presentation, from transient deficits to severe cases with coma and early death; the underlying mechanism, i.e., cerebral ischemia, parenchymal hemorrhage, subdural hemorrhage, or subarachnoid hemorrhage (SAH); and the cause, i.e., atherosclerosis, cardioembolism, small-vessel occlusion, rare vasculopathies and undetermined

## **Chapter 5** The Treatment of Acute Stroke

*Irina Alexandrovna Savvina and Anna Olegovna Petrova*

## **Abstract**

Stroke is a major public health issue, because of its high incidence rate, high case fatality rate, risk of residual physical and neuropsychological disabilities, and direct and indirect costs. Many strokes are preventable and treatable in the acute stage, provided that patients are admitted soon enough. The term stroke covers a wide range of heterogeneous disorders, depending on the severity of the clinical presentation, from transient deficits to severe cases with coma and early death; the underlying mechanism, i.e., cerebral ischemia, parenchymal hemorrhage, subdural hemorrhage, or subarachnoid hemorrhage (SAH); and the cause, i.e., atherosclerosis, cardioembolism, small-vessel occlusion, rare vasculopathies and undetermined causes in cerebral ischemia, or vascular malformations, cerebral amyloid angiopathies, small-vessel diseases, rare vasculopathies and undetermined causes in parenchymal hemorrhages. This chapter will focus only on acute cerebral ischemia and parenchymal hemorrhage. We will cover the general assessment of stroke patients, the complications that can occur in the acute stage, the treatment of acute stroke, and finally a few situations that require specific managements and where evidence-based data are scarce.

**Keywords:** cerebral ischemia, parenchymal hemorrhages, thrombolytic therapy, complications

## **1. Introduction**

This chapter focuses on the treatment of acute cerebral ischemia and intracranial hemorrhage, which are two types of stroke. Stroke is characterized by a sudden loss of brain function with no established cause other than vascular origin. This applies to both ischemic stroke and intracranial hemorrhage.

## **1.1 The diagnosis of stroke**

Acute stroke suggests the following signs:


For the differential diagnosis of ischemic and hemorrhagic strokes, it is necessary to conduct a neuroimaging study [1]. This is the most important stage of diagnosis, because patients with ischemic and hemorrhagic strokes require different therapies in the acute period and various measures of secondary prevention [2].

Magnetic resonance imaging (MRI) is the most appropriate diagnostic method for patients with acute cerebral circulation disorders due to the following reasons [3]:

1.T1- and T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences allow the differentiation of old foci and foci of nonvascular origin.

**1.2 Examination of patients with acute stroke**

*Non-contrast CT scan shows a spontaneous hyperdensity of the right cerebral hemisphere.*

**Figure 1.**

*The Treatment of Acute Stroke*

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

antinuclear antibodies, etc.

**87**

For all patients in the acute stage, the following examinations should be carried out, which will determine the treatment plan: a thorough collection of anamnesis to determine the presence of hypertension, medications used, alcohol abuse, and substance abuse and a family history of stroke, oncology, and trauma; a clinical examination; blood test to detect polycythemia and plateletemia, erythrocyte sedimentation rate (ESR) to detect vasculitis, and the level of glycemia to detect diabetes or hypoglycemia, and coagulation tests. Cardiac assessment including electrocardiogram (ECG) and echocardiography (EchoCG) is quite important in all cases and Holter in selected cases. ECG recording to detect heart attacks, atrial fibrillation, continuous ECG monitoring to detect arrhythmias; monitoring of systolic, diastolic, and mean blood pressure (BP) by noninvasive method;

dopplerography to detect stenoses and dissections of cervical and intracranial vessels; transthoracic EchoCG to detect blood clots, tumors, valve pathology, vegetations on the valves, reduction of ejection fraction, and the presence of an open oval window. Neuroimaging methods include MRI and CT of the brain to detect caverns,

malformations (AVM), tumors, and indirect signs of unknown injuries. Additional examinations are prescribed depending on the initial results obtained, the patient's age, and the presumed etiology of the stroke: angiography (usually MR, CT angiog-

There are neurological complications that occur in the acute phase of stroke in any type in the form of convulsive syndrome; hyper- and hypoactive delirium, especially with a pre-existing decrease of cognitive functions and the development of metabolic or infectious complications; as well as intracranial hypertension.

Nonspecific complications include bedsores, pneumonia, urinary tract infection, hyponatremia due to inadequate secretion of antidiuretic hormone (ADH), deep vein thrombosis, and pulmonary thromboembolism. They are more likely to

intracranial venous thromboses, cerebral microhemorrhages, arteriovenous

raphy) and specific biological tests when it comes to specific causes, such as


When MRI is not available in an emergency or cannot be performed due to contraindications (established rhythm driver, claustrophobia, psychomotor agitation), an emergency computed tomography (CT) scan of the brain is performed without contrast. CT scan reveals an intracranial hemorrhage in the form of a hyperintensive zone in the brain parenchyma. **Figure 1** shows a non-contrast CT scan with a spontaneous hyperdensity of the right cerebral hemisphere, due to a deep intracerebral hemorrhage (ICH). In the early stages of acute cerebral ischemia, CT signs of ischemia may be absent. But within 3 hours, you can see signs of ischemia, for example, the disappearance of a clear border of gray and white matter. With the occlusion of the middle cerebral artery, CT signs will appear in the form of a hyperintensive zone. CT with contrast allows you to visualize the anatomy of the arteries and perfusion.

The most common causes of ischemic stroke are common atherosclerosis, atrial fibrillation (AF), occlusion of small perforating arteries of the brain, pathology of heart valves, and infectious diseases, in young patients—cerebral artery dissection.

Intracerebral hemorrhages in most cases are the result of the damage to small cerebral vessels due to chronic arterial hypertension or amyloid angiopathy.

• Symptoms suggesting a loss of function: limb tremors, convulsions, paresthesias, visual hallucinations, and flashes before the eyes.

• Symptoms such as loss of consciousness, dizziness, general weakness, confusion, urinary incontinence, syncopal condition, and tinnitus do not indicate the development of a stroke if they are not associated with focal

For the differential diagnosis of ischemic and hemorrhagic strokes, it is necessary to conduct a neuroimaging study [1]. This is the most important stage of diagnosis, because patients with ischemic and hemorrhagic strokes require different therapies in the acute period and various measures of secondary

Magnetic resonance imaging (MRI) is the most appropriate diagnostic method for patients with acute cerebral circulation disorders due to the following reasons [3]:

1.T1- and T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences allow the differentiation of old foci and foci of nonvascular origin.

2.Diffusion-weighted images allow the identification of new ischemic foci. Low brain blood flow causes the development of cytotoxic cell edema and, as a result, a decrease in the movement of extracellular fluid, which is displayed as a hyperintensive signal on diffusion-weighted images, and a decrease in the water diffusion coefficient. These changes appear earlier than changes in T1

4.Time-of-flight (TOF) MR angiography can be used to visualize the occlusion

When MRI is not available in an emergency or cannot be performed due to contraindications (established rhythm driver, claustrophobia, psychomotor agitation), an emergency computed tomography (CT) scan of the brain is performed without contrast. CT scan reveals an intracranial hemorrhage in the form of a hyperintensive zone in the brain parenchyma. **Figure 1** shows a non-contrast CT scan with a spontaneous hyperdensity of the right cerebral hemisphere, due to a deep intracerebral hemorrhage (ICH). In the early stages of acute cerebral ischemia, CT signs of ischemia may be absent. But within 3 hours, you can see signs of ischemia, for example, the disappearance of a clear border of gray and white matter. With the occlusion of the middle cerebral artery, CT signs will appear in the form of a hyperintensive zone. CT with contrast allows you to visualize the anatomy of the

The most common causes of ischemic stroke are common atherosclerosis, atrial fibrillation (AF), occlusion of small perforating arteries of the brain, pathology of heart valves, and infectious diseases, in young patients—cerebral artery dissection. Intracerebral hemorrhages in most cases are the result of the damage to small

cerebral vessels due to chronic arterial hypertension or amyloid angiopathy.

a stroke localized in the brain stem.

neurological symptoms.

and T2 and FLAIR.

arteries and perfusion.

**86**

3.T\* sequences are used to detect hemorrhages.

of extra- and intracranial arteries.

prevention [2].

*Ischemic Stroke*

• Headache, nausea and vomiting, dysphagia, dysarthria, dysphonia, diplopia, ataxia, hiccups, one-sided acute hearing loss, respiratory disorder, convulsive syndrome, and transient loss of consciousness may be clinical manifestations of

**Figure 1.** *Non-contrast CT scan shows a spontaneous hyperdensity of the right cerebral hemisphere.*

## **1.2 Examination of patients with acute stroke**

For all patients in the acute stage, the following examinations should be carried out, which will determine the treatment plan: a thorough collection of anamnesis to determine the presence of hypertension, medications used, alcohol abuse, and substance abuse and a family history of stroke, oncology, and trauma; a clinical examination; blood test to detect polycythemia and plateletemia, erythrocyte sedimentation rate (ESR) to detect vasculitis, and the level of glycemia to detect diabetes or hypoglycemia, and coagulation tests. Cardiac assessment including electrocardiogram (ECG) and echocardiography (EchoCG) is quite important in all cases and Holter in selected cases. ECG recording to detect heart attacks, atrial fibrillation, continuous ECG monitoring to detect arrhythmias; monitoring of systolic, diastolic, and mean blood pressure (BP) by noninvasive method; dopplerography to detect stenoses and dissections of cervical and intracranial vessels; transthoracic EchoCG to detect blood clots, tumors, valve pathology, vegetations on the valves, reduction of ejection fraction, and the presence of an open oval window. Neuroimaging methods include MRI and CT of the brain to detect caverns, intracranial venous thromboses, cerebral microhemorrhages, arteriovenous malformations (AVM), tumors, and indirect signs of unknown injuries. Additional examinations are prescribed depending on the initial results obtained, the patient's age, and the presumed etiology of the stroke: angiography (usually MR, CT angiography) and specific biological tests when it comes to specific causes, such as antinuclear antibodies, etc.

There are neurological complications that occur in the acute phase of stroke in any type in the form of convulsive syndrome; hyper- and hypoactive delirium, especially with a pre-existing decrease of cognitive functions and the development of metabolic or infectious complications; as well as intracranial hypertension.

Nonspecific complications include bedsores, pneumonia, urinary tract infection, hyponatremia due to inadequate secretion of antidiuretic hormone (ADH), deep vein thrombosis, and pulmonary thromboembolism. They are more likely to

develop in patients with severe neurological deficits. Hyponatremia is a common accompaniment during the acute stage of stroke. Its relevance to the clinical presentation, treatment and prognosis should be mentioned.

A. Restoring of fluid deficit

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

B. Positive sodium balance

≤10 mmol/l/24 hours

D.HyperHAES: 0.25 ml/kg/hour or 0.9%NaCl

the main component of the stroke treatment program [6, 7].

explains the need for a constant monitoring for 2–3 days.

F. Acute hyponatremia correction rate (<48 h): ≤24 mmol/l/24 hours

H.In the presence of an accompanying potassium deficit: ≤4 mmol/l/

Stroke patients should be treated in specialized departments. For every 24 patients treated in a specialized rather than general ward, one death and one disability are prevented [4]. This does not depend on the age, type, and severity of stroke [4, 5]. Therefore, specialized departments are very important for the treatment of stroke patients [1, 4]. For all strokes with persistent neurological deficits, the treatment aimed at stabilizing the patient's condition, controlling vital functions, and actively curating problems that may worsen recovery is indicated. This is

In the detection and treatment of emergency life-threatening conditions (risk of

The stabilization of most physiological parameters, blood pressure, saturation (more than 93%), glycemic level (less than 180 mg), body temperature (below 37.50°C), and hydration, is necessary in the first few days to prevent negative

A normal respiratory function with adequate blood oxygenation is necessary in the acute period of stroke to maintain an adequate oxygen delivery to brain cells, but there is no conclusive evidence that all patients with stroke receive oxygen therapy with a positive result [4]. In cases of hypoxemia, improved blood oxygenation is achieved by oxygen therapy via a nasal catheter and noninvasive or invasive

Complications of acute stroke include neurogenic stressful cardiomyopathy, paroxysmal sympathetic hyperactivity, atrial fibrillation, acute heart failure, myocardial infarction, and sudden death [1, 2]. The frequency of these complications

Many stroke patients are in a state of dehydration, which leads to a worse outcome of the disease [1, 2]. Despite limited clinical data, the administration of

aspiration, epileptic status, respiratory failure, etc.), the patency of the upper respiratory tract should be ensured in the case of deprivation of consciousness to the level of coma, respiratory failure of central origin, or local causes leading to respi-

G.Chronic hyponatremia correction rate (>48 h): ≤0.5 mmol/l/hour, but

E. Fludrocortisone: 0.4 mg per 24 hours

C. Rehydration

*The Treatment of Acute Stroke*

25 hours

ratory disorders.

ventilation.

**89**

dynamics in the penumbra zone.

**2. Treatment of acute stroke**

**2.1 General principles of the therapy**

## *1.2.1 Protocol of hypernatremia correction in patients with stroke*

Hypernatremia: Na >145 mmol/l (the main reason—central DI) Criteria: polyuria: rate of diuresis >3 ml/kg/hour Hypernatremia: >145 mmol/l Urine specific gravity: <1005

## *Infusion therapy*:

Base 75–100 ml/hour monitoring of sodium concentration every 6 hours. Fluid deficit replenishment: in case of polyuria—compensation of fluid loss.

*If ineffective, symptoms of diabetes insipidus (DI) persist—ADH*

Desmopressin: 2–4 mcg per 24 hours Vasomirin (nasal spray): 10 mcg

## *1.2.1.1 Fluid loss calculation*

Total body fluid = 0.6 body weight Free water deficit = (0.6 body weight) (0.6 body weight) (140/Na act) Example: body weight = 75 kg, Na = 154 mmol/l Free water deficit = 0.6 75 [0.6 75 (140/154)] = 45 40.9 = 4.1 l

## *1.2.2 Protocol of hyponatremia correction in patients with stroke*

Hyponatremia: Na < 135 mmol/l If Na <125 mmol/l, there is a high risk of neurological disorders.

## 1.Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

A. No neurological deterioration

	- Hyponatremia: no longer than 24 hours acute not prolonged reducing the level of sodium
	- Negative fluid balance: IV 3% NaCl—4 ml/kg during 15–30 min
	- 2/3 of physiological need for fluid + furosemide 1 mg/kg
	- Intravenous (IV): only sodium solutions
	- Monitoring: fluid balance, diuresis, sodium in plasma/urine, and urine specific gravity

2.Central salt wasting syndrome


develop in patients with severe neurological deficits. Hyponatremia is a common accompaniment during the acute stage of stroke. Its relevance to the clinical pre-

Base 75–100 ml/hour monitoring of sodium concentration every 6 hours. Fluid deficit replenishment: in case of polyuria—compensation of fluid loss.

Free water deficit = (0.6 body weight) (0.6 body weight) (140/Na act)

• Hyponatremia: no longer than 24 hours acute not prolonged

• 2/3 of physiological need for fluid + furosemide 1 mg/kg

• Negative fluid balance: IV 3% NaCl—4 ml/kg during 15–30 min

• Monitoring: fluid balance, diuresis, sodium in plasma/urine, and

Free water deficit = 0.6 75 [0.6 75 (140/154)] = 45 40.9 = 4.1 l

If Na <125 mmol/l, there is a high risk of neurological disorders.

1.Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

sentation, treatment and prognosis should be mentioned.

Criteria: polyuria: rate of diuresis >3 ml/kg/hour

Hypernatremia: >145 mmol/l Urine specific gravity: <1005

Desmopressin: 2–4 mcg per 24 hours Vasomirin (nasal spray): 10 mcg

Total body fluid = 0.6 body weight

Hyponatremia: Na < 135 mmol/l

A. No neurological deterioration

B. Acute neurological deterioration

urine specific gravity

2.Central salt wasting syndrome

**88**

reducing the level of sodium

• Intravenous (IV): only sodium solutions

Example: body weight = 75 kg, Na = 154 mmol/l

*1.2.2 Protocol of hyponatremia correction in patients with stroke*

*Infusion therapy*:

*Ischemic Stroke*

*1.2.1.1 Fluid loss calculation*

*1.2.1 Protocol of hypernatremia correction in patients with stroke*

*If ineffective, symptoms of diabetes insipidus (DI) persist—ADH*

Hypernatremia: Na >145 mmol/l (the main reason—central DI)


## **2. Treatment of acute stroke**

#### **2.1 General principles of the therapy**

Stroke patients should be treated in specialized departments. For every 24 patients treated in a specialized rather than general ward, one death and one disability are prevented [4]. This does not depend on the age, type, and severity of stroke [4, 5]. Therefore, specialized departments are very important for the treatment of stroke patients [1, 4]. For all strokes with persistent neurological deficits, the treatment aimed at stabilizing the patient's condition, controlling vital functions, and actively curating problems that may worsen recovery is indicated. This is the main component of the stroke treatment program [6, 7].

In the detection and treatment of emergency life-threatening conditions (risk of aspiration, epileptic status, respiratory failure, etc.), the patency of the upper respiratory tract should be ensured in the case of deprivation of consciousness to the level of coma, respiratory failure of central origin, or local causes leading to respiratory disorders.

The stabilization of most physiological parameters, blood pressure, saturation (more than 93%), glycemic level (less than 180 mg), body temperature (below 37.50°C), and hydration, is necessary in the first few days to prevent negative dynamics in the penumbra zone.

A normal respiratory function with adequate blood oxygenation is necessary in the acute period of stroke to maintain an adequate oxygen delivery to brain cells, but there is no conclusive evidence that all patients with stroke receive oxygen therapy with a positive result [4]. In cases of hypoxemia, improved blood oxygenation is achieved by oxygen therapy via a nasal catheter and noninvasive or invasive ventilation.

Complications of acute stroke include neurogenic stressful cardiomyopathy, paroxysmal sympathetic hyperactivity, atrial fibrillation, acute heart failure, myocardial infarction, and sudden death [1, 2]. The frequency of these complications explains the need for a constant monitoring for 2–3 days.

Many stroke patients are in a state of dehydration, which leads to a worse outcome of the disease [1, 2]. Despite limited clinical data, the administration of infusion therapy (0.9% sodium chloride solution) is considered part of the overall treatment of stroke, especially in patients with an increased risk of dehydration due to depression of consciousness or respiratory disorders. Experience in the treatment of hyperglycemia recommends avoiding the introduction of glucose solutions in the early period of stroke and strict control of the level of glycemia [4].

etc. All should be started as early as possible. Rehabilitation should begin as soon as the patient's condition stabilizes: passive measures to minimize contractures, bedsores, and pneumonia. A coordinated multidisciplinary approach to patient management with the help of constantly trained staff is important, which leads to a

The intravenous administration of a recombinant tissue plasminogen activator (tPA) increases the chances of a favorable outcome approximately 8 times within 3 months if performed in the first 90 minutes, 2 times when performed within 91– 180 minutes after a stroke, and 1.4 times when performed in 181–270 minutes [6, 13]. The mortality does not change when administered up to 270 min after stroke onset, but increases with later administration of tPA [6]. Indications and contraindications

Hemorrhagic transformation is more often observed in patients with large strokes and of old age [7]. The earlier the tPA is introduced, the more likely the beneficial effect is, and despite the fact that the probability of a favorable effect is also present when used later than 3 hours from a stroke, it is significantly reduced. The dose is 0.9 mg/kg (10% intravenous bolus, 90%—within an hour microjet). In Japan, the recommended dose is lower—0.6 mg/kg. Thus, thrombolytic therapy is recommended as early as possible after the onset of a stroke, no later than 4.5 hours. Restrictions apply both to contraindications [increased risk of hemorrhage, delay of more than 4.5 hours, blood pressure (BP) above 185 mm Hg, blood glucose above 4 G/l] and strict rules of use (only by a doctor trained in the management of stroke

Other ways to achieve rapid recanalization are currently being investigated and

Aspirin at a starting dose of 300 mg and then 75–150 mg daily prevents 9 cases of disability and death per 1000 patients. Aspirin should be prescribed 24 hours after any thrombolytic therapy. Recently, a Clopidogrel in High-Risk Patients with Acute Nondisabling of Cerebrovascular Events (CHANCE) study showed that patients with small strokes and transient ischemic attack (TIA) who received a loading dose of clopidogrel for 24 hours, against the background of aspirin, and then for 90 days on 75 mg of aspirin and 75 mg of clopidogrel had better outcomes without the risk of

2. The time from the symptoms onset to the thrombolysis procedure less than 4.5 hours

3. Age from 18 years and older (after 80 years with caution, individual decision about TLT, taking into

do not change the existing recommendations: other thrombolytic drugs, MRI patient selection criteria, intra-arterial thrombolytic therapy, and ultrasoundassisted intravenous thrombolysis. Mechanical thrombextraction is considered a promising technique in addition to intravenous thrombolysis in patients with proximal occlusions. In patients receiving oral anticoagulants, mechanical thrombectomy is often the only recommended recanalization strategy.

for thrombolytic therapy are noted in **Tables 1** and **2**, respectively.

patients and only in the stroke department) [6].

**2.3 Antithrombotic therapy**

bleeding.

**Table 1.**

**91**

**No. of wording**

1. Stroke, ischemic type

account the perceived risk)

*Indications for thrombolytic therapy.*

reduction in mortality and disability.

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

**2.2 Thrombolytic therapy**

*The Treatment of Acute Stroke*

According to the literature, there are no mechanisms for autoregulation of cerebral blood flow in the penumbra zone. Therefore, a decrease in blood pressure in the first hours after a stroke before the penumbra zone appears can cause significant hypoperfusion, which worsens the development of the ischemia zone. Therefore, in the acute period, it is not necessary to aggressively treat arterial hypertension if there are no concomitant life-threatening conditions, such as aortic dissection or intracranial hematoma [2, 4].

In practice, blood pressure correction is usually started when the systolic blood pressure exceeds 220 mm Hg and diastolic blood pressure exceeds 120 mm Hg. However, in many clinics, antihypertensive therapy is performed only in cases of heart failure, acute renal failure, aortic arch dissection, or malignant hypertension. When conducting a thrombolytic therapy (TLT), it is common practice to maintain blood pressure below 185 mm Hg. The intravenous administration of labetalol (10 mg bolus, followed by an infusion of 0.1–0.3 mg/kg/hour) or urapidil (12.5 mg bolus for 20 seconds, followed by an infusion of 6–30 mg/hour) is often used.

Hyperglycemia occurs in 60% of stroke patients who have not previously suffered from diabetes [2, 7]. Hyperglycemia after a stroke is usually associated with a large volume of infarction and cortical damage and is associated with an adverse outcome of the disease [4]. Currently, the routine use of insulin infusions in patients with moderate hyperglycemia is not recommended. The European Stroke Association recommends maintaining glycemia below 180 mg/dl (10 mmol/l) [4].

*Body temperature control*: hyperthermia is associated with an increase in the size of the infarction zone and a worsening of the outcome of the disease [8]. Fever is associated with a worse clinical outcome [9]. When the body temperature increases, it is necessary to quickly exclude concomitant infections and, if necessary, treat them.

#### *2.1.1 Prevention of acute stroke complications*

The prevention of trophic disorders in the form of bedsores is carried out by establishing an early enteral nutrition through a nasogastric probe with an adequate calorie of nutritional mixtures: early mobilization, anti-bedsore mattresses, suitable beds, and nursing care.

*Aspiration pneumonia*: diagnosis of dysphagia (special examination of the function of swallowing by doctors, nurses, or speech therapists) [10, 11] or use of a nasogastric probe if necessary.

Deep vein thrombosis and pulmonary embolism: low-molecular-weight heparins (LMWH) in prophylactic doses reduce the risk of thromboembolic complications without affecting mortality [2]. Their use slightly increases the risk of intracranial hemorrhages. The use of LMWH is recommended only if the patient has risk factors for deep vein thrombosis and pulmonary embolism, such as lower limb immobilization, in the first few hours after a stroke [2], and not earlier than 24 hours in patients with intracranial hemorrhage [9]. A recent study of Clots in Legs Or sTockings after Stroke (CLOTS) [12] has shown that an intermittent pneumatic compression reduces the risk of deep vein thrombosis and can improve stroke survival in patients who cannot go to the toilet with an assistant.

*Rehabilitation*: it is an important issue both in acute phase and in chronic phase. Points to be covered are position turning to avoid pressure sores, chest physiotherapy to minimize lung complication, swallowing assessment and training, limb movements to prevent deep vein thrombosis, speech therapy, early mobilization,

etc. All should be started as early as possible. Rehabilitation should begin as soon as the patient's condition stabilizes: passive measures to minimize contractures, bedsores, and pneumonia. A coordinated multidisciplinary approach to patient management with the help of constantly trained staff is important, which leads to a reduction in mortality and disability.

## **2.2 Thrombolytic therapy**

infusion therapy (0.9% sodium chloride solution) is considered part of the overall treatment of stroke, especially in patients with an increased risk of dehydration due to depression of consciousness or respiratory disorders. Experience in the treatment of hyperglycemia recommends avoiding the introduction of glucose solutions in the

According to the literature, there are no mechanisms for autoregulation of cerebral blood flow in the penumbra zone. Therefore, a decrease in blood pressure in the first hours after a stroke before the penumbra zone appears can cause significant hypoperfusion, which worsens the development of the ischemia zone. Therefore, in the acute period, it is not necessary to aggressively treat arterial hypertension if there are no concomitant life-threatening conditions, such as aortic dissection or

In practice, blood pressure correction is usually started when the systolic blood pressure exceeds 220 mm Hg and diastolic blood pressure exceeds 120 mm Hg. However, in many clinics, antihypertensive therapy is performed only in cases of heart failure, acute renal failure, aortic arch dissection, or malignant hypertension. When conducting a thrombolytic therapy (TLT), it is common practice to maintain blood pressure below 185 mm Hg. The intravenous administration of labetalol (10 mg bolus, followed by an infusion of 0.1–0.3 mg/kg/hour) or urapidil (12.5 mg bolus for 20 seconds, followed by an infusion of 6–30 mg/hour) is often used. Hyperglycemia occurs in 60% of stroke patients who have not previously suffered from diabetes [2, 7]. Hyperglycemia after a stroke is usually associated with a large volume of infarction and cortical damage and is associated with an adverse outcome of the disease [4]. Currently, the routine use of insulin infusions in patients with moderate hyperglycemia is not recommended. The European Stroke Association recommends maintaining glycemia below 180 mg/dl (10 mmol/l) [4]. *Body temperature control*: hyperthermia is associated with an increase in the size of

the infarction zone and a worsening of the outcome of the disease [8]. Fever is associated with a worse clinical outcome [9]. When the body temperature increases, it is necessary to quickly exclude concomitant infections and, if necessary, treat them.

The prevention of trophic disorders in the form of bedsores is carried out by establishing an early enteral nutrition through a nasogastric probe with an adequate calorie of nutritional mixtures: early mobilization, anti-bedsore mattresses, suitable

*Aspiration pneumonia*: diagnosis of dysphagia (special examination of the function of swallowing by doctors, nurses, or speech therapists) [10, 11] or use of a

Deep vein thrombosis and pulmonary embolism: low-molecular-weight heparins (LMWH) in prophylactic doses reduce the risk of thromboembolic complications without affecting mortality [2]. Their use slightly increases the risk of intracranial hemorrhages. The use of LMWH is recommended only if the patient has risk factors for deep vein thrombosis and pulmonary embolism, such as lower limb immobilization, in the first few hours after a stroke [2], and not earlier than 24 hours in patients with intracranial hemorrhage [9]. A recent study of Clots in Legs Or sTockings after Stroke (CLOTS) [12] has shown that an intermittent pneumatic compression reduces the risk of deep vein thrombosis and can improve stroke

*Rehabilitation*: it is an important issue both in acute phase and in chronic phase. Points to be covered are position turning to avoid pressure sores, chest physiotherapy to minimize lung complication, swallowing assessment and training, limb movements to prevent deep vein thrombosis, speech therapy, early mobilization,

survival in patients who cannot go to the toilet with an assistant.

early period of stroke and strict control of the level of glycemia [4].

intracranial hematoma [2, 4].

*Ischemic Stroke*

*2.1.1 Prevention of acute stroke complications*

beds, and nursing care.

**90**

nasogastric probe if necessary.

The intravenous administration of a recombinant tissue plasminogen activator (tPA) increases the chances of a favorable outcome approximately 8 times within 3 months if performed in the first 90 minutes, 2 times when performed within 91– 180 minutes after a stroke, and 1.4 times when performed in 181–270 minutes [6, 13]. The mortality does not change when administered up to 270 min after stroke onset, but increases with later administration of tPA [6]. Indications and contraindications for thrombolytic therapy are noted in **Tables 1** and **2**, respectively.

Hemorrhagic transformation is more often observed in patients with large strokes and of old age [7]. The earlier the tPA is introduced, the more likely the beneficial effect is, and despite the fact that the probability of a favorable effect is also present when used later than 3 hours from a stroke, it is significantly reduced. The dose is 0.9 mg/kg (10% intravenous bolus, 90%—within an hour microjet). In Japan, the recommended dose is lower—0.6 mg/kg. Thus, thrombolytic therapy is recommended as early as possible after the onset of a stroke, no later than 4.5 hours. Restrictions apply both to contraindications [increased risk of hemorrhage, delay of more than 4.5 hours, blood pressure (BP) above 185 mm Hg, blood glucose above 4 G/l] and strict rules of use (only by a doctor trained in the management of stroke patients and only in the stroke department) [6].

Other ways to achieve rapid recanalization are currently being investigated and do not change the existing recommendations: other thrombolytic drugs, MRI patient selection criteria, intra-arterial thrombolytic therapy, and ultrasoundassisted intravenous thrombolysis. Mechanical thrombextraction is considered a promising technique in addition to intravenous thrombolysis in patients with proximal occlusions. In patients receiving oral anticoagulants, mechanical thrombectomy is often the only recommended recanalization strategy.

## **2.3 Antithrombotic therapy**

Aspirin at a starting dose of 300 mg and then 75–150 mg daily prevents 9 cases of disability and death per 1000 patients. Aspirin should be prescribed 24 hours after any thrombolytic therapy. Recently, a Clopidogrel in High-Risk Patients with Acute Nondisabling of Cerebrovascular Events (CHANCE) study showed that patients with small strokes and transient ischemic attack (TIA) who received a loading dose of clopidogrel for 24 hours, against the background of aspirin, and then for 90 days on 75 mg of aspirin and 75 mg of clopidogrel had better outcomes without the risk of bleeding.

**No. of wording**

<sup>1.</sup> Stroke, ischemic type

<sup>2.</sup> The time from the symptoms onset to the thrombolysis procedure less than 4.5 hours

<sup>3.</sup> Age from 18 years and older (after 80 years with caution, individual decision about TLT, taking into account the perceived risk)


We report below the current clinical status of drugs that have been developed as

Hypothermia is a potential opportunity to provide neuroprotection, but due to side effects and the need for intensive therapy, it can only be used in severe cases, especially in patients with malignant heart attacks, and currently requires random-

Decompressive neurosurgery (hemispherectomy) reduces mortality and disability in patients younger than 60 years old who recently suffered a massive stroke

Nimodipine: no benefit (VENUS) Noncompetitive

**Category, mechanism**

NMDA antagonist

Competitive NMDA antagonist

receptor antagonist

Metabotropic receptor antagonist

LMWH-CoA reductase inhibitor

Hemodiluting agent

stabilizer

pleiotropic protective effects

MgSO4 FAST-MAG: ongoing (IMAGE) Iron chelator Deferoxamine mesylate:

*VENUS, very early nimodipine use in stroke; NMDA, N-methyl-D-aspartic acid; GABA gamma-aminobutyric acid; AMPA, amino-hydroxy-methyl-isoxalone propionic acid; KA, kainate; NBQX, 2,3dihydroxy-6-nitro-7-sulfamoylbenzo [f]quinoxaline-2,3-dione; RCT, randomized controlled trial; bFGF basic fibroblast growth factor; ALIAS, albumin in acute stroke; FAST-MAG, Field Administration of Stroke Therapy—Magnesium; ACEA-1021, 5-nitro-*

Eliprodil: discontinued Antibiotic,

ACEA-1021, no benefit; gavestinel, no

*Neuroprotective drugs developed so far and results of clinical trials.*

Nalmefene: no benefit Metal ion chelator DP-b99: phase III

**Drug name, name of multicenter study, and**

Dizocilpine, discontinued Dextrorphan, no benefit

Selfotel: discontinued

NBQX, discontinued YM872, RCT

Lovastatin, phase II; simvastatin, phase III

Albumin: phase III (ALIAS)

phase III

phase II

Others Piracetam: phase III

Citicoline (CDP choline):

Minocycline: phase III

being planned

Groups I, II, and III: RCT

**its results**

neuroprotective agents (**Table 3**) [14].

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

*The Treatment of Acute Stroke*

**2.5 Decompressive neurosurgery**

**Drug name, name of multicenter**

Lifarizine, no benefit; lubeluzole, no benefit; fosphenytoin, discontinued

GABA agonist Clomethiazole: no effect AMPA/KA

Edaravone, clinical use; ebselen, phase III; NXY059: phase III; tirilazad,

**study, and its results**

discontinued

phase II

benefit

*6,7-dichloro-1,4dihydro-2,3-quinoxalinedione.*

Growth factor bFGF: abandoned AX200 (filgrastim, G-CSF analogue), phase II

> Human chorionic gonadotropin (hCG)/erythropoietin (Ntx-265):

Ganglioside No benefit Membrane

ized trials [8, 15].

**Category, mechanism**

Ca2+ channel blocker

Na+ channel blocker

Free radical scavenger

Growth factors, oxygen delivery

Opioid receptor antagonist

Polyamine receptor antagonist

Glycine antagonist

**Table 3.**

**93**

#### **Table 2.**

*Contraindications for thrombolytic therapy.*

Low-molecular-weight heparins do not have advantages, because a decrease in the frequency of early recurrent strokes is balanced by an increase in the frequency of hemorrhagic transformations. There is no reason to recommend heparin in the acute stage of ischemic stroke, even in patients with atrial fibrillation.

#### **2.4 Hypothermia and neuroprotection**

Experimental studies have shown that potential neuroprotectors are effective, but this is not confirmed in the human population. Many neuroprotective agents have been developed based on a cascade of biochemical events leading to cell death.

## *The Treatment of Acute Stroke DOI: http://dx.doi.org/10.5772/intechopen.92763*

We report below the current clinical status of drugs that have been developed as neuroprotective agents (**Table 3**) [14].

Hypothermia is a potential opportunity to provide neuroprotection, but due to side effects and the need for intensive therapy, it can only be used in severe cases, especially in patients with malignant heart attacks, and currently requires randomized trials [8, 15].

## **2.5 Decompressive neurosurgery**

Decompressive neurosurgery (hemispherectomy) reduces mortality and disability in patients younger than 60 years old who recently suffered a massive stroke


*VENUS, very early nimodipine use in stroke; NMDA, N-methyl-D-aspartic acid; GABA gamma-aminobutyric acid; AMPA, amino-hydroxy-methyl-isoxalone propionic acid; KA, kainate; NBQX, 2,3dihydroxy-6-nitro-7-sulfamoylbenzo [f]quinoxaline-2,3-dione; RCT, randomized controlled trial; bFGF basic fibroblast growth factor; ALIAS, albumin in acute stroke; FAST-MAG, Field Administration of Stroke Therapy—Magnesium; ACEA-1021, 5-nitro-6,7-dichloro-1,4dihydro-2,3-quinoxalinedione.*

#### **Table 3.**

*Neuroprotective drugs developed so far and results of clinical trials.*

Low-molecular-weight heparins do not have advantages, because a decrease in the frequency of early recurrent strokes is balanced by an increase in the frequency of hemorrhagic transformations. There is no reason to recommend heparin in the

27.With previous administration of new oral anticoagulants (dabigatran, rivaroxaban, apixaban), indicators of aPTT, INR, quantity of platelets, thrombin time, or Xa factor activity should be within normal values. In the absence of the ability to determine the laboratory data, the last intake of a drug from the oral anticoagulant group should be

28. Other diseases or conditions with increased risk of bleeding or other complications of TLT (the decision is made

Experimental studies have shown that potential neuroprotectors are effective, but this is not confirmed in the human population. Many neuroprotective agents have been developed based on a cascade of biochemical events leading to cell death.

acute stage of ischemic stroke, even in patients with atrial fibrillation.

**2.4 Hypothermia and neuroprotection**

No. of wording **Cerebral**

*Ischemic Stroke*

Todd's paresis)

**Cerebral and somatic**

12. Hemorrhagic diathesis

17. Acute pancreatitis

20. Recent myocardial infarction

25. Thrombocytopenia less than 100,000/mm<sup>3</sup> 26. Glycemia less than 2.8 and more than 22.5 mmol/l

by the council of physicians)

*Contraindications for thrombolytic therapy.*

10 days

21. Pregnancy

**Laboratory**

**Table 2.**

**92**

**Somatic**

1. Neuroimaging (CT, MRI) signs of intracranial hemorrhages, brain tumors 2. Hemorrhagic stroke or stroke of an unspecified nature in the anamnes

6. Previous stroke or severe traumatic brain injury within 3 months

8. Surgical intervention on the brain or spinal cord in the anamnesis

9. Arterial aneurysms, defects in the development of arteries or veins

absence of data for occlusion of the main vessels

7. Suspected subarachnoid hemorrhage (SAH)

11. Hypersensitivity to any component of the drug

the stomach and duodenum during the last 3 months 16. Liver failure (cirrhosis, active hepatitis, portal hypertension)

18. Present bleeding or extensive bleeding in the recent 6 months

22. Data on bleeding or acute injury (fracture) at the time of examination

23. Taking indirect anticoagulants (warfarin) if international normalized ratio (INR) >1.3 24. Use of heparin for 48 hours with increased activated partial thromboplastin time (aPTT)

>2 days before the development of stroke (with normal kidney function)

10. Tumors with a high risk of bleeding

14. Bacterial endocarditis, pericarditis

3. Rapid improvement or mild symptoms by the time of the beginning of TLT (non-invalidizing symptoms) in the

neuroimaging (based on CT of the brain and/or MRI of the brain in the diffusion-weighted imaging (DWI) mode,

5. Convulsions at the beginning of a stroke (if there is reason to assume that focal symptoms are represented by

4. Signs of a severe stroke: clinical [score on the National Institutes of Health Stroke Scale (NIHSS) > 25),

13. Arterial hypertension over 185/110 mm Hg or necessity in intensive reduction of less than these figures

15. Gastrointestinal or urogenital bleeding during the last 3 weeks. Confirmed exacerbations of peptic ulcer disease of

19. Extensive surgery, trauma, delivery, puncture of large vessels, cardiopulmonary resuscitation within the last

the focus of ischemia extends to the territory of a larger basin medium cerebral artery (MCA)]

### *Ischemic Stroke*

in the middle cerebral artery basin [16]. In order to be effective, the operation must be performed before the development of a malignant brain attack. The best selection criterion is the volume of damage on a diffusion-weighted MRI within 24 hours; a volume greater than 145 cm3 is a good predictor of malignant infarction. Therefore, the best candidates for surgical treatment are patients younger than 60 years with a lesion volume of more than 145 cm3 on diffusion-weighted MRI (6.50). The effectiveness of hemispherectomy is great—every second death is prevented. Results of the Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II (DESTINY II) study also showed effectiveness in patients over 60 years of age [3].

the possible benefit of prescribing drugs. In clinical practice, low doses of fractionated or low-molecular-weight heparin can be prescribed after 24 hours [16]. According to the results of the CLOTS 3 study [12], intermittent pneumatic com-

ICP negatively affects the functional outcome. The superiority of invasive ICP monitoring over clinical observation and neuroimaging has not been proven. Ways to reduce ICP by medication help to buy time to prepare for surgical decompres-

recommended to avoid corticosteroids. These recommendations are based on low confidence data. For the medical treatment of ICH, glycerol, mannitol, HAES, and short-term hyperventilation (confidence class 4) are used. For example, mannitol (20%) at a dose of 0.75–1.0 g/kg can be administered as an intravenous bolus followed by 0.25–0.5 g/kg every 3–6 hours, depending on the neurological status

sion, if it is planned. In the acute phase of intracranial hemorrhage, it is

**3.3 Intracranial hemorrhage in patients receiving oral anticoagulants**

In the acute stage, every patient with intracranial hemorrhage and an INR greater than 1.4 should receive intravenous vitamin K and drugs that replace the deficiency of clotting factors, despite the reason for taking oral anticoagulants (including patients with artificial valves). The goal is to prevent the growth of hematoma volume. In European protocols, it is recommended to use a concentrated prothrombin complex or SPP together with the intravenous administration of vitamin K [18]. Doses of concentrated prothrombin complex: 10–20 U/kg, if the INR is less than 3.5; or 20–30 units/kg, if the INR exceeds 3.5; together with 10 mg of

Recombinant factor VIIa is not recommended for routine use outside of

new oral anticoagulants. This limits the use of these drugs.

lar system, which can improve the functional outcome [9].

favorable outcome is doubtful due to old age or coma.

There is currently no antidote for patients with intracranial hematoma receiving

There are no specific recommendations for the treatment of hemorrhage on the background of antiplatelet drugs. Studies of the use of thrombosis have not proved

In patients with intracranial hemorrhage with increased ventricles and obstruction of the third and fourth ventricles, according to some data, it is recommended to use a recombinant tissue plasminogen activator inserted directly into the ventricu-

The removal of a blood clot should be considered in cases where there is neurological dysfunction or neuroimaging data about occlusion of cerebrospinal fluid spaces subtentorially. According to European recommendations, ventricular drainage and hematoma removal should be performed when the size of the hematoma is more than 2–3 cm in diameter or in the presence of hydrocephalus, even if the

pression is effective.

*The Treatment of Acute Stroke*

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

and fluid balance.

vitamin K in/B.

clinical trials.

**95**

its effectiveness [6, 13].

**3.4 Thrombolytic therapy**

**3.5 Neurosurgical intervention**

**3.2 Intracranial hypertension**

## **3. Treatment of intracranial hemorrhage**

It is necessary to control blood pressure (BP). Lowering blood pressure in the first hours can prevent or slow down the growth of hematoma, as well as reduce the risk of repeated hemorrhage.

An early decrease in blood pressure can cause cerebral ischemia in low-perfused and hypometabolic regions of the brain adjacent to the hematoma.

European recommendations are based on the evidence of a low level of significance (class 4) [9]:


The INTERACT 2 study recently showed that in patients with intracerebral hematoma, an intensive reduction in blood pressure with targets below 140 mm Hg within an hour slightly improves the outcome and is well tolerated by the patient.

#### **3.1 Prevention of deep vein thrombosis and pulmonary embolism**

In patients with intracerebral hematoma, complications such as deep vein thrombosis and pulmonary embolism are feared. A small study conducted on patients with intracerebral hematoma showed that the use of intermittent pneumatic compression is more effective than the use of compression knitwear alone [17]. The CLOTS study [12] showed that the use of compression knitwear is ineffective, but only 232 patients with intracerebral hematoma were included out of 2518 stroke patients. The expediency of using heparin and low-molecular-weight heparins is justified only in cases where the probability of bleeding risk is less than

#### *The Treatment of Acute Stroke DOI: http://dx.doi.org/10.5772/intechopen.92763*

the possible benefit of prescribing drugs. In clinical practice, low doses of fractionated or low-molecular-weight heparin can be prescribed after 24 hours [16]. According to the results of the CLOTS 3 study [12], intermittent pneumatic compression is effective.

## **3.2 Intracranial hypertension**

in the middle cerebral artery basin [16]. In order to be effective, the operation must be performed before the development of a malignant brain attack. The best selection criterion is the volume of damage on a diffusion-weighted MRI within

24 hours; a volume greater than 145 cm3 is a good predictor of malignant infarction. Therefore, the best candidates for surgical treatment are patients younger than 60 years with a lesion volume of more than 145 cm3 on diffusion-weighted MRI (6.50). The effectiveness of hemispherectomy is great—every second death is prevented. Results of the Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery II (DESTINY II) study also showed

It is necessary to control blood pressure (BP). Lowering blood pressure in the first hours can prevent or slow down the growth of hematoma, as well as reduce the

An early decrease in blood pressure can cause cerebral ischemia in low-perfused

European recommendations are based on the evidence of a low level of signifi-

• In patients with a history of primary arterial hypertension or signs (ECG, changes in the fundus vessels) of chronic hypertension, systolic pressure above 180 mm Hg or diastolic pressure above 105 mm Hg and in patients without a history of hypertension, the target blood pressure is 170/100 or average

• In patients without a history of arterial hypertension (systolic blood pressure above 160 mm Hg and/or diastolic blood pressure above 95 mm Hg), the target

• Avoid lowering blood pressure by more than 20%. These targets should be revised for patients who are being monitored for intracranial pressure (ICP) and are experiencing intracranial hypertension in order to maintain adequate

The INTERACT 2 study recently showed that in patients with intracerebral hematoma, an intensive reduction in blood pressure with targets below 140 mm Hg within an hour slightly improves the outcome and is well tolerated by the patient.

In patients with intracerebral hematoma, complications such as deep vein thrombosis and pulmonary embolism are feared. A small study conducted on patients with intracerebral hematoma showed that the use of intermittent pneumatic compression is more effective than the use of compression knitwear alone [17]. The CLOTS study [12] showed that the use of compression knitwear is ineffective, but only 232 patients with intracerebral hematoma were included out of 2518 stroke patients. The expediency of using heparin and low-molecular-weight heparins is justified only in cases where the probability of bleeding risk is less than

and hypometabolic regions of the brain adjacent to the hematoma.

blood pressure is 150/90 mm Hg or BP mean 110 mm Hg.

cerebral perfusion pressure (greater than 70 mm Hg).

**3.1 Prevention of deep vein thrombosis and pulmonary embolism**

effectiveness in patients over 60 years of age [3].

**3. Treatment of intracranial hemorrhage**

• No specific drug is recommended.

risk of repeated hemorrhage.

cance (class 4) [9]:

*Ischemic Stroke*

125 mm Hg.

**94**

ICP negatively affects the functional outcome. The superiority of invasive ICP monitoring over clinical observation and neuroimaging has not been proven. Ways to reduce ICP by medication help to buy time to prepare for surgical decompression, if it is planned. In the acute phase of intracranial hemorrhage, it is recommended to avoid corticosteroids. These recommendations are based on low confidence data. For the medical treatment of ICH, glycerol, mannitol, HAES, and short-term hyperventilation (confidence class 4) are used. For example, mannitol (20%) at a dose of 0.75–1.0 g/kg can be administered as an intravenous bolus followed by 0.25–0.5 g/kg every 3–6 hours, depending on the neurological status and fluid balance.

#### **3.3 Intracranial hemorrhage in patients receiving oral anticoagulants**

In the acute stage, every patient with intracranial hemorrhage and an INR greater than 1.4 should receive intravenous vitamin K and drugs that replace the deficiency of clotting factors, despite the reason for taking oral anticoagulants (including patients with artificial valves). The goal is to prevent the growth of hematoma volume. In European protocols, it is recommended to use a concentrated prothrombin complex or SPP together with the intravenous administration of vitamin K [18]. Doses of concentrated prothrombin complex: 10–20 U/kg, if the INR is less than 3.5; or 20–30 units/kg, if the INR exceeds 3.5; together with 10 mg of vitamin K in/B.

Recombinant factor VIIa is not recommended for routine use outside of clinical trials.

There is currently no antidote for patients with intracranial hematoma receiving new oral anticoagulants. This limits the use of these drugs.

There are no specific recommendations for the treatment of hemorrhage on the background of antiplatelet drugs. Studies of the use of thrombosis have not proved its effectiveness [6, 13].

#### **3.4 Thrombolytic therapy**

In patients with intracranial hemorrhage with increased ventricles and obstruction of the third and fourth ventricles, according to some data, it is recommended to use a recombinant tissue plasminogen activator inserted directly into the ventricular system, which can improve the functional outcome [9].

#### **3.5 Neurosurgical intervention**

The removal of a blood clot should be considered in cases where there is neurological dysfunction or neuroimaging data about occlusion of cerebrospinal fluid spaces subtentorially. According to European recommendations, ventricular drainage and hematoma removal should be performed when the size of the hematoma is more than 2–3 cm in diameter or in the presence of hydrocephalus, even if the favorable outcome is doubtful due to old age or coma.

Dynamic monitoring and conservative medical treatment are the first stage in the treatment of patients with intracranial hematoma. A special analysis of subgroups from the STICH study and a recent meta-analysis showed that craniotomy should be considered as a treatment option in cases of depression of consciousness (from 12 to 9 points on the Glasgow scale) [19] or in cases of superficial intracranial hemorrhage (less than 1 cm from the surface and does not reach the basal ganglia) [20–22]. With deep-seated hematomas, craniotomy does not bring a positive result. The STICH II study showed that early surgical treatment did not increase mortality and disability within 6 months, but slightly improved survival in patients with spontaneous intracranial hemorrhage in the absence of intraventricular hemorrhage.

*4.1.2 Thrombolytic therapy*

*The Treatment of Acute Stroke*

*4.1.3 Oral anticoagulants*

thrombophilia.

**97**

*4.1.4 Anticonvulsant therapy*

**4.2 Cardiac surgery and strokes**

favorable effect in comatose patients [24].

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

There is no data from randomized controlled trials on the efficacy and safety of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. A recently published systematic review of thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis suggests a

According to European protocols [18], there is insufficient data to recommend the use of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. Thrombolytic therapy may be an option if the

After the acute phase, they switch to oral anticoagulant therapy. The Target INR is 2.0–3.0. In cases of cerebral vein thrombosis and sinus thrombosis during pregnancy, oral anticoagulants are not prescribed due to their possible teratogenic effects and the ability to penetrate the placenta. In these cases, anticoagulant therapy is continued with heparin. There is no available data from controlled studies concerning the optimal duration of anticoagulant therapy in patients with cerebral vein thrombosis and sinus thrombosis. MRI data from 33 patients showed that recanalization occurs within 4 months after cerebral vein thrombosis and sinus

According to European protocols [18], anticoagulants can be prescribed for 3 months if cerebral vein thrombosis occurred due to transient factors and for 6–12 months in patients with idiopathic thrombosis and congenital "moderate"

The preventive use of anticonvulsants is controversial. Some studies have shown that sensory and motor deficits, parenchymal lesions on MRI/CT, and cortical vein thrombosis can be independent predictors of early symptomatic epileptic seizures [26]. According to European recommendations [18], prophylactic administration of anticonvulsants is possible for patients with local neurological deficits and foci of parenchymal lesions. Treatment can be continued for a year. Despite the fact that 50% of patients with venous thrombosis experience brain edema, mild edema can be relieved by isolated administration of heparin to restore venous outflow. Steroids are not recommended for the treatment of intracranial hypertension due to their unproven effectiveness. In severe cases, with the threat of transtentorial dislocation, surgical decompression is considered the only lifesaving method of treatment.

The incidence of strokes in the postoperative period in patients with coronary artery bypass grafting (CABG) is about 2%, and a higher incidence of strokes is observed in patients after valve replacement operations and other cardiac surgeries [3]. The causes of stroke after cardiac surgery include perioperative embolism from the aortic arch or heart chambers, systemic hypoperfusion, ischemia associated with occlusion of large vessels, or a combination of these factors [3]. Risk factors for stroke after cardiac surgery are old age; a history of strokes, hypertension, and diabetes mellitus; the presence of noise in the projection of the carotid arteries; the use of bronchodilators and diuretics; high serum creatinine levels; recovery of large

patient's condition worsens despite an adequate anticoagulant therapy.

thrombosis, regardless of further anticoagulation therapy [25].

### **4. Specific clinical situations**

#### **4.1 Treatment of stroke due to sinus thrombosis**

Sinus thrombosis is the cause of approximately 1% of strokes. It occurs due to the occlusion of the venous sinuses and/or cortical veins. This can lead to a venous infarction with petechial hemorrhages or a perivascular venous infarction. Usually, the cause of sinus thrombosis is congenital and acquired prothrombotic disorders, such as pregnancy and infections, including infections of the central nervous system as well as ear, sinuses, mouth, face, or neck. Also the predisposing factors are various diagnostic and therapeutic procedures, such as surgery, lumbar puncture, jugular vein catheterization, and administration of certain medications, especially oral contraceptives, hormone replacement therapy, steroids, and antitumor drugs [23].

The clinical picture may be different, but sinus thrombosis should be excluded in young patients with recent headache and stroke-like symptoms, transient neurological deficits, convulsions, or lobar intracranial hemorrhages. This is especially true for patients with intracranial hypertension and patients with signs of hemorrhagic infarctions, especially if they are numerous and correspond to certain vascular pools.

The gold standard for diagnosing sinus thrombosis is MRI, which provides direct visualization of occluded veins, sinuses, and blood clots [23]. Sometimes CT is used for diagnostics, but if MRI is available, this is not the method of choice for diagnostics. On CT, you can see a hyperintensive shadow of a blood clot in the occluded sinus, the so-called cord symptom.

#### *4.1.1 Heparin therapy*

The available research data on the treatment of venous thrombosis recommend the use of heparin, as it reduces the risk of death and severe disability without the risk of intracranial hematoma. It has been shown that anticoagulant therapy leads to an absolute reduction in the risk of death and disability by 13% and a relative reduction in the risk by 54%, as well as a positive effect of using heparin without increasing the risk of intracranial hemorrhage.

According to European recommendations [18], venous thrombosis should be treated with low-molecular-weight heparins subcutaneously or intravenous heparin; doses are selected by body weight. The presence of intracranial hemorrhage accompanying venous thrombosis is not a contraindication to a heparin therapy [18].

#### *4.1.2 Thrombolytic therapy*

Dynamic monitoring and conservative medical treatment are the first stage in the treatment of patients with intracranial hematoma. A special analysis of subgroups from the STICH study and a recent meta-analysis showed that craniotomy should be considered as a treatment option in cases of depression of consciousness (from 12 to 9 points on the Glasgow scale) [19] or in cases of superficial intracranial hemorrhage (less than 1 cm from the surface and does not reach the basal ganglia) [20–22]. With deep-seated hematomas, craniotomy does not bring a positive result. The STICH II study showed that early surgical treatment did not increase mortality and disability within 6 months, but slightly improved survival in patients with spontaneous intracranial hemorrhage in the absence of intraventricular

Sinus thrombosis is the cause of approximately 1% of strokes. It occurs due to the occlusion of the venous sinuses and/or cortical veins. This can lead to a venous infarction with petechial hemorrhages or a perivascular venous infarction. Usually, the cause of sinus thrombosis is congenital and acquired prothrombotic disorders, such as pregnancy and infections, including infections of the central nervous system as well as ear, sinuses, mouth, face, or neck. Also the predisposing factors are various diagnostic and therapeutic procedures, such as surgery, lumbar puncture,

The clinical picture may be different, but sinus thrombosis should be excluded in young patients with recent headache and stroke-like symptoms, transient neurological deficits, convulsions, or lobar intracranial hemorrhages. This is especially true for patients with intracranial hypertension and patients with signs of hemorrhagic infarctions, especially if they are numerous and correspond to certain

The gold standard for diagnosing sinus thrombosis is MRI, which provides direct visualization of occluded veins, sinuses, and blood clots [23]. Sometimes CT is used for diagnostics, but if MRI is available, this is not the method of choice for diagnostics. On CT, you can see a hyperintensive shadow of a blood clot in the occluded

The available research data on the treatment of venous thrombosis recommend the use of heparin, as it reduces the risk of death and severe disability without the risk of intracranial hematoma. It has been shown that anticoagulant therapy leads to an absolute reduction in the risk of death and disability by 13% and a relative reduction in the risk by 54%, as well as a positive effect of using heparin without

According to European recommendations [18], venous thrombosis should be

treated with low-molecular-weight heparins subcutaneously or intravenous heparin; doses are selected by body weight. The presence of intracranial hemorrhage accompanying venous thrombosis is not a contraindication to a heparin

jugular vein catheterization, and administration of certain medications, especially oral contraceptives, hormone replacement therapy, steroids, and

hemorrhage.

*Ischemic Stroke*

**4. Specific clinical situations**

antitumor drugs [23].

sinus, the so-called cord symptom.

increasing the risk of intracranial hemorrhage.

vascular pools.

*4.1.1 Heparin therapy*

therapy [18].

**96**

**4.1 Treatment of stroke due to sinus thrombosis**

There is no data from randomized controlled trials on the efficacy and safety of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. A recently published systematic review of thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis suggests a favorable effect in comatose patients [24].

According to European protocols [18], there is insufficient data to recommend the use of systemic or local thrombolytic therapy in patients with cerebral vein thrombosis and sinus thrombosis. Thrombolytic therapy may be an option if the patient's condition worsens despite an adequate anticoagulant therapy.

### *4.1.3 Oral anticoagulants*

After the acute phase, they switch to oral anticoagulant therapy. The Target INR is 2.0–3.0. In cases of cerebral vein thrombosis and sinus thrombosis during pregnancy, oral anticoagulants are not prescribed due to their possible teratogenic effects and the ability to penetrate the placenta. In these cases, anticoagulant therapy is continued with heparin. There is no available data from controlled studies concerning the optimal duration of anticoagulant therapy in patients with cerebral vein thrombosis and sinus thrombosis. MRI data from 33 patients showed that recanalization occurs within 4 months after cerebral vein thrombosis and sinus thrombosis, regardless of further anticoagulation therapy [25].

According to European protocols [18], anticoagulants can be prescribed for 3 months if cerebral vein thrombosis occurred due to transient factors and for 6–12 months in patients with idiopathic thrombosis and congenital "moderate" thrombophilia.

#### *4.1.4 Anticonvulsant therapy*

The preventive use of anticonvulsants is controversial. Some studies have shown that sensory and motor deficits, parenchymal lesions on MRI/CT, and cortical vein thrombosis can be independent predictors of early symptomatic epileptic seizures [26]. According to European recommendations [18], prophylactic administration of anticonvulsants is possible for patients with local neurological deficits and foci of parenchymal lesions. Treatment can be continued for a year. Despite the fact that 50% of patients with venous thrombosis experience brain edema, mild edema can be relieved by isolated administration of heparin to restore venous outflow. Steroids are not recommended for the treatment of intracranial hypertension due to their unproven effectiveness. In severe cases, with the threat of transtentorial dislocation, surgical decompression is considered the only lifesaving method of treatment.

#### **4.2 Cardiac surgery and strokes**

The incidence of strokes in the postoperative period in patients with coronary artery bypass grafting (CABG) is about 2%, and a higher incidence of strokes is observed in patients after valve replacement operations and other cardiac surgeries [3]. The causes of stroke after cardiac surgery include perioperative embolism from the aortic arch or heart chambers, systemic hypoperfusion, ischemia associated with occlusion of large vessels, or a combination of these factors [3]. Risk factors for stroke after cardiac surgery are old age; a history of strokes, hypertension, and diabetes mellitus; the presence of noise in the projection of the carotid arteries; the use of bronchodilators and diuretics; high serum creatinine levels; recovery of large vessels; the use of inotropes after artificial circulation; and the duration of artificial blood circulation.

*4.5.1 Treatment*

*The Treatment of Acute Stroke*

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

**5. Conclusion**

specific therapy.

in Russia.

**99**

**Abbreviations**

**Conflict of interest**

In the acute phase of stroke, heparin is not recommended; its use leads to a slight decrease in repeated strokes, an indefinite decrease in mortality, and a disability

The connection between the brain and the heart reflects a complex multidirectional complex regulation of systemic hemodynamics and organ autoregulation of local perfusion, which is especially pronounced in a cerebral catastrophe. Arrhythmias, in particular AF, often accompany the development of stroke, while myocardial infarction, Takotsubo syndrome, and sudden death are rare, although they are also described in strokes [27–29]. Sometimes stroke patients are found to have high

To ensure adequate treatment, a rapid diagnosis of stroke and its nature and cause is necessary. Specialized stroke departments allow for effective treatment and

We would like to thank our teachers—neurologists, anesthesiologists, and neurosurgeons—of Russian Polenov's Neurosurgical Institute, the first institute of neurological surgery in the world founded in 1926 in St. Petersburg (Petrograd)

with an increase in the frequency of intracranial hemorrhages [7].

levels of troponin, indicating myocardial damage.

The authors declare no conflict of interest.

**Notes/thanks/other declarations**

ACS acute coronary syndrome

AVM arteriovenous malformation

DWI diffusion-weighted imaging

CABG coronary artery bypass grafting

ESR erythrocyte sedimentation rate LMWH low-molecular-weight heparins

CT computed tomography

aPTT activated partial thromboplastin time

AF atrial fibrillation ADH antidiuretic hormone

BP blood pressure

DI diabetes insipidus

ECG electrocardiogram EchoCG echocardiography

**4.6 Cerebrocardial syndrome (neurogenic stress cardiomyopathy)**

Currently, there are no special recommendations for the treatment of patients with stroke after CABG [3]. Moreover, patients with stroke after CABG are treated as patients with acute stroke with loading doses of aspirin (160–320 mg) [3].

## **4.3 Operations on the carotid arteries and strokes**

Carotid endarterectomy is the standard method for treating carotid artery stenosis [3]. It is recommended for 70–99% of patients with symptomatic stenosis. It is confirmed that surgical treatment of asymptomatic stenosis reduces the risk of ipsilateral stroke; however, the absolute advantage of this method has not been proven. Currently, stenting is not recommended for revascularization of the carotid arteries.

The pathophysiological mechanism of stroke in carotid revascularization may be associated with hemodynamic cerebral ischemia or arterio-arterial embolism. The latter mechanism may be more frequent during stenting due to endovascular access.

## **4.4 Acute coronary syndrome (ACS) and stroke**

Intracranial hemorrhage can be a severe side effect of thrombolytic therapy in ACS. The risk of intracranial hemorrhage depends on the previous episodes in the history, age, and mode of thrombolytic therapy. Usually, the risk of intracranial hemorrhage during thrombolytic therapy of acute myocardial infarction is 0.5–1%.

There are no special recommendations for the treatment of ischemic stroke in ACS in European protocols. In the presence of ACS, the protocols of the European Stroke Organization recommend lowering blood pressure [4, 6]. An anticoagulant therapy is not recommended, while a combination of clopidogrel and aspirin is recommended in terms of cardiac causes [4, 7].

## **4.5 Stroke in patients with atrial fibrillation**

Cardio-cerebral embolism is considered to be the cause of at least 20% of ischemic strokes, and non-valvular AF is the most common cause, associated with a fivefold increase in the risk of stroke, and accounts for 25% of all strokes in patients older than 80 years [3]. Long-term thromboprophylaxis is necessary to prevent strokes in patients with AF. Recently, for patients who cannot be treated with warfarin and clopidogrel, it has been shown that clopidogrel and aspirin therapy reduces the risk of vascular accidents [7]. Oral direct thrombin inhibitors such as dabigatran have been shown to be effective in preventing stroke and systemic embolism with a risk of intracranial hemorrhage comparable to that of warfarin. Stroke in patients with AF can be divided into three groups:


The incidence of intracranial hemorrhage increases 7–10 times compared to patients who do not receive oral anticoagulants and is 1.8% per year in patients at risk of stroke [7].

## *The Treatment of Acute Stroke DOI: http://dx.doi.org/10.5772/intechopen.92763*

## *4.5.1 Treatment*

vessels; the use of inotropes after artificial circulation; and the duration of artificial

Currently, there are no special recommendations for the treatment of patients with stroke after CABG [3]. Moreover, patients with stroke after CABG are treated as patients with acute stroke with loading doses of aspirin (160–320 mg) [3].

Carotid endarterectomy is the standard method for treating carotid artery stenosis [3]. It is recommended for 70–99% of patients with symptomatic stenosis. It is confirmed that surgical treatment of asymptomatic stenosis reduces the risk of ipsilateral stroke; however, the absolute advantage of this method has not been proven. Currently, stenting is not recommended for revascularization of the carotid

The pathophysiological mechanism of stroke in carotid revascularization may be associated with hemodynamic cerebral ischemia or arterio-arterial embolism. The latter mechanism may be more frequent during stenting due to endovascular access.

Intracranial hemorrhage can be a severe side effect of thrombolytic therapy in ACS. The risk of intracranial hemorrhage depends on the previous episodes in the history, age, and mode of thrombolytic therapy. Usually, the risk of intracranial hemorrhage during thrombolytic therapy of acute myocardial infarction is 0.5–1%. There are no special recommendations for the treatment of ischemic stroke in ACS in European protocols. In the presence of ACS, the protocols of the European Stroke Organization recommend lowering blood pressure [4, 6]. An anticoagulant therapy is not recommended, while a combination of clopidogrel and aspirin is

Cardio-cerebral embolism is considered to be the cause of at least 20% of ische-

mic strokes, and non-valvular AF is the most common cause, associated with a fivefold increase in the risk of stroke, and accounts for 25% of all strokes in patients older than 80 years [3]. Long-term thromboprophylaxis is necessary to prevent strokes in patients with AF. Recently, for patients who cannot be treated with warfarin and clopidogrel, it has been shown that clopidogrel and aspirin therapy reduces the risk of vascular accidents [7]. Oral direct thrombin inhibitors such as dabigatran have been shown to be effective in preventing stroke and systemic embolism with a risk of intracranial hemorrhage comparable to that of warfarin.

1. Ischemic stroke in patients with insufficient therapy, i.e., not receiving anticoagulants, despite scores on the CHADS2 scale greater than 2 [3]

3. Intracranial hemorrhage that occurred in a patient receiving anticoagulants

The incidence of intracranial hemorrhage increases 7–10 times compared to patients who do not receive oral anticoagulants and is 1.8% per year in patients at

**4.3 Operations on the carotid arteries and strokes**

**4.4 Acute coronary syndrome (ACS) and stroke**

recommended in terms of cardiac causes [4, 7].

**4.5 Stroke in patients with atrial fibrillation**

Stroke in patients with AF can be divided into three groups:

2. Ischemic stroke that developed despite warfarin therapy

blood circulation.

*Ischemic Stroke*

arteries.

risk of stroke [7].

**98**

In the acute phase of stroke, heparin is not recommended; its use leads to a slight decrease in repeated strokes, an indefinite decrease in mortality, and a disability with an increase in the frequency of intracranial hemorrhages [7].

## **4.6 Cerebrocardial syndrome (neurogenic stress cardiomyopathy)**

The connection between the brain and the heart reflects a complex multidirectional complex regulation of systemic hemodynamics and organ autoregulation of local perfusion, which is especially pronounced in a cerebral catastrophe. Arrhythmias, in particular AF, often accompany the development of stroke, while myocardial infarction, Takotsubo syndrome, and sudden death are rare, although they are also described in strokes [27–29]. Sometimes stroke patients are found to have high levels of troponin, indicating myocardial damage.

## **5. Conclusion**

To ensure adequate treatment, a rapid diagnosis of stroke and its nature and cause is necessary. Specialized stroke departments allow for effective treatment and specific therapy.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Notes/thanks/other declarations**

We would like to thank our teachers—neurologists, anesthesiologists, and neurosurgeons—of Russian Polenov's Neurosurgical Institute, the first institute of neurological surgery in the world founded in 1926 in St. Petersburg (Petrograd) in Russia.

## **Abbreviations**



**References**

*The Treatment of Acute Stroke*

jnnp.2008.149401

1999;**354**:1457-1463

[1] Cordonnier C, Leys D. Stroke: The bare essentials. Practical Neurology. 2008;**8**:263-272. DOI: 10.1136/

*DOI: http://dx.doi.org/10.5772/intechopen.92763*

[9] Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage—Part I:

haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovascular

[10] Bussell SA, González-Fernández M. Racial disparities in the development of dysphagia after stroke: Further evidence from the medicare database. Archives of Physical Medicine and Rehabilitation.

Spontaneous intracerebral

Diseases. 2006;**22**:294-316

2011;**92**(5):737-742

**69**(8):637-640

[11] Splaingard ML, Hutchins B, Sulton LD, et al. Aspiration in rehabilitation patients:

Videofluoroscopy vs bedside clinical assessment. Archives of Physical Medicine and Rehabilitation. 1988;

[12] Dennis M, Sandercock P, Graham C, Forbes J. The Clots in Legs or sTockings

determine whether or not intermittent pneumatic compression reduces the risk of post-stroke deep vein thrombosis and to estimate its cost-effectiveness. Health Technology Assessment. 2015;**19**(76). DOI: doi.org/10.3310/hta19760

[13] Hacke W, Brott T, Caplan L, et al. Thrombolysis in acute ischemic stroke: Controlled trials and clinical experience.

[14] Murozono M. Neuroprotective drugs. In: Uchino H, Ushijima K, Ikeda Y, editors. Neuroanesthesia and Cerebrospinal Protection. Japan: Springer; 2015. pp. 119-126. DOI: 10.1007/978-4-431-54490-6

[15] Bart van der Worp H, Macleod MR, Kollmar R. Therapeutic hypothermia for acute ischemic stroke: Ready to start

Neurology. 1999;**53**:S3-S14

after Stroke (CLOTS) 3 trial: A randomised controlled trial to

[2] Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: Evidence, costs, and effects on individuals and populations. Lancet.

[3] Leys D, Cordonnier C, Caso V. Stroke. In: Tubaro M, Vranckx P, Price S, Vrints C, editors. The ESC Textbook of Intensive and Acute Cardiovascular Care. 2nd ed. Oxford, UK: Oxford University Press; 2015.

pp. 645-656. DOI: 10.1093/ med/9780199687039.001.0001

[4] Georgiadis D, Schwab S.

[5] Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;**24**:35-41. DOI: 10.1161/01.

**7**:119-127

STR.24.1.35

000131083

**101**

2008;**359**:1317-1329

Hypothermia in acute stroke. Current Treatment Options in Neurology. 2005;

[6] Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England Journal of Medicine.

[7] Warlow C, van Gijn J, Dennis M, et al. Stroke: Practical Management. 3rd ed. Oxford: Blackwell Science; 2008

[8] European Stroke Organisation Working Group. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovascular Diseases. 2008;**25**:457-507. DOI: 10.1159/

## **Author details**

Irina Alexandrovna Savvina1,2 and Anna Olegovna Petrova<sup>1</sup> \*

1 Almazov National Medical Research Centre of Ministry of Health of Russian Federation, Saint Petersburg, Russia

2 Mechnikov State North-West Medical University, Saint Petersburg, Russia

\*Address all correspondence to: petrovaanna2803@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

ICH intracranial hemorrhage ICP intracranial pressure

*Ischemic Stroke*

INR international normalized ratio MCA medium cerebral artery MRI magnetic resonance imaging

SAH subarachnoid hemorrhage

**Author details**

**100**

Federation, Saint Petersburg, Russia

provided the original work is properly cited.

tPA tissue plasminogen activator TLT thrombolytic therapy

NIHSS National Institutes of Health Stroke Scale

Irina Alexandrovna Savvina1,2 and Anna Olegovna Petrova<sup>1</sup>

\*Address all correspondence to: petrovaanna2803@gmail.com

1 Almazov National Medical Research Centre of Ministry of Health of Russian

2 Mechnikov State North-West Medical University, Saint Petersburg, Russia

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*

SIADH syndrome of inappropriate antidiuretic hormone secretion

[1] Cordonnier C, Leys D. Stroke: The bare essentials. Practical Neurology. 2008;**8**:263-272. DOI: 10.1136/ jnnp.2008.149401

[2] Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: Evidence, costs, and effects on individuals and populations. Lancet. 1999;**354**:1457-1463

[3] Leys D, Cordonnier C, Caso V. Stroke. In: Tubaro M, Vranckx P, Price S, Vrints C, editors. The ESC Textbook of Intensive and Acute Cardiovascular Care. 2nd ed. Oxford, UK: Oxford University Press; 2015. pp. 645-656. DOI: 10.1093/ med/9780199687039.001.0001

[4] Georgiadis D, Schwab S. Hypothermia in acute stroke. Current Treatment Options in Neurology. 2005; **7**:119-127

[5] Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;**24**:35-41. DOI: 10.1161/01. STR.24.1.35

[6] Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England Journal of Medicine. 2008;**359**:1317-1329

[7] Warlow C, van Gijn J, Dennis M, et al. Stroke: Practical Management. 3rd ed. Oxford: Blackwell Science; 2008

[8] European Stroke Organisation Working Group. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovascular Diseases. 2008;**25**:457-507. DOI: 10.1159/ 000131083

[9] Steiner T, Kaste M, Forsting M, et al. Recommendations for the management of intracranial haemorrhage—Part I: Spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovascular Diseases. 2006;**22**:294-316

[10] Bussell SA, González-Fernández M. Racial disparities in the development of dysphagia after stroke: Further evidence from the medicare database. Archives of Physical Medicine and Rehabilitation. 2011;**92**(5):737-742

[11] Splaingard ML, Hutchins B, Sulton LD, et al. Aspiration in rehabilitation patients: Videofluoroscopy vs bedside clinical assessment. Archives of Physical Medicine and Rehabilitation. 1988; **69**(8):637-640

[12] Dennis M, Sandercock P, Graham C, Forbes J. The Clots in Legs or sTockings after Stroke (CLOTS) 3 trial: A randomised controlled trial to determine whether or not intermittent pneumatic compression reduces the risk of post-stroke deep vein thrombosis and to estimate its cost-effectiveness. Health Technology Assessment. 2015;**19**(76). DOI: doi.org/10.3310/hta19760

[13] Hacke W, Brott T, Caplan L, et al. Thrombolysis in acute ischemic stroke: Controlled trials and clinical experience. Neurology. 1999;**53**:S3-S14

[14] Murozono M. Neuroprotective drugs. In: Uchino H, Ushijima K, Ikeda Y, editors. Neuroanesthesia and Cerebrospinal Protection. Japan: Springer; 2015. pp. 119-126. DOI: 10.1007/978-4-431-54490-6

[15] Bart van der Worp H, Macleod MR, Kollmar R. Therapeutic hypothermia for acute ischemic stroke: Ready to start

large randomized trials? Journal of Cerebral Blood Flow and Metabolism. 2010;**30**(6):1079-1093. DOI: 10.1038/ jcbfm.2010.44 Jrащищен

[16] Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: A pooled analysis of three randomised controlled trials. Lancet Neurology. 2007;**6**:215-222

[17] Sachdeva A, Dalton M, Amaragiri SV, Lees T. Graduated compression stockings for prevention of deep vein thrombosis. Cochrane Database of Systematic Reviews. Dec 2014;(12):CD001484. DOI: 10.1002/14651858.CD001484.pub3

[18] Duranteau J, Taccone FS, Verhamme P, et al. For the ESA VTE Guidelines Task Force. European guidelines on perioperative venous thromboembolism prophylaxis. Intensive care. European Journal of Anaesthesiology. 2018;**35**:142-146. DOI: 10.1097/EJA.0000000000000702

[19] Kim JE, Ko S-B, Kang H-S, et al. Clinical practice guidelines for the medical and surgical management of primary intracerebral hemorrhage in Korea. Journal of Korean Neurosurgical Association. 2014;**56**(3):175-187. DOI: 10.3340/jkns.2014.56.3.175

[20] Rost NS et al. Prediction of functional outcome in patients with primary intracerebral hemorrhage: The FUNC score. Stroke. 2008;**39**(8): 2304-2309

[21] Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH Score: A simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;**32**:891-897

[22] Clarke JL, Johnston SC, Farrant M, Bernstein R, Tong D, Hemphill JC. External validation of the ICH score. Neurocritical Care. 2004;**1**(1):53-60

[23] Tadi P, Babak Behgam B, Baruffi S. Cerebral Venous Thrombosis [Internet]. StatPearls Publishing. 2020. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK459315/ [Accessed: 16 March 2020]

[24] Viegas L, Viegas LD, Stolz E, Canhão P, Ferro JM. Systemic thrombolysis for cerebral venous and dural sinus thrombosis: A systematic review. Cerebrovascular Diseases. 2014; **37**:43-50. DOI: doi.org/10.1159/ 000356840

[25] Caso V, Agnelli G, Paciaroni M, editors. Handbook on Cerebral Venous Thrombosis. Frontiers of Neurology and Neuroscience. Vol. 23. Basel, Karger. 2008. pp. I-VI. DOI: 10.1159/ isbn.978-3-8055-8379-4

[26] Habibabadi JM, Mohammad Saadatni M, Tabrizi N. Seizure in cerebral venous and sinus thrombosis. Epilepsia Open. 2018;**3**(3):316-322. DOI: 10.1002/epi4.12229

[27] Weiner MM, Asher DI, Augoustides JG, et al. Takotsubo cardiomyopathy: A clinical update for the cardiovascular anesthesiologist. Journal of Cardiothoracic and Vascular Anesthesia. 2017;**31**(1):334-344. DOI: 10.1053/j.jvca.2016.06.004

[28] Belkin AA, Gromov VS, Levit AL, et al. Cerebrocardial syndrome. Differential diagnostic, treatment tactics. Anesthesiologia and Reanimatologia. 2012;**4**:81-85. (In Russ.) ISSN: 2410-4698 (Online), 0201-7563 (Print), ISSN-L 0201-7563

[29] Kato K, Lyon AR, Ghadri J-R, et al. Takotsubo syndrome: Aetiology, presentation and treatment. Heart. 2017;**103**:1461-1469. DOI: 10.1136/ heartjnl-2016-309783

**103**

**Chapter 6**

**Abstract**

and anti-oxidant effects.

alcohol, acetone and sulfoxide, **Figure 1** [1].

renal stone, hair loss and peptic ulceration [2].

the management of ischemic stroke.

stroke, post-stroke

**1. Introduction**

Vinpocetine and Ischemic Stroke

Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from *Vinca minor* leaves. VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) has potential neurological effects through inhibition of voltage gated sodium channel and reduction of neuronal calcium influx. VPN have noteworthy antioxidant, anti-inflammatory and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following ischemic stroke (IS). VPN is effective as an adjuvant therapy in the management of epilepsy; it reduces seizure frequency by 50% in a dose of 2 mg/kg/day. VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms. VPN recover cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE-1with augmentation of cAMP/cGMP ratio, enhancement of cholinergic neurotransmission and inhibition of neuronal inflammatory mediators. Therefore, VPN is an effective agent in the management of ischemic stroke and plays an integral role in the prevention and attenuation of post-stroke epilepsy, depression and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly through anti-inflammatory

**Keywords:** vinpocetine, phosphodiesterase type 1, antioxidant, anti-inflammatory,

Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from *Vinca minor* leaves which is known as lesser periwinkle. A VPN has a specific chemical structure contains carboxylic acid ethyl ester which is soluble in

VPN is widely used in the treatment of different cerebro-vascular disorders, cognitive dysfunction, memory disorders, tinnitus, macular degeneration and glaucoma. In addition, VPN is effective in the management of acute kidney injury,

Nevertheless, this critical review only focused on the potential role of VPN in

A multiplicity of search strategies was taken and assumed which included electronic database searches of Medline and Pubmed using MeSH terms, keywords and title words during the search. The terms used for these searches were as follows: [Vinpocetine OR apovincamine] AND [cognitive function OR stroke OR brain ischemia OR blood flow OR cerebral circulation OR oxidative stress OR blood

*Hayder M. Al-kuraishy and Ali I. Al-Gareeb*

## **Chapter 6**

large randomized trials? Journal of Cerebral Blood Flow and Metabolism. 2010;**30**(6):1079-1093. DOI: 10.1038/

[23] Tadi P, Babak Behgam B, Baruffi S. Cerebral Venous Thrombosis [Internet]. StatPearls Publishing. 2020. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK459315/ [Accessed: 16 March

[24] Viegas L, Viegas LD, Stolz E, Canhão P, Ferro JM. Systemic

**37**:43-50. DOI: doi.org/10.1159/

Neuroscience. Vol. 23. Basel,

isbn.978-3-8055-8379-4

10.1002/epi4.12229

[27] Weiner MM, Asher DI, Augoustides JG, et al. Takotsubo cardiomyopathy: A clinical update for the cardiovascular anesthesiologist. Journal of Cardiothoracic and Vascular Anesthesia. 2017;**31**(1):334-344. DOI:

10.1053/j.jvca.2016.06.004

(Print), ISSN-L 0201-7563

heartjnl-2016-309783

[28] Belkin AA, Gromov VS, Levit AL, et al. Cerebrocardial syndrome. Differential diagnostic, treatment tactics. Anesthesiologia and

Reanimatologia. 2012;**4**:81-85. (In Russ.) ISSN: 2410-4698 (Online), 0201-7563

[29] Kato K, Lyon AR, Ghadri J-R, et al. Takotsubo syndrome: Aetiology, presentation and treatment. Heart. 2017;**103**:1461-1469. DOI: 10.1136/

[25] Caso V, Agnelli G, Paciaroni M, editors. Handbook on Cerebral Venous Thrombosis. Frontiers of Neurology and

Karger. 2008. pp. I-VI. DOI: 10.1159/

[26] Habibabadi JM, Mohammad Saadatni M, Tabrizi N. Seizure in cerebral venous and sinus thrombosis. Epilepsia Open. 2018;**3**(3):316-322. DOI:

thrombolysis for cerebral venous and dural sinus thrombosis: A systematic review. Cerebrovascular Diseases. 2014;

2020]

000356840

[16] Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: A pooled analysis of three randomised controlled trials. Lancet Neurology. 2007;**6**:215-222

jcbfm.2010.44 Jrащищен

*Ischemic Stroke*

[17] Sachdeva A, Dalton M, Amaragiri SV, Lees T. Graduated compression stockings for prevention of deep vein thrombosis. Cochrane Database of Systematic Reviews. Dec 2014;(12):CD001484. DOI: 10.1002/14651858.CD001484.pub3

[18] Duranteau J, Taccone FS,

Verhamme P, et al. For the ESA VTE Guidelines Task Force. European guidelines on perioperative venous thromboembolism prophylaxis. Intensive care. European Journal of Anaesthesiology. 2018;**35**:142-146. DOI: 10.1097/EJA.0000000000000702

[19] Kim JE, Ko S-B, Kang H-S, et al. Clinical practice guidelines for the medical and surgical management of primary intracerebral hemorrhage in Korea. Journal of Korean Neurosurgical Association. 2014;**56**(3):175-187. DOI:

10.3340/jkns.2014.56.3.175

2304-2309

**102**

[20] Rost NS et al. Prediction of functional outcome in patients with primary intracerebral hemorrhage: The FUNC score. Stroke. 2008;**39**(8):

[21] Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH Score: A simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;**32**:891-897

[22] Clarke JL, Johnston SC, Farrant M, Bernstein R, Tong D, Hemphill JC. External validation of the ICH score. Neurocritical Care. 2004;**1**(1):53-60

## Vinpocetine and Ischemic Stroke

*Hayder M. Al-kuraishy and Ali I. Al-Gareeb*

## **Abstract**

Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from *Vinca minor* leaves. VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) has potential neurological effects through inhibition of voltage gated sodium channel and reduction of neuronal calcium influx. VPN have noteworthy antioxidant, anti-inflammatory and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following ischemic stroke (IS). VPN is effective as an adjuvant therapy in the management of epilepsy; it reduces seizure frequency by 50% in a dose of 2 mg/kg/day. VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms. VPN recover cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE-1with augmentation of cAMP/cGMP ratio, enhancement of cholinergic neurotransmission and inhibition of neuronal inflammatory mediators. Therefore, VPN is an effective agent in the management of ischemic stroke and plays an integral role in the prevention and attenuation of post-stroke epilepsy, depression and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly through anti-inflammatory and anti-oxidant effects.

**Keywords:** vinpocetine, phosphodiesterase type 1, antioxidant, anti-inflammatory, stroke, post-stroke

## **1. Introduction**

Vinpocetine (VPN) is a synthetic ethyl-ester derivative of the alkaloid apovincamine from *Vinca minor* leaves which is known as lesser periwinkle. A VPN has a specific chemical structure contains carboxylic acid ethyl ester which is soluble in alcohol, acetone and sulfoxide, **Figure 1** [1].

VPN is widely used in the treatment of different cerebro-vascular disorders, cognitive dysfunction, memory disorders, tinnitus, macular degeneration and glaucoma. In addition, VPN is effective in the management of acute kidney injury, renal stone, hair loss and peptic ulceration [2].

Nevertheless, this critical review only focused on the potential role of VPN in the management of ischemic stroke.

A multiplicity of search strategies was taken and assumed which included electronic database searches of Medline and Pubmed using MeSH terms, keywords and title words during the search. The terms used for these searches were as follows: [Vinpocetine OR apovincamine] AND [cognitive function OR stroke OR brain ischemia OR blood flow OR cerebral circulation OR oxidative stress OR blood

**Figure 1.** *Chemical structure of Vinpocetine.*

viscosity OR cerebral blood flow]. [Vinpocetine OR apovincamine] AND [cerebral metabolism OR cerebral hypoxia OR ischemic degeneration OR minor stroke]. Reference lists of identified and notorious articles were reviewed. In addition, only English articles were considered and case reports were not concerned in the review. The key features of recognized applicable search studies were considered and the conclusions summarized in a critical review.

## **2. Pharmacology of vinpocetine**

VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) which increasing of cAMP and cGMP leading to vasodilatation. Also, it inhibits the release of pro-inflammatory cytokines through inhibition of IKK/NF-kB activator protein-1 (AP-1) pathway which is involved in the propagation of inflammatory cytokines translocation and release [3]. Moreover, VPN has potential neurological effects through inhibition of voltage gated sodium channel, reduction of neuronal calcium influx and antioxidant effect with augmentation of dopamine metabolism since it increases 3, 4-dihydroxyphenylacetic acid (DOPAC) which is the breakdown metabolites of dopamine [4].

It has been reported that VPN is a safe drug for long-term use and it well tolerated during the management of cerebrovascular disorders. Mild side effects such as headache, flushing, anxiety, dry mouth and nausea have been accounted during VPN uses. In spite of potent non-selective vasodilator effect it does not produce stealing effect on cerebral vasculatures due to the viscosity lowering effect and inhibition of platelet aggregations which together improve cerebral vessels rheological properties. Nevertheless, VPN does not reduce blood pressure and systemic circulation during acute and chronic uses [5].

VPN is well absorbed from small intestine, which increased by food, therefore, fasting bioavailability is 6.7% and non-fasting bioavailability is 60–100%. Similarly, VPN has no significant drug-drug interactions with different drugs such as oxazepam, imipramine, glibenclamide and other agents that are used in the management of ischemic stroke [6].

#### **3. Vinpocetine in ischemic stroke**

Ischemic stroke (IS) represents the main leading cause of death in the American Unite State and developed countries and regarded it as the main cause of long-term disability. IS represents 11.9% of annual total death and accounts for 90% of all

**105**

*Vinpocetine and Ischemic Stroke*

*DOI: http://dx.doi.org/10.5772/intechopen.90551*

stroke cases [7]. Arboix study discussed briefly the risk factor of IS [8]. These risk factors are divided into non-modifiable risk factors (sex, age, inherited factors, ethicinity and low birth weight at birth) and modifiable risk factors (diabetes mellitus, hypertension, smoking, obesity, alcohol abuse, oral contraceptive and metabolic syndrome). [9] IS is mainly caused by arterial thrombosis on the atherosclerotic plaque of cerebral vessels, causing cerebral ischemia, infarction and induction of peri-infarct inflammation. Neuro-inflammations contribute into tissue repair and neuronal damage as well as retrograde and anterograde axonal degenerations [10]. IS leads to glucose and oxygen deprivation of neuronal cells which causing oxidative stress, excitotoxicity and calcium overload which eventually causing neuronal cell death and development of infarction core [11]. The infracted core and damaged neuronal cells due to induced oxidative stress, releasing of various inflammatory molecules that causing vasculitis and damage of blood brain barrier (BBB) [12]. Moreover, activated microglia and infiltrated macrophage during IS release neurotransmitters which are interact with neurons causing neuroinflammation and neuronal injury. As well, interleukin-8(IL-8), NF-kB and tumor necrosis factor (TNF-α) are overexpressed during IS which play a potential role in the initiation of inflammation and apoptosis [13]. In a similar way, vascular smooth muscle and endothelial cells of cerebral vasculature are activated by NF-kB pathway leading to further obstruction and thrombosis. Therefore, NF-kB pathway is an important pathway in the pathogeneses and development of neurological deficit thus; inhibition of NF-kB pathway by VPN is regarded as important and main mechanism of VPN neuroprotection [14].

In addition, activated microglia expresses cholesterol transporter protein (TSPO)

Different studies illustrated that oxidative stress, excitotoxicity and impaired energy metabolism leading to neuronal death by both apoptosis and necrosis during IS. These events lead to reduction of cAMP system which is important in the expression and regulation of brain derived neurotrophic factor (BDNF), which improves neuronal survival. PDE1 is mainly localized in striatum and cortex which

Indeed, VPN increases neuronal cGMP through inhibition of calmodulin dependent phosphodiesterase which improves cerebral blood flow and oxygen consumption [19]. VPN improves cerebral metabolism through enhancing glucose and oxygen supply and ATP production by cerebral vasodilation. These effects prevent IS induced-memory and cognitive dysfunctions due to improvement of neurotransmitters such as serotonin, dopamine and noradrenaline, which are involved in the

In IS overproduction of free radicals and reactive oxygen and/or nitrogen species lead to neuro-pathological changes through complex interactions with cellular components such as proteins, DNA and lipids. Free radicals, mainly superoxide and non-radicals such as hydrogen peroxide may cause further neurological injury through depletion of endogenous antioxidant capacity. Therefore, drug with antioxidant potential may play a role in the prevention of cerebral injury during IS [21].

which is over-expressed during brain injury and IS and inhibited by VPN [15]. During IS voltage gated sodium channels are activated causing intracellular accumulation of Na and Ca leading to neuronal cell damage, excitotoxicity, edema, acidosis and acute cellular dysfunctions. VPN inhibits voltage gated sodium channels leading to dose dependent reduction of intracellular concentrations of Na and Ca. Thus, the neuroprotective effect of VPN during IS is chiefly mediated by

inhibition of neuronal voltage gated sensitive Na-channel [16].

participating in the regulation of neuronal motor activity [17, 18].

**3.1 Antioxidant effects of vinpocetine in ischemic stroke**

regulation of cognitive function [20].

#### *Vinpocetine and Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.90551*

*Ischemic Stroke*

**Figure 1.**

*Chemical structure of Vinpocetine.*

viscosity OR cerebral blood flow]. [Vinpocetine OR apovincamine] AND [cerebral metabolism OR cerebral hypoxia OR ischemic degeneration OR minor stroke]. Reference lists of identified and notorious articles were reviewed. In addition, only English articles were considered and case reports were not concerned in the review. The key features of recognized applicable search studies were considered and the

VPN is a selective inhibitor of phosphodiesterase type 1 (PDE1) which increasing of cAMP and cGMP leading to vasodilatation. Also, it inhibits the release of pro-inflammatory cytokines through inhibition of IKK/NF-kB activator protein-1 (AP-1) pathway which is involved in the propagation of inflammatory cytokines translocation and release [3]. Moreover, VPN has potential neurological effects through inhibition of voltage gated sodium channel, reduction of neuronal calcium influx and antioxidant effect with augmentation of dopamine metabolism since it increases 3, 4-dihydroxyphenylacetic acid (DOPAC) which is the breakdown

It has been reported that VPN is a safe drug for long-term use and it well tolerated during the management of cerebrovascular disorders. Mild side effects such as headache, flushing, anxiety, dry mouth and nausea have been accounted during VPN uses. In spite of potent non-selective vasodilator effect it does not produce stealing effect on cerebral vasculatures due to the viscosity lowering effect and inhibition of platelet aggregations which together improve cerebral vessels rheological properties. Nevertheless, VPN does not reduce blood pressure and systemic

VPN is well absorbed from small intestine, which increased by food, therefore, fasting bioavailability is 6.7% and non-fasting bioavailability is 60–100%. Similarly, VPN has no significant drug-drug interactions with different drugs such as oxazepam, imipramine, glibenclamide and other agents that are used in the management

Ischemic stroke (IS) represents the main leading cause of death in the American Unite State and developed countries and regarded it as the main cause of long-term disability. IS represents 11.9% of annual total death and accounts for 90% of all

conclusions summarized in a critical review.

circulation during acute and chronic uses [5].

**3. Vinpocetine in ischemic stroke**

**2. Pharmacology of vinpocetine**

metabolites of dopamine [4].

of ischemic stroke [6].

**104**

stroke cases [7]. Arboix study discussed briefly the risk factor of IS [8]. These risk factors are divided into non-modifiable risk factors (sex, age, inherited factors, ethicinity and low birth weight at birth) and modifiable risk factors (diabetes mellitus, hypertension, smoking, obesity, alcohol abuse, oral contraceptive and metabolic syndrome). [9] IS is mainly caused by arterial thrombosis on the atherosclerotic plaque of cerebral vessels, causing cerebral ischemia, infarction and induction of peri-infarct inflammation. Neuro-inflammations contribute into tissue repair and neuronal damage as well as retrograde and anterograde axonal degenerations [10]. IS leads to glucose and oxygen deprivation of neuronal cells which causing oxidative stress, excitotoxicity and calcium overload which eventually causing neuronal cell death and development of infarction core [11]. The infracted core and damaged neuronal cells due to induced oxidative stress, releasing of various inflammatory molecules that causing vasculitis and damage of blood brain barrier (BBB) [12]. Moreover, activated microglia and infiltrated macrophage during IS release neurotransmitters which are interact with neurons causing neuroinflammation and neuronal injury. As well, interleukin-8(IL-8), NF-kB and tumor necrosis factor (TNF-α) are overexpressed during IS which play a potential role in the initiation of inflammation and apoptosis [13]. In a similar way, vascular smooth muscle and endothelial cells of cerebral vasculature are activated by NF-kB pathway leading to further obstruction and thrombosis. Therefore, NF-kB pathway is an important pathway in the pathogeneses and development of neurological deficit thus; inhibition of NF-kB pathway by VPN is regarded as important and main mechanism of VPN neuroprotection [14].

In addition, activated microglia expresses cholesterol transporter protein (TSPO) which is over-expressed during brain injury and IS and inhibited by VPN [15].

During IS voltage gated sodium channels are activated causing intracellular accumulation of Na and Ca leading to neuronal cell damage, excitotoxicity, edema, acidosis and acute cellular dysfunctions. VPN inhibits voltage gated sodium channels leading to dose dependent reduction of intracellular concentrations of Na and Ca. Thus, the neuroprotective effect of VPN during IS is chiefly mediated by inhibition of neuronal voltage gated sensitive Na-channel [16].

Different studies illustrated that oxidative stress, excitotoxicity and impaired energy metabolism leading to neuronal death by both apoptosis and necrosis during IS. These events lead to reduction of cAMP system which is important in the expression and regulation of brain derived neurotrophic factor (BDNF), which improves neuronal survival. PDE1 is mainly localized in striatum and cortex which participating in the regulation of neuronal motor activity [17, 18].

Indeed, VPN increases neuronal cGMP through inhibition of calmodulin dependent phosphodiesterase which improves cerebral blood flow and oxygen consumption [19]. VPN improves cerebral metabolism through enhancing glucose and oxygen supply and ATP production by cerebral vasodilation. These effects prevent IS induced-memory and cognitive dysfunctions due to improvement of neurotransmitters such as serotonin, dopamine and noradrenaline, which are involved in the regulation of cognitive function [20].

#### **3.1 Antioxidant effects of vinpocetine in ischemic stroke**

In IS overproduction of free radicals and reactive oxygen and/or nitrogen species lead to neuro-pathological changes through complex interactions with cellular components such as proteins, DNA and lipids. Free radicals, mainly superoxide and non-radicals such as hydrogen peroxide may cause further neurological injury through depletion of endogenous antioxidant capacity. Therefore, drug with antioxidant potential may play a role in the prevention of cerebral injury during IS [21].

Recent study by Al-Kuraishy et al. reported that VPN is a potent antioxidant agent which improves antioxidant capacity and reduces of oxidative stress [22]. As well, Santos et al., study illustrated that VPN attenuates oxidative stress during IS through inhibition of lipid peroxidation and generation of free radical [23]. In addition, VPN has a potential neuroprotective effect, though antioxidant effect since it prevents oxidative stress injury and toxic demyelination in rat brain [24]. The antioxidant neuroprotective effect of VPN is mainly at low-moderate doses since; high doses of VPN lead to oxidative stress due to prooxidant and proinflammatory effects [25]. Deshmukh et al. reported that antioxidant potential of VPN contributes into the prevention of IS induced-neuronal injury through modulation of cholinergic neurons [26]. Therefore, antioxidant mechanisms of VPN are related to direct free radical scavenging effect, potentiating of endogenous antioxidant capacity and inhibition the generation of free radicals. The molecular antioxidant effect of VPN is linked to the suppression of ADP stimulated respiration, mitochondrial Na+/Ca+ exchange, mitochondrial swelling and regulation of mitochondrial membrane potentials [16, 27].

## **3.2 Anti-inflammatory effects of vinpocetine in ischemic stroke**

IS induced-inflammatory changes and neuroinflammations lead to secondary brain damage. Toll-like receptors (TLRs) are over-expressed in IS, leading to the induction the release of pro-inflammatory mediators through myeloid differentiation factor-88 (MyD88) dependent pathway and Toll /IL-IR domain-containing adaptor factor protein inducing interferon-beta (TRIF) dependent pathway [28]. Therefore, inhibition of TLR4/MyD88 and NF-KB pathways lead to noteworthy neuroprotection against IS. It has been noted that VPN inhibits TNF-α induced NF-KB activation, pro-inflammatory releases and inflammatory biomarkers such as

**107**

*Vinpocetine and Ischemic Stroke*

dent pathway [34].

IS, **Figure 3** [35, 36].

mitochondrial Na+

*DOI: http://dx.doi.org/10.5772/intechopen.90551*

IB-Kinase (IKK) pathway in IS, **Figure 2** [30, 31].

IL-1β and IL-33 in an experimental ischemic model [5]. In intriguing way, Zhang and Yang reported that VPN inhibits the release of chemokines and inflammatory cytokines from microglia, macrophage and endothelial cells in IS through inhibition of NF-KB pathways in IS and associated atherosclerosis [29]. In a similar way, VNP leads to the significant neuroprotective effect and regulation of neuronal plasticity through the anti-inflammatory effect which is mediated by suppression of

Usually, microglia cells are resident macrophages in the brain and act as an active immune defense against cerebral injury and infection through induction and regulation of neuro-inflammatory reactions. Microglia improves brain homeostasis through removal of tissue debris, dead cells, and induction of neurogenesis and preservation of myelin sheath with secretion of neuroprotective factors such as insulin-like growth factor. On the other hand, activated microglia leads to neuronal injury during IS through the release of TNF-α, IL-6, IL1β and nitric oxide (NO) [32]. It has been reported that VPN inhibits neuronal inflammation in IS through suppression of microglia activity [33]. Also, VPN inhibits IS induced-inflammatory changes and reduces brain edema and infarction size mainly through inhibition the expression of NF-KB and TNF-α in the activated microglia which is PDE1 indepen-

**3.3 Effects of vinpocetine on ischemic reperfusion injury in ischemic stroke**

Ischemic-reperfusion (I/R) injury in IS leads to activations of perivascular macrophages, which play a role in the progression of neuronal damage through the release of proinflammatory biomarkers which also participate in the injury to blood brain barrier. Furthermore, activate macrophages, microglia, T-cells and dendritic cells infiltrate the infarct site following I/R injury causing further damage through the release of monocyte chemoattracting protein (MCP-1) which attracts circulating neutrophils into the injury site. VPN inhibits TNF-α induced-IKKα/β activation with reduction of target genes activations and reduction of various forms of proinflammatory cytokines and mediator following I/R injury in

In addition, injured neurons in IS release specific proteins called danger associated molecular patterns including; heat shock protein (HSP), high mobility groupbox 1 protein (HMGB-1), ATP and nicotinamide adenine dinucleotide (NAD) which activate TLR4 receptors on perivascular macrophage, microglia and endothelial cells. Therefore, TLR4 antagonist reduces infarct size attenuates IS-induced inflammatory changes and I/R injury [37, 38]. Different in *vitro* and in *vivo* studies illustrated that VPN inhibits I/R injury in IS through suppression of TLR4 receptors

Neuronal mitochondrial reactive oxygen species (ROS) contribute into the pathogenesis of I/R injury in IS as well as neurodegeneration and glutamate excitotoxicity [40]. VPN activates peripheral benzodiazepine receptors (BBRs) which regulate mitochondrial outer cell membrane and prevent the opening of mitochondrial permeability transition pore (MPTP). Furthermore, VPN prevents mitochondrial dysfunction through the prevention of mitochondrial depolarization, inhibition of

opening and the release of free radicals from outer mitochondrial membrane during neuronal injury [41]. Therefore, VPN regulates mitochondrial redox homeostasis through induction of ATP hydrolysis, inhibition of mitochondrial respiration and regulation of ATP synthesis. Thus, VPN preserves mitochondrial integrity and attenuates inflammatory and oxidative damage following I/R injury in IS. Moreover, Qiu et al., illustrated that VPN is effective in reducing the volume of cerebral infarct and

/Ca2+ exchange, prevention of mitochondrial Ca+2 release, MPTP

and NF-KB signaling pathway in animal model studies [39].

#### *Vinpocetine and Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.90551*

*Ischemic Stroke*

membrane potentials [16, 27].

Recent study by Al-Kuraishy et al. reported that VPN is a potent antioxidant agent which improves antioxidant capacity and reduces of oxidative stress [22]. As well, Santos et al., study illustrated that VPN attenuates oxidative stress during IS through inhibition of lipid peroxidation and generation of free radical [23]. In addition, VPN has a potential neuroprotective effect, though antioxidant effect since it prevents oxidative stress injury and toxic demyelination in rat brain [24]. The antioxidant neuroprotective effect of VPN is mainly at low-moderate doses since; high doses of VPN lead to oxidative stress due to prooxidant and proinflammatory effects [25]. Deshmukh et al. reported that antioxidant potential of VPN contributes into the prevention of IS induced-neuronal injury through modulation of cholinergic neurons [26]. Therefore, antioxidant mechanisms of VPN are related to direct free radical scavenging effect, potentiating of endogenous antioxidant capacity and inhibition the generation of free radicals. The molecular antioxidant effect of VPN is linked to the suppression of ADP stimulated respiration, mitochondrial Na+/Ca+ exchange, mitochondrial swelling and regulation of mitochondrial

**3.2 Anti-inflammatory effects of vinpocetine in ischemic stroke**

*Anti-inflammator effects of vinpocetine. (A) Basic effect, (B) Anti-inflammatory effect.*

IS induced-inflammatory changes and neuroinflammations lead to secondary brain damage. Toll-like receptors (TLRs) are over-expressed in IS, leading to the induction the release of pro-inflammatory mediators through myeloid differentiation factor-88 (MyD88) dependent pathway and Toll /IL-IR domain-containing adaptor factor protein inducing interferon-beta (TRIF) dependent pathway [28]. Therefore, inhibition of TLR4/MyD88 and NF-KB pathways lead to noteworthy neuroprotection against IS. It has been noted that VPN inhibits TNF-α induced NF-KB activation, pro-inflammatory releases and inflammatory biomarkers such as

**106**

**Figure 2.**

IL-1β and IL-33 in an experimental ischemic model [5]. In intriguing way, Zhang and Yang reported that VPN inhibits the release of chemokines and inflammatory cytokines from microglia, macrophage and endothelial cells in IS through inhibition of NF-KB pathways in IS and associated atherosclerosis [29]. In a similar way, VNP leads to the significant neuroprotective effect and regulation of neuronal plasticity through the anti-inflammatory effect which is mediated by suppression of IB-Kinase (IKK) pathway in IS, **Figure 2** [30, 31].

Usually, microglia cells are resident macrophages in the brain and act as an active immune defense against cerebral injury and infection through induction and regulation of neuro-inflammatory reactions. Microglia improves brain homeostasis through removal of tissue debris, dead cells, and induction of neurogenesis and preservation of myelin sheath with secretion of neuroprotective factors such as insulin-like growth factor. On the other hand, activated microglia leads to neuronal injury during IS through the release of TNF-α, IL-6, IL1β and nitric oxide (NO) [32]. It has been reported that VPN inhibits neuronal inflammation in IS through suppression of microglia activity [33]. Also, VPN inhibits IS induced-inflammatory changes and reduces brain edema and infarction size mainly through inhibition the expression of NF-KB and TNF-α in the activated microglia which is PDE1 independent pathway [34].

## **3.3 Effects of vinpocetine on ischemic reperfusion injury in ischemic stroke**

Ischemic-reperfusion (I/R) injury in IS leads to activations of perivascular macrophages, which play a role in the progression of neuronal damage through the release of proinflammatory biomarkers which also participate in the injury to blood brain barrier. Furthermore, activate macrophages, microglia, T-cells and dendritic cells infiltrate the infarct site following I/R injury causing further damage through the release of monocyte chemoattracting protein (MCP-1) which attracts circulating neutrophils into the injury site. VPN inhibits TNF-α induced-IKKα/β activation with reduction of target genes activations and reduction of various forms of proinflammatory cytokines and mediator following I/R injury in IS, **Figure 3** [35, 36].

In addition, injured neurons in IS release specific proteins called danger associated molecular patterns including; heat shock protein (HSP), high mobility groupbox 1 protein (HMGB-1), ATP and nicotinamide adenine dinucleotide (NAD) which activate TLR4 receptors on perivascular macrophage, microglia and endothelial cells. Therefore, TLR4 antagonist reduces infarct size attenuates IS-induced inflammatory changes and I/R injury [37, 38]. Different in *vitro* and in *vivo* studies illustrated that VPN inhibits I/R injury in IS through suppression of TLR4 receptors and NF-KB signaling pathway in animal model studies [39].

Neuronal mitochondrial reactive oxygen species (ROS) contribute into the pathogenesis of I/R injury in IS as well as neurodegeneration and glutamate excitotoxicity [40]. VPN activates peripheral benzodiazepine receptors (BBRs) which regulate mitochondrial outer cell membrane and prevent the opening of mitochondrial permeability transition pore (MPTP). Furthermore, VPN prevents mitochondrial dysfunction through the prevention of mitochondrial depolarization, inhibition of mitochondrial Na+ /Ca2+ exchange, prevention of mitochondrial Ca+2 release, MPTP opening and the release of free radicals from outer mitochondrial membrane during neuronal injury [41]. Therefore, VPN regulates mitochondrial redox homeostasis through induction of ATP hydrolysis, inhibition of mitochondrial respiration and regulation of ATP synthesis. Thus, VPN preserves mitochondrial integrity and attenuates inflammatory and oxidative damage following I/R injury in IS. Moreover, Qiu et al., illustrated that VPN is effective in reducing the volume of cerebral infarct and

**Figure 3.**

*Effects of vinpocetine on proiinflammatory mediators during ischemic-reperfusion (I/R) injury in ischemic stroke.*

attenuation I/R injury through down-regulation of NF-KB p65 and cyclo-oxygenase 2(COX-2) with up-regulation of peroxisome proliferator-activator receptor γ(PPARγ) which is neuroprotective mediator during IS [42].

#### **3.4 Vinpocetine and post-ischemic stroke**

### *3.4.1 Immunological and inflammatory reactions in post-ischemic stroke*

In the brain, there is multiple communications between glial cell and other immune cells, which together participate in the immune reactions during ischemic events. In the post-ischemic stroke (PIS), B-cell, T-cell, macrophage and neutrophils enter the brain to connect and engage glial cells in immune interactions. This interaction maintains homeostasis and prevents further neuronal damage through generation of pro-survival factors like transforming growth factor-β and IL-10 which promote the resolution of inflammations [43].

It has been noticed, that IS activates neuro-inflammations which increase the permeability of BBB leading to activation of mast cells and macrophages which release histamine and pro-inflammatory cytokines respectively which recruit immune cell to the site of injury leading to progression of ischemic injury [44].

Therefore, the relationship between immune cells and neurons during IS is so intricate relationship.

Microglia is regarded as a first line defense mechanism of innate immunity against ischemic injury which activated within hours following IS. There are two activation pathways for microglia, which are classical pathway (M1) and alternative pathway (M2). M1 activation leads to induction of inducible nitric oxide synthase

**109**

with IS [46].

*killer; CD: cluster of differentiation.*

**Figure 4.**

dependent-PKA pathway [51].

*3.4.2 Vinpocetin for post-ischemic stroke epilepsy*

presynaptic Ca and Na permeability [54, 55].

*Vinpocetine and Ischemic Stroke*

*DOI: http://dx.doi.org/10.5772/intechopen.90551*

(iNOS) and TNF-α causing neuronal damage while; M2 activation leads to induction the release of pro-inflammatory cytokines and arginase leading to neuroprotection [45]. Aging is associated with impaired M2 activation and thus; M1 activation overriding M2 causing more inflammatory changes in elderly patients

*Microglial and astrocyte activations in post-ischemic stroke. CCR2: chemokine receptor 2; PAMPs: pathogenassociated molecular patterns; LPS: lipopolysaccharides; PD-1: programmed death-ligand 1; NK: natural* 

Similarly, astrocyte which is another type of glial cell contributes in the formation of BBB and activated following IS. Reactive astrocyte subdivided into A1plays a role in the neuronal damage through upregulation of complement genes, and A2 plays a role in the neuroprotection through up-regulation of neurotrophic factors [47]. One month following PIS, astrocyte undergoes morphological and functional changes leading to reactive gliosis and activation of T-cell at ischemic regions [48]. Therefore, astrocyte and glial cells act as bridge interaction between neurons and immune system through different pro-inflammatory cytokines, **Figure 4** [49]. It has been shown that inflammatory changes, glial and astrocyte activations at poststroke period participating together in the induction of different PIS complications such as depression, epilepsy, dementia and cognitive dysfunctions [50]. Vardian study illustrated that VPN have noteworthy antioxidant, anti-inflammatory and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following IS. Also, VPN reduces astrocyte edema and excitability through cAMP

Kim et al. reported that PIS predisposes for early and late onset epilepsy which called post-stroke seizure (PSS) due to the disturbances in the neuronal metabolic homeostasis, reactive gliosis, glutamate release and neuronal hyper-excitability [52]. Recently, Garza-Morales et al., found that VPN is effective as an adjuvant therapy in the management of epilepsy, it reduces seizure frequency by 50% in a dose of 2 mg/kg/day as compared with placebo [53]. The anti-epileptic mechanisms of VPN are through blockade of presynaptic Na-channels mediated glutamate release, inhibition of TNF-α and IL-1β which play a role in the augmentation of

#### **Figure 4.**

*Ischemic Stroke*

**Figure 3.**

*stroke.*

attenuation I/R injury through down-regulation of NF-KB p65 and cyclo-oxygenase 2(COX-2) with up-regulation of peroxisome proliferator-activator receptor γ(PPARγ)

*Effects of vinpocetine on proiinflammatory mediators during ischemic-reperfusion (I/R) injury in ischemic* 

In the brain, there is multiple communications between glial cell and other immune cells, which together participate in the immune reactions during ischemic events. In the post-ischemic stroke (PIS), B-cell, T-cell, macrophage and neutrophils enter the brain to connect and engage glial cells in immune interactions. This interaction maintains homeostasis and prevents further neuronal damage through generation of pro-survival factors like transforming growth factor-β and IL-10

It has been noticed, that IS activates neuro-inflammations which increase the permeability of BBB leading to activation of mast cells and macrophages which release histamine and pro-inflammatory cytokines respectively which recruit immune cell to the site of injury leading to progression of ischemic injury [44]. Therefore, the relationship between immune cells and neurons during IS is so

Microglia is regarded as a first line defense mechanism of innate immunity against ischemic injury which activated within hours following IS. There are two activation pathways for microglia, which are classical pathway (M1) and alternative pathway (M2). M1 activation leads to induction of inducible nitric oxide synthase

*3.4.1 Immunological and inflammatory reactions in post-ischemic stroke*

which is neuroprotective mediator during IS [42].

which promote the resolution of inflammations [43].

**3.4 Vinpocetine and post-ischemic stroke**

**108**

intricate relationship.

*Microglial and astrocyte activations in post-ischemic stroke. CCR2: chemokine receptor 2; PAMPs: pathogenassociated molecular patterns; LPS: lipopolysaccharides; PD-1: programmed death-ligand 1; NK: natural killer; CD: cluster of differentiation.*

(iNOS) and TNF-α causing neuronal damage while; M2 activation leads to induction the release of pro-inflammatory cytokines and arginase leading to neuroprotection [45]. Aging is associated with impaired M2 activation and thus; M1 activation overriding M2 causing more inflammatory changes in elderly patients with IS [46].

Similarly, astrocyte which is another type of glial cell contributes in the formation of BBB and activated following IS. Reactive astrocyte subdivided into A1plays a role in the neuronal damage through upregulation of complement genes, and A2 plays a role in the neuroprotection through up-regulation of neurotrophic factors [47]. One month following PIS, astrocyte undergoes morphological and functional changes leading to reactive gliosis and activation of T-cell at ischemic regions [48].

Therefore, astrocyte and glial cells act as bridge interaction between neurons and immune system through different pro-inflammatory cytokines, **Figure 4** [49]. It has been shown that inflammatory changes, glial and astrocyte activations at poststroke period participating together in the induction of different PIS complications such as depression, epilepsy, dementia and cognitive dysfunctions [50]. Vardian study illustrated that VPN have noteworthy antioxidant, anti-inflammatory and anti-apoptotic effects with inhibitory effect on glial and astrocyte cells during and following IS. Also, VPN reduces astrocyte edema and excitability through cAMP dependent-PKA pathway [51].

#### *3.4.2 Vinpocetin for post-ischemic stroke epilepsy*

Kim et al. reported that PIS predisposes for early and late onset epilepsy which called post-stroke seizure (PSS) due to the disturbances in the neuronal metabolic homeostasis, reactive gliosis, glutamate release and neuronal hyper-excitability [52]. Recently, Garza-Morales et al., found that VPN is effective as an adjuvant therapy in the management of epilepsy, it reduces seizure frequency by 50% in a dose of 2 mg/kg/day as compared with placebo [53]. The anti-epileptic mechanisms of VPN are through blockade of presynaptic Na-channels mediated glutamate release, inhibition of TNF-α and IL-1β which play a role in the augmentation of presynaptic Ca and Na permeability [54, 55].

#### *3.4.3 Vinpocetin for post-stroke depression*

Post-stroke depression (PSD) is a critical psychiatric complication of IS characterized by psychomotor disturbances, fatigue and sleep disorders with a prevalence of 33% following IS [56]. PSD is developed due to inflammatory reactions inducedneuroplasticity and imbalance of pro-inflammatory/anti-inflammatory ratio which causing glutamate excitotoxicity and intracellular Ca dysregulation [57]. Different studies illustrated that inflammatory cytokines induced-PSD lead to a reduction in the synthesis of serotonin, brain derived neurotrophic factor and fibroblast growth factor-2 which are important in the regulation of mood and neurotransmission [58, 59].

Inflammatory cytokines are implicated in the induction of PSD through activation of indolamine-2,3-dioxygenase at the marginal zone of the infracted area leading to depletion of serotonin and initiation of depression [60]. Furthermore, Wierner et al. found that nerve growth factor (NGF) which important secretory protein inhibits apoptosis and improves neuronal differentiations was low in PSD [61]. On the other hand, calcitonin gene-related peptide (CGRP) which is a neuroprotective peptide is elevated in patients with PSD and thus; CGRP antagonist could improve depressive symptoms [62].

Therefore, anti-inflammatory drugs with rehabilitation therapy enhance neuronal plasticity and functional recovery after IS [63]. VPN reduces the inflammatory processes and improves neuronal plasticity through inhibition the releases of inflammatory cytokines and chemokines from macrophage, microglia, and vascular smooth and endothelial cells with restoration of synaptic neurotransmissions [64]. As well, VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms [65]. Chen et al. reported that VPN improves neuronal functions and neurotransmission through modulation of NGF levels following IS [66]. Similarly, VPN improves neuronal transmission and inhibits induced pain pathway in PSD through down-regulation of CGRP [67]. Herewith, VPN attenuates PSD through different pathways either directly by activation of neuronal cAMP/cGMP pathway or indirectly through anti-oxidant, anti-inflammatory and modulation of brain peptides and neurotransmitters. Since, hippocampal cAMP-PKA response element of BDNF signaling pathway is decreased in patients with PSD. So, improvement of neuronal cAMP could interestingly prevent PSD [68].

#### *3.4.4 Vinpocetin for post-stroke cognitive deficit*

Post-stroke cognitive deficit (PSCD) is defined as global cognitive disability within 6 months after stroke regardless of presumptive causes according to American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorder. As well, 30% of stroke survivor found to have a noteworthy degree of cognitive decline within the first month after the stroke [69]. It has been noticed that some cognitive disorders may also develop subsequent to transient ischemic attack (TIA) suggesting that PSCD used in this way does not propose underlying neuro-pathological changes. Therefore, PSCD seems to be suitable for dementia, which associated with vascular insult and neuro-degenerative processes [70]. Various cross-sectional and longitudinal studies illustrated a link between high levels of inflammatory biomarkers in stroke survivors and risk of PSCD. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IL-12 and IL-6 sera levels are elevated in patients with PSD and regarded as predictor factors [71, 72].

The inflammatory mechanism of PSCD is related to the dysregulation in inflammatory and immune factors since; reduction of IL-8 and IL-6 are associated with changes in both white and gray matters, suggesting a role in the pathogenesis of

**111**

**4. Conclusions**

**Author details**

*Vinpocetine and Ischemic Stroke*

*DOI: http://dx.doi.org/10.5772/intechopen.90551*

PSCD. As well, IL-1, IL-10, TNF-α and α-synuclien are increased in PSCD [73]. Shen and Gao study reported that high somatostatin and low neuron specific

Other mechanisms of PSCD are cerebral hypoperfusion, reduction in cerebrovascular reserve capacity, impairment of cerebral vasoreactivity and autoregulatory ability which together initiate abnormal neuronal cell membrane phosphorylation and amyloid beta formation [75]. In addition, irreversibly injured astrocytes are converted to clasmatodendrosis which leads to disruption of gliovascular association at BBB in the white matter. Clasmatodendrosis is associated with cognitive disorders in patients with PSCD [76]. From these points, the mechanisms of PSCD remain obscure due to overlapping between neuro-pathological data and findings of PSCD and Alzheimer disease [77]. VPN improves cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE-1with augmentation of cAMP/cGMP ratio, enhancement of cholinergic neurotransmission and inhibition of neuronal IKK/NF-kB [78, 79]. It has been noticed by Bitner study that both cAMP and cGMP activate PKA and cAMP-response element-binding protein (CREP) which improves synaptic plasticity and neurogenesis through up-regulation of BDNF. cAMP/cGMP/CREP pathway increases early and late long-term potentiation of memory [80] Besides, other PDE inhibitors like sildenafil (PDE-5 inhibitors) and cilostazol (PDE-3 inhibitor) also improve cognitive function and PSCD [81]. Recently, McQuown et al. illustrated that VPN improves memory function mainly through inhibition of PDE-1B isoform as it mainly located in regions with high dopaminergic neurotransmission such as the prefrontal cortex, striatum and dentate gyrus [78]. Therefore, VPN is an effective therapy in rehabilitation of cognitive, memory deficit and PSCD through modulation of inflammatory changes

enolase in patients with PSCD compared to the healthy controls [74].

and enhancement of neuronal cAMP/cGMP in post-stroke survivors [82].

through anti-inflammatory and anti-oxidant effects.

Hayder M. Al-kuraishy\* and Ali I. Al-Gareeb

\*Address all correspondence to: hayderm36@yahoo.com

Al-Mustansiriya University, Iraq, Baghdad

provided the original work is properly cited.

VPN is an effective agent in the management of ischemic stroke and plays an integral role in the prevention and attenuation of post-stroke epilepsy, depression and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly

Department of Pharmacology, Toxicology and Medicine College of Medicine

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

#### *Vinpocetine and Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.90551*

*Ischemic Stroke*

*3.4.3 Vinpocetin for post-stroke depression*

improve depressive symptoms [62].

*3.4.4 Vinpocetin for post-stroke cognitive deficit*

Post-stroke depression (PSD) is a critical psychiatric complication of IS characterized by psychomotor disturbances, fatigue and sleep disorders with a prevalence of 33% following IS [56]. PSD is developed due to inflammatory reactions inducedneuroplasticity and imbalance of pro-inflammatory/anti-inflammatory ratio which causing glutamate excitotoxicity and intracellular Ca dysregulation [57]. Different studies illustrated that inflammatory cytokines induced-PSD lead to a reduction in the synthesis of serotonin, brain derived neurotrophic factor and fibroblast growth factor-2 which are important in the regulation of mood and neurotransmission [58, 59]. Inflammatory cytokines are implicated in the induction of PSD through activa-

tion of indolamine-2,3-dioxygenase at the marginal zone of the infracted area leading to depletion of serotonin and initiation of depression [60]. Furthermore, Wierner et al. found that nerve growth factor (NGF) which important secretory protein inhibits apoptosis and improves neuronal differentiations was low in PSD [61]. On the other hand, calcitonin gene-related peptide (CGRP) which is a neuroprotective peptide is elevated in patients with PSD and thus; CGRP antagonist could

Therefore, anti-inflammatory drugs with rehabilitation therapy enhance neuronal plasticity and functional recovery after IS [63]. VPN reduces the inflammatory processes and improves neuronal plasticity through inhibition the releases of inflammatory cytokines and chemokines from macrophage, microglia, and vascular smooth and endothelial cells with restoration of synaptic neurotransmissions [64]. As well, VPN improves psychomotor performances through modulation of brain monoamine pathway mainly on dopamine and serotonin, which play an integral role in attenuation of depressive symptoms [65]. Chen et al. reported that VPN improves neuronal functions and neurotransmission through modulation of NGF levels following IS [66]. Similarly, VPN improves neuronal transmission and inhibits induced pain pathway in PSD through down-regulation of CGRP [67]. Herewith, VPN attenuates PSD through different pathways either directly by activation of neuronal cAMP/cGMP pathway or indirectly through anti-oxidant, anti-inflammatory and modulation of brain peptides and neurotransmitters. Since, hippocampal cAMP-PKA response element of BDNF signaling pathway is decreased in patients with PSD. So, improvement of neuronal cAMP could interestingly prevent PSD [68].

Post-stroke cognitive deficit (PSCD) is defined as global cognitive disability within 6 months after stroke regardless of presumptive causes according to American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorder. As well, 30% of stroke survivor found to have a noteworthy degree of cognitive decline within the first month after the stroke [69]. It has been noticed that some cognitive disorders may also develop subsequent to transient ischemic attack (TIA) suggesting that PSCD used in this way does not propose underlying neuro-pathological changes. Therefore, PSCD seems to be suitable for dementia, which associated with vascular insult and neuro-degenerative processes [70]. Various cross-sectional and longitudinal studies illustrated a link between high levels of inflammatory biomarkers in stroke survivors and risk of PSCD. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IL-12 and IL-6 sera levels are

elevated in patients with PSD and regarded as predictor factors [71, 72].

The inflammatory mechanism of PSCD is related to the dysregulation in inflammatory and immune factors since; reduction of IL-8 and IL-6 are associated with changes in both white and gray matters, suggesting a role in the pathogenesis of

**110**

PSCD. As well, IL-1, IL-10, TNF-α and α-synuclien are increased in PSCD [73]. Shen and Gao study reported that high somatostatin and low neuron specific enolase in patients with PSCD compared to the healthy controls [74].

Other mechanisms of PSCD are cerebral hypoperfusion, reduction in cerebrovascular reserve capacity, impairment of cerebral vasoreactivity and autoregulatory ability which together initiate abnormal neuronal cell membrane phosphorylation and amyloid beta formation [75]. In addition, irreversibly injured astrocytes are converted to clasmatodendrosis which leads to disruption of gliovascular association at BBB in the white matter. Clasmatodendrosis is associated with cognitive disorders in patients with PSCD [76]. From these points, the mechanisms of PSCD remain obscure due to overlapping between neuro-pathological data and findings of PSCD and Alzheimer disease [77]. VPN improves cognitive functions and spatial memory through inhibition of hippocampal and cortical PDE-1with augmentation of cAMP/cGMP ratio, enhancement of cholinergic neurotransmission and inhibition of neuronal IKK/NF-kB [78, 79]. It has been noticed by Bitner study that both cAMP and cGMP activate PKA and cAMP-response element-binding protein (CREP) which improves synaptic plasticity and neurogenesis through up-regulation of BDNF. cAMP/cGMP/CREP pathway increases early and late long-term potentiation of memory [80] Besides, other PDE inhibitors like sildenafil (PDE-5 inhibitors) and cilostazol (PDE-3 inhibitor) also improve cognitive function and PSCD [81]. Recently, McQuown et al. illustrated that VPN improves memory function mainly through inhibition of PDE-1B isoform as it mainly located in regions with high dopaminergic neurotransmission such as the prefrontal cortex, striatum and dentate gyrus [78]. Therefore, VPN is an effective therapy in rehabilitation of cognitive, memory deficit and PSCD through modulation of inflammatory changes and enhancement of neuronal cAMP/cGMP in post-stroke survivors [82].

## **4. Conclusions**

VPN is an effective agent in the management of ischemic stroke and plays an integral role in the prevention and attenuation of post-stroke epilepsy, depression and cognitive deficit through direct cAMP/cGMP-dependent pathway or indirectly through anti-inflammatory and anti-oxidant effects.

## **Author details**

Hayder M. Al-kuraishy\* and Ali I. Al-Gareeb Department of Pharmacology, Toxicology and Medicine College of Medicine Al-Mustansiriya University, Iraq, Baghdad

\*Address all correspondence to: hayderm36@yahoo.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Alkuraishy HM, Al-Gareeb AI, Albuhadilly AK. Vinpocetine and pyritinol: A new model for blood rheological modulation in cerebrovascular disorders a randomized controlled clinical study. BioMed Research International. 2014;**2014**:1-8

[2] El-Laithy HM, Shoukry O, Mahran LG. Novel sugar esters proniosomes for transdermal delivery of vinpocetine: Preclinical and clinical studies. European Journal of Pharmaceutics and Biopharmaceutics. 2011;**77**(1):43-55

[3] Cao B, Ding Q, Liu X, Liu C, Songhua HU. Clinical observation of sofren injection combined with vinpocetine injection in the treatment of acute massive cerebral infarction. China Pharmacy. 2017;**28**(32):4527-4529

[4] Nadeem RI. Evaluation of the possible neurobehavioral effects of vinpocetine in parkinsonian-like models in rats [CU Theses]; 2018

[5] Zhang F, Yan C, Wei C, Yao Y, Ma X, Gong Z, et al. Vinpocetine inhibits NF-κB-dependent inflammation in acute ischemic stroke patients. Translational Stroke Research. 2018;**9**(2):174-184

[6] Manda V, Avula B, Dale O, Chittiboyina A, Khan I, Walker L, et al. Studies on pharmacokinetic drug interaction potential of vinpocetine. Medicine. 2015;**2**(2):93-105

[7] Cerami C, Perani D. Imaging neuroinflammation in ischemic stroke and in the atherosclerotic vascular disease. Current Vascular Pharmacology. 2015;**13**(2):218-222

[8] Arboix A. Cardiovascular risk factors for acute stroke: Risk profiles in the different subtypes of ischemic stroke. World Journal of Clinical Cases. 2015;**3**(5):418

[9] Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation. 2013;**127**(1):143-152

[10] Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U, et al. Stroke and the immune system: From pathophysiology to new therapeutic strategies. The Lancet Neurology. 2011;**10**(5):471-480

[11] Sidorov E, Sanghera DK, Vanamala JK. Biomarker for ischemic stroke using metabolome: A clinician perspective. Journal of Stroke. 2019;**21**(1):31

[12] Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. American Journal of Physiology-Cell Physiology. 2018;**316**(2):C135-C153

[13] Zarruk JG, Greenhalgh AD, David S. Microglia and macrophages differ in their inflammatory profile after permanent brain ischemia. Experimental Neurology. 2018;**301**:120-132

[14] Wu LR, Liu L, Xiong XY, Zhang Q, Wang FX, Gong CX, et al. Vinpocetine alleviate cerebral ischemia/reperfusion injury by down-regulating TLR4/ MyD88/NF-κB signaling. Oncotarget. 2017;**8**(46):80315

[15] Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral

**113**

*Vinpocetine and Ischemic Stroke*

biomarker for inflammation. NeuroImage. 2008;**40**(1):43-52

Research. 2019;**18**:1-3

*DOI: http://dx.doi.org/10.5772/intechopen.90551*

International Journal of Preventive

[23] Santos MS, Duarte AI, Moreira PI, Oliveira CR. Synaptosomal response to oxidative stress: Effect of vinpocetine. Free Radical Research. 2000;**32**(1):57-66

[24] Abdel-Salam OM, Khadrawy YA, Salem NA, Sleem AA. Oxidative stress in a model of toxic demyelination in rat brain: The effect of piracetam and vinpocetine. Neurochemical Research.

[25] Abdel-Salam OM, Hamdy SM, Seadawy SA, Galal AF, Abouelfadl DM,

aluminum chloride in rats. Comparative Clinical Pathology. 2016;**25**(2):305-318

[26] Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL. Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine—A PDE1 inhibitor. European Journal of Pharmacology. 2009;**620**(1-3):49-56

[27] Ishola IO, Akinyede AA, Adeluwa TP, Micah C. Novel action of vinpocetine in the prevention of paraquat-induced parkinsonism in mice: Involvement of oxidative stress and neuroinflammation. Metabolic Brain Disease. 2018;**33**(5):1493-1500

[28] Gao W, Xiong Y, Li Q, Yang H. Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: A journey from molecular to nano therapeutics. Frontiers in

Physiology. 2017;**8**:508

2015;**20**(1):335-347

[29] Zhang L, Yang L. Anti-

inflammatory effects of vinpocetine in atherosclerosis and ischemic stroke: A review of the literature. Molecules.

Atrees SS. Effect of piracetam, vincamine, vinpocetine, and donepezil on oxidative stress and neurodegeneration induced by

Medicine. 2019;**10**:1-6

2011;**36**(6):1062-1072

benzodiazepine receptor, a potential

[16] Svab G, Doczi J, Gerencser AA, Ambrus A, Gallyas F, Sümegi B, et al. The mitochondrial targets of neuroprotective drug vinpocetine on primary neuron cultures, brain capillary endothelial cells, synaptosomes, and brain mitochondria. Neurochemical

[17] Patyar S, Prakash A, Modi M, Medhi B. Role of vinpocetine in cerebrovascular diseases. Pharmacological Reports. 2011;**63**(3):618-628

[18] Ahmed HI, Abdel-Sattar SA, Zaky HS. Vinpocetine halts ketamine-

[19] Zhang W, Huang Y, Li Y, Tan L, Nao J, Hu H, et al. Efficacy and safety of vinpocetine as part of treatment for acute cerebral infarction: A randomized, open-label, controlled, multicenter CAVIN (Chinese assessment for

vinpocetine in neurology) trial. Clinical Drug Investigation. 2016;**36**(9):697-704

[21] Slemmer JE, Shacka JJ, Sweeney MI, Weber JT. Antioxidants and free radical

[20] Jack C. Interventions that may increase cerebral blood flow. In: Alzheimer's Turning Point. Cham:

Springer; 2016. pp. 217-228

scavengers for the treatment of stroke, traumatic brain injury and aging. Current Medicinal Chemistry.

[22] Al-Kuraishy HM, Al-Gareeb AI, Al-Nami MS. Vinpocetine improves oxidative stress and pro-inflammatory mediators in acute kidney injury.

2008;**15**(4):404-414

induced schizophrenia-like deficits in rats: Impact on BDNF and GSK-3β/β-catenin pathway. Naunyn-Schmiedeberg's Archives of Pharmacology. 2018;**391**(12):1327-1338 *Vinpocetine and Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.90551*

benzodiazepine receptor, a potential biomarker for inflammation. NeuroImage. 2008;**40**(1):43-52

[16] Svab G, Doczi J, Gerencser AA, Ambrus A, Gallyas F, Sümegi B, et al. The mitochondrial targets of neuroprotective drug vinpocetine on primary neuron cultures, brain capillary endothelial cells, synaptosomes, and brain mitochondria. Neurochemical Research. 2019;**18**:1-3

[17] Patyar S, Prakash A, Modi M, Medhi B. Role of vinpocetine in cerebrovascular diseases. Pharmacological Reports. 2011;**63**(3):618-628

[18] Ahmed HI, Abdel-Sattar SA, Zaky HS. Vinpocetine halts ketamineinduced schizophrenia-like deficits in rats: Impact on BDNF and GSK-3β/β-catenin pathway. Naunyn-Schmiedeberg's Archives of Pharmacology. 2018;**391**(12):1327-1338

[19] Zhang W, Huang Y, Li Y, Tan L, Nao J, Hu H, et al. Efficacy and safety of vinpocetine as part of treatment for acute cerebral infarction: A randomized, open-label, controlled, multicenter CAVIN (Chinese assessment for vinpocetine in neurology) trial. Clinical Drug Investigation. 2016;**36**(9):697-704

[20] Jack C. Interventions that may increase cerebral blood flow. In: Alzheimer's Turning Point. Cham: Springer; 2016. pp. 217-228

[21] Slemmer JE, Shacka JJ, Sweeney MI, Weber JT. Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. Current Medicinal Chemistry. 2008;**15**(4):404-414

[22] Al-Kuraishy HM, Al-Gareeb AI, Al-Nami MS. Vinpocetine improves oxidative stress and pro-inflammatory mediators in acute kidney injury.

International Journal of Preventive Medicine. 2019;**10**:1-6

[23] Santos MS, Duarte AI, Moreira PI, Oliveira CR. Synaptosomal response to oxidative stress: Effect of vinpocetine. Free Radical Research. 2000;**32**(1):57-66

[24] Abdel-Salam OM, Khadrawy YA, Salem NA, Sleem AA. Oxidative stress in a model of toxic demyelination in rat brain: The effect of piracetam and vinpocetine. Neurochemical Research. 2011;**36**(6):1062-1072

[25] Abdel-Salam OM, Hamdy SM, Seadawy SA, Galal AF, Abouelfadl DM, Atrees SS. Effect of piracetam, vincamine, vinpocetine, and donepezil on oxidative stress and neurodegeneration induced by aluminum chloride in rats. Comparative Clinical Pathology. 2016;**25**(2):305-318

[26] Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL. Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine—A PDE1 inhibitor. European Journal of Pharmacology. 2009;**620**(1-3):49-56

[27] Ishola IO, Akinyede AA, Adeluwa TP, Micah C. Novel action of vinpocetine in the prevention of paraquat-induced parkinsonism in mice: Involvement of oxidative stress and neuroinflammation. Metabolic Brain Disease. 2018;**33**(5):1493-1500

[28] Gao W, Xiong Y, Li Q, Yang H. Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: A journey from molecular to nano therapeutics. Frontiers in Physiology. 2017;**8**:508

[29] Zhang L, Yang L. Antiinflammatory effects of vinpocetine in atherosclerosis and ischemic stroke: A review of the literature. Molecules. 2015;**20**(1):335-347

**112**

*Ischemic Stroke*

**References**

[1] Alkuraishy HM, Al-Gareeb AI, Albuhadilly AK. Vinpocetine and pyritinol: A new model for blood rheological modulation in

[2] El-Laithy HM, Shoukry O, Mahran LG. Novel sugar esters proniosomes for transdermal delivery of vinpocetine: Preclinical and clinical studies. European Journal of Pharmaceutics and Biopharmaceutics.

[3] Cao B, Ding Q, Liu X, Liu C, Songhua HU. Clinical observation of sofren injection combined with vinpocetine injection in the treatment of acute massive cerebral infarction. China Pharmacy. 2017;**28**(32):4527-4529

[4] Nadeem RI. Evaluation of the possible neurobehavioral effects of vinpocetine in parkinsonian-like models

[5] Zhang F, Yan C, Wei C, Yao Y, Ma X, Gong Z, et al. Vinpocetine inhibits NF-κB-dependent inflammation in acute ischemic stroke patients. Translational Stroke Research.

in rats [CU Theses]; 2018

2018;**9**(2):174-184

[6] Manda V, Avula B, Dale O, Chittiboyina A, Khan I, Walker L, et al. Studies on pharmacokinetic drug interaction potential of vinpocetine.

Medicine. 2015;**2**(2):93-105

[7] Cerami C, Perani D. Imaging neuroinflammation in ischemic stroke and in the atherosclerotic vascular disease. Current Vascular Pharmacology. 2015;**13**(2):218-222

[8] Arboix A. Cardiovascular risk factors for acute stroke: Risk profiles in the different subtypes of ischemic

2011;**77**(1):43-55

cerebrovascular disorders a randomized controlled clinical study. BioMed Research International. 2014;**2014**:1-8

stroke. World Journal of Clinical Cases.

[9] Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation.

[10] Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U, et al. Stroke and the immune system: From pathophysiology to new therapeutic strategies. The Lancet Neurology.

2015;**3**(5):418

2013;**127**(1):143-152

2011;**10**(5):471-480

2019;**21**(1):31

[11] Sidorov E, Sanghera DK,

Vanamala JK. Biomarker for ischemic stroke using metabolome: A clinician perspective. Journal of Stroke.

[12] Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. American Journal of Physiology-Cell Physiology.

[13] Zarruk JG, Greenhalgh AD, David S. Microglia and macrophages

[14] Wu LR, Liu L, Xiong XY, Zhang Q, Wang FX, Gong CX, et al. Vinpocetine alleviate cerebral ischemia/reperfusion injury by down-regulating TLR4/ MyD88/NF-κB signaling. Oncotarget.

[15] Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral

differ in their inflammatory profile after permanent brain ischemia. Experimental Neurology.

2018;**316**(2):C135-C153

2018;**301**:120-132

2017;**8**(46):80315

[30] Cohen PA. Vinpocetine: An unapproved drug sold as a dietary supplement. In: Mayo Clinic Proceedings. Elsevier; 2015;**90**(10):1455

[31] Medina AE. Vinpocetine as a potent antiinflammatory agent. Proceedings of the National Academy of Sciences. 2010;**107**(22):9921-9922

[32] Ma Y, Wang J, Wang Y, Yang GY. The biphasic function of microglia in ischemic stroke. Progress in Neurobiology. 2017;**157**:247-272

[33] Zhao YY, Yu JZ, Li QY, Ma CG, Lu CZ, Xiao BG. TSPO-specific ligand vinpocetine exerts a neuroprotective effect by suppressing microglial inflammation. Neuron Glia Biology. 2011;**7**(2-4):187-197

[34] Wang H, Zhang K, Zhao L, Tang J, Gao L, Wei Z. Anti-inflammatory effects of vinpocetine on the functional expression of nuclear factor-kappa B and tumor necrosis factor-alpha in a rat model of cerebral ischemia–reperfusion injury. Neuroscience Letters. 2014;**566**:247-251

[35] Jeon KI, Xu X, Aizawa T, Lim JH, Jono H, Kwon DS, et al. Vinpocetine inhibits NF-κB–dependent inflammation via an IKK-dependent but PDE-independent mechanism. Proceedings of the National Academy of Sciences. 2010;**107**(21):9795-9800

[36] Nivison-Smith L, Khoo P, Acosta ML, Kalloniatis M. Pretreatment with vinpocetine protects against retinal ischemia. Experimental Eye Research. 2017;**154**:126-138

[37] Abdel-Rahman EA, Mahmoud AM, Aaliya A, Radwan Y, Yasseen B, Al-Okda A, et al. Resolving contributions of oxygen-consuming and ROS-generating enzymes at the synapse. Oxidative Medicine and Cellular Longevity. 2016;**2016**:1-7

[38] Valencia A, Sapp E, Kimm JS, McClory H, Reeves PB, Alexander J, et al. Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington's disease. Human Molecular Genetics. 2013;**22**(6):1112

[39] Essam RM, Ahmed LA, Abdelsalam RM, El-Khatib AS. Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/ TLR4 inflammatory and fibrogenic pathways. Life Sciences. 2019;**222**:245-254

[40] Colombo BB, Fattori V, Guazelli CF, Zaninelli TH, Carvalho TT, Ferraz CR, et al. Vinpocetine ameliorates acetic acid-induced colitis by inhibiting NF-κB activation in mice. Inflammation. 2018;**41**(4):1276-1289

[41] Nag S, Krasikova R, Airaksinen AJ, Arakawa R, Petukhovd M, Gulyas B. Synthesis and biological evaluation of [18F] fluorovinpocetine, a potential PET radioligand for TSPO imaging. Bioorganic & Medicinal Chemistry Letters. 2019;**20**:2270-2274

[42] Qiu X, Wang J, Lanying HE, Luo Y. Vinpocetine alleviates cerebral ischemia-reperfusion injury in rats by regulation of the expressions of nuclear factor κB p65, peroxisome proliferator-activated receptor γ and cyclooxygenase-2. International Journal of Cerebrovascular Disease and Stroke. 2015;**23**(7):517-521

[43] Yan J, Greer JM, Etherington K, Cadigan GP, Cavanagh H, Henderson RD, et al. Immune activation in the peripheral blood of patients with acute ischemic stroke. Journal of Neuroimmunology. 2009;**206**(1-2):112-117

[44] Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation— Target or tool for therapy? Acta Neuropathologica. 2019;**137**(5):693-714

**115**

*Vinpocetine and Ischemic Stroke*

[45] Xu L, He D, Bai Y. Microgliamediated inflammation and

[46] Lee DC, Ruiz CR, Lebson L, Selenica ML, Rizer J, Hunt JB Jr, et al. Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiology of Aging. 2013;**34**(6):1610-1620

[47] Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Progress in Neurobiology.

[48] Pekny M, Wilhelmsson U, Tatlisumak T, Pekna M. Astrocyte activation and reactive gliosis—A new target in stroke? Neuroscience Letters.

[49] Hersh J, Yang SH. Glia–immune

[50] Ahangar AA, Saadat P, Alijanpour S, Galeshi M, Hosseinalipour S. Post ischemic stroke complication: How much nursing diagnosis are confirms by neurologist. Journal of Patient Care.

interactions post-ischemic stroke and potential therapies. Experimental Biology and Medicine.

2018;**243**(17-18):1302-1312

[51] Vardjan N. Mechanism and drug targets for reducing cell edema (neuroprotection) and cytoplasmic excitability in astrocytes in normal and pathological states. United States patent

[52] Kim HJ, Park KD, Choi KG, Lee HW. Clinical predictors of seizure recurrence after the first post-ischemic stroke seizure (vol. 16, p. 212, 2016).

BMC Neurology. 2017;**17**:1-9

[53] Garza-Morales S, Briceño-González E, Ceja-Moreno H, Ruiz-Sandoval JL, Góngora-Rivera F, Rodríguez-Leyva I,

US 9,970,924; 2018. p. 15

2016;**144**:103-120

2019;**689**:45-55

2018;**4**(140):2

*DOI: http://dx.doi.org/10.5772/intechopen.90551*

et al. Extended-release vinpocetine: A possible adjuvant treatment for focal onset epileptic seizures. Boletín Médico del Hospital Infantil de México.

[54] Sitges M, Sanchez-Tafolla BM, Chiu LM, Aldana BI, Guarneros A. Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs. Epilepsy Research. 2011;**96**(3):257-266

[55] Gómez CD, Buijs RM, Sitges M. The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1β and TNF-α expression in rat hippocampus.

Journal of Neurochemistry. 2014;**130**(6):770-779

[56] Llorca GE, Castilla-Guerra L, Moreno MF, Doblado SR, Hernández MJ. Post-stroke depression: An update. Neurología. 2015;**30**(1):23-31

[57] Levada OA, Troyan AS. Poststroke depression biomarkers: A narrative review. Frontiers in Neurology. 2018;**9**:577-586

Carey LM, Crewther DP. Inflammation and depression: Why poststroke depression may be the norm and not the exception. International Journal of

[59] Anisman H, Hayley S. Inflammatory factors contribute to depression and its comorbid conditions. Science Signaling.

[60] Spalletta G, Bossu P, Ciaramella A, Bria P, Caltagirone C, Robinson RG. The etiology of poststroke depression: A review of the literature and a new hypothesis involving inflammatory cytokines. Molecular Psychiatry.

[61] Wiener CD, de Mello Ferreira S, Moreira FP, Bittencourt G, de Oliveira JF,

[58] Pascoe MC, Crewther SG,

Stroke. 2011;**6**(2):128-135

2012;**5**(244):pe45

2006;**11**(11):984

2019;**76**(5):215-224

neurodegenerative disease. Molecular Neurobiology. 2016;**53**(10):6709-6715

*Vinpocetine and Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.90551*

*Ischemic Stroke*

[30] Cohen PA. Vinpocetine: An unapproved drug sold as a dietary supplement. In: Mayo Clinic

2010;**107**(22):9921-9922

2011;**7**(2-4):187-197

2014;**566**:247-251

Proceedings. Elsevier; 2015;**90**(10):1455

[38] Valencia A, Sapp E, Kimm JS, McClory H, Reeves PB, Alexander J, et al. Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington's disease. Human Molecular Genetics. 2013;**22**(6):1112

[39] Essam RM, Ahmed LA, Abdelsalam RM, El-Khatib AS. Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/ TLR4 inflammatory and

2019;**222**:245-254

2018;**41**(4):1276-1289

Arakawa R, Petukhovd M,

fibrogenic pathways. Life Sciences.

[40] Colombo BB, Fattori V, Guazelli CF, Zaninelli TH, Carvalho TT, Ferraz CR, et al. Vinpocetine ameliorates acetic acid-induced colitis by inhibiting NF-κB activation in mice. Inflammation.

[41] Nag S, Krasikova R, Airaksinen AJ,

Gulyas B. Synthesis and biological evaluation of [18F] fluorovinpocetine, a potential PET radioligand for TSPO imaging. Bioorganic & Medicinal Chemistry Letters. 2019;**20**:2270-2274

[42] Qiu X, Wang J, Lanying HE, Luo Y. Vinpocetine alleviates cerebral ischemia-reperfusion injury in rats by regulation of the expressions of nuclear factor κB p65, peroxisome proliferator-activated receptor γ and cyclooxygenase-2. International Journal of Cerebrovascular Disease and Stroke.

[43] Yan J, Greer JM, Etherington K,

Cadigan GP, Cavanagh H, Henderson RD, et al. Immune activation in the peripheral blood of patients with acute ischemic stroke. Journal of Neuroimmunology.

2009;**206**(1-2):112-117

[44] Lambertsen KL, Finsen B,

Target or tool for therapy? Acta

Clausen BH. Post-stroke inflammation—

Neuropathologica. 2019;**137**(5):693-714

2015;**23**(7):517-521

[31] Medina AE. Vinpocetine as a potent antiinflammatory agent. Proceedings of the National Academy of Sciences.

[32] Ma Y, Wang J, Wang Y, Yang GY. The biphasic function of microglia in ischemic stroke. Progress in Neurobiology. 2017;**157**:247-272

[33] Zhao YY, Yu JZ, Li QY, Ma CG, Lu CZ, Xiao BG. TSPO-specific ligand vinpocetine exerts a neuroprotective effect by suppressing microglial inflammation. Neuron Glia Biology.

[34] Wang H, Zhang K, Zhao L, Tang J, Gao L, Wei Z. Anti-inflammatory effects

of vinpocetine on the functional expression of nuclear factor-kappa B and tumor necrosis factor-alpha in a rat model of cerebral ischemia–reperfusion

injury. Neuroscience Letters.

inhibits NF-κB–dependent

[36] Nivison-Smith L, Khoo P, Acosta ML, Kalloniatis M. Pretreatment with vinpocetine protects against retinal ischemia. Experimental

Eye Research. 2017;**154**:126-138

Al-Okda A, et al. Resolving

Longevity. 2016;**2016**:1-7

[37] Abdel-Rahman EA, Mahmoud AM, Aaliya A, Radwan Y, Yasseen B,

Oxidative Medicine and Cellular

contributions of oxygen-consuming and ROS-generating enzymes at the synapse.

[35] Jeon KI, Xu X, Aizawa T, Lim JH, Jono H, Kwon DS, et al. Vinpocetine

inflammation via an IKK-dependent but PDE-independent mechanism. Proceedings of the National Academy of Sciences. 2010;**107**(21):9795-9800

**114**

[45] Xu L, He D, Bai Y. Microgliamediated inflammation and neurodegenerative disease. Molecular Neurobiology. 2016;**53**(10):6709-6715

[46] Lee DC, Ruiz CR, Lebson L, Selenica ML, Rizer J, Hunt JB Jr, et al. Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiology of Aging. 2013;**34**(6):1610-1620

[47] Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Progress in Neurobiology. 2016;**144**:103-120

[48] Pekny M, Wilhelmsson U, Tatlisumak T, Pekna M. Astrocyte activation and reactive gliosis—A new target in stroke? Neuroscience Letters. 2019;**689**:45-55

[49] Hersh J, Yang SH. Glia–immune interactions post-ischemic stroke and potential therapies. Experimental Biology and Medicine. 2018;**243**(17-18):1302-1312

[50] Ahangar AA, Saadat P, Alijanpour S, Galeshi M, Hosseinalipour S. Post ischemic stroke complication: How much nursing diagnosis are confirms by neurologist. Journal of Patient Care. 2018;**4**(140):2

[51] Vardjan N. Mechanism and drug targets for reducing cell edema (neuroprotection) and cytoplasmic excitability in astrocytes in normal and pathological states. United States patent US 9,970,924; 2018. p. 15

[52] Kim HJ, Park KD, Choi KG, Lee HW. Clinical predictors of seizure recurrence after the first post-ischemic stroke seizure (vol. 16, p. 212, 2016). BMC Neurology. 2017;**17**:1-9

[53] Garza-Morales S, Briceño-González E, Ceja-Moreno H, Ruiz-Sandoval JL, Góngora-Rivera F, Rodríguez-Leyva I,

et al. Extended-release vinpocetine: A possible adjuvant treatment for focal onset epileptic seizures. Boletín Médico del Hospital Infantil de México. 2019;**76**(5):215-224

[54] Sitges M, Sanchez-Tafolla BM, Chiu LM, Aldana BI, Guarneros A. Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs. Epilepsy Research. 2011;**96**(3):257-266

[55] Gómez CD, Buijs RM, Sitges M. The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1β and TNF-α expression in rat hippocampus. Journal of Neurochemistry. 2014;**130**(6):770-779

[56] Llorca GE, Castilla-Guerra L, Moreno MF, Doblado SR, Hernández MJ. Post-stroke depression: An update. Neurología. 2015;**30**(1):23-31

[57] Levada OA, Troyan AS. Poststroke depression biomarkers: A narrative review. Frontiers in Neurology. 2018;**9**:577-586

[58] Pascoe MC, Crewther SG, Carey LM, Crewther DP. Inflammation and depression: Why poststroke depression may be the norm and not the exception. International Journal of Stroke. 2011;**6**(2):128-135

[59] Anisman H, Hayley S. Inflammatory factors contribute to depression and its comorbid conditions. Science Signaling. 2012;**5**(244):pe45

[60] Spalletta G, Bossu P, Ciaramella A, Bria P, Caltagirone C, Robinson RG. The etiology of poststroke depression: A review of the literature and a new hypothesis involving inflammatory cytokines. Molecular Psychiatry. 2006;**11**(11):984

[61] Wiener CD, de Mello Ferreira S, Moreira FP, Bittencourt G, de Oliveira JF, Molina ML, et al. Serum levels of nerve growth factor (NGF) in patients with major depression disorder and suicide risk. Journal of Affective Disorders. 2015;**184**:245-248

[62] Shao B, Zhou YL, Wang H, Lin YS. The role of calcitonin generelated peptide in post-stroke depression in chronic mild stresstreated ischemic rats. Physiology & Behavior. 2015;**139**:224-230

[63] Greifzu F, Schmidt S, Schmidt KF, Kreikemeier K, Witte OW, Löwel S. Global impairment and therapeutic restoration of visual plasticity mechanisms after a localized cortical stroke. Proceedings of the National Academy of Sciences. 2011;**108**(37):15450-15455

[64] Lourenco-Gonzalez Y, Fattori V, Domiciano TP, Rossaneis AC, Borghi SM, Zaninelli TH, et al. Repurposing of the nootropic drug Vinpocetine as an analgesic and anti-inflammatory agent: Evidence in a mouse model of superoxide aniontriggered inflammation. Mediators of Inflammation. 2019;**2019**:1-9

[65] Al-Gareeb AI, Al-Windy S, Al-Kuraishy H. The effects of vinpocetine on the psychomotor performances: Randomized clinical trial, single blind random clinical study. Al-Nahrain Journal of Science. 2012;**15**(3):129-133

[66] Chen Q, Li GQ, Li JT. Effect of ganglioside combined with vinpocetine therapy on neural functional reconstruction in convalescents with acute cerebral infarction. Journal of Hainan Medical University. 2016;**22**(22):27-30

[67] Csillik B, Mihály A, Knyihár-Csillik E. Antinociceptive effect of vinpocetine--a comprehensive survey. Ideggyógyászati Szemle. 2010;**63**(5-6):185-192

[68] Wang C, Guo J, Guo R. Effect of XingPiJieYu decoction on spatial learning and memory and cAMP-PKA-CREB-BDNF pathway in rat model of depression through chronic unpredictable stress. BMC Complementary and Alternative Medicine. 2017;**17**(1):73

[69] Henon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D. Poststroke dementia: Incidence and relationship to prestroke cognitive decline. Neurology. 2001;**57**(7):1216-1222

[70] Justin BN, Turek M, Hakim AM. Heart disease as a risk factor for dementia. Clinical Epidemiology. 2013;**5**:135

[71] Rothenburg LS, Herrmann N, Swardfager W, Black SE, Tennen G, Kiss A, et al. The relationship between inflammatory markers and post stroke cognitive impairment. Journal of Geriatric Psychiatry and Neurology. 2010;**23**(3):199-205

[72] Narasimhalu K, Lee J, Leong YL, Ma L, De Silva DA, Wong MC, et al. Inflammatory markers and their association with post stroke cognitive decline. International Journal of Stroke. 2015;**10**(4):513-518

[73] Jokinen H, Melkas S, Ylikoski R, Pohjasvaara T, Kaste M, Erkinjuntti T, et al. Post-stroke cognitive impairment is common even after successful clinical recovery. European Journal of Neurology. 2015;**22**(9):1288-1294

[74] Shen Y, Gao HM. Serum somatostatin and neuron-specific enolase might be biochemical markers of vascular dementia in the early stage. International Journal of Clinical and Experimental Medicine. 2015;**8**(10):19471

[75] Hagberg G, Fure B, Thommessen B, Ihle-Hansen H, Øksengård AR, Nygård S, et al. Predictors for favorable cognitive

**117**

*Vinpocetine and Ischemic Stroke*

*DOI: http://dx.doi.org/10.5772/intechopen.90551*

outcome post-stroke: A-seven-year follow-up study. Dementia and Geriatric

Cognitive Disorders. 2019;**28**:1-1

2018;**144**(5):617-633

[77] Akinyemi RO, Allan LM, Oakley A, Kalaria RN. Hippocampal neurodegenerative pathology in poststroke dementia compared to other dementias and aging controls. Frontiers

in Neuroscience. 2017;**11**:717

Neuroscience. 2019;**12**:21-33

aluminum-induced cognitive impairment in socially isolated rats. Physiology & Behavior. 2019;**1**:112571-112586

[79] Ali AA, Ahmed HI, Khaleel SA, Abu-Elfotuh K. Vinpocetine mitigates

[80] Bitner RS. Cyclic AMP response element-binding protein (CREB) phosphorylation: A mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics. Biochemical Pharmacology. 2012;**83**(6):705-714

[81] Reneerkens OA, Rutten K,

2009;**202**(1-3):419-443

2014;**40**(4):1029-1038

Steinbusch HW, Blokland A, Prickaerts J. Selective phosphodiesterase inhibitors: A promising target for cognition enhancement. Psychopharmacology.

[82] Jacquin A, Binquet C, Rouaud O, Graule-Petot A, Daubail B, Osseby GV, et al. Post-stroke cognitive impairment: high prevalence and determining factors in a cohort of mild stroke. Journal of Alzheimer's Disease.

[78] McQuown S, Xia S, Baumgärtel K, Barido R, Anderson G, Dyck B, et al. Phosphodiesterase 1b (PDE1B) regulates spatial and contextual memory in hippocampus. Frontiers in Molecular

[76] Hase Y, Horsburgh K, Ihara M, Kalaria RN. White matter degeneration in vascular and other ageing-related dementias. Journal of Neurochemistry.

*Vinpocetine and Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.90551*

*Ischemic Stroke*

2015;**184**:245-248

Molina ML, et al. Serum levels of nerve growth factor (NGF) in patients with major depression disorder and suicide risk. Journal of Affective Disorders.

[68] Wang C, Guo J, Guo R. Effect of XingPiJieYu decoction on spatial learning and memory and cAMP-PKA-CREB-BDNF pathway in rat model of depression through chronic unpredictable stress. BMC Complementary and Alternative

[69] Henon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D. Poststroke dementia: Incidence and relationship to prestroke cognitive decline. Neurology.

[70] Justin BN, Turek M, Hakim AM. Heart disease as a risk factor for dementia. Clinical Epidemiology.

[71] Rothenburg LS, Herrmann N, Swardfager W, Black SE, Tennen G, Kiss A, et al. The relationship between inflammatory markers and post stroke cognitive impairment. Journal of Geriatric Psychiatry and Neurology.

[72] Narasimhalu K, Lee J, Leong YL, Ma L, De Silva DA, Wong MC, et al. Inflammatory markers and their association with post stroke cognitive decline. International Journal of Stroke.

[73] Jokinen H, Melkas S, Ylikoski R, Pohjasvaara T, Kaste M, Erkinjuntti T, et al. Post-stroke cognitive impairment is common even after successful clinical recovery. European Journal of Neurology. 2015;**22**(9):1288-1294

[75] Hagberg G, Fure B, Thommessen B, Ihle-Hansen H, Øksengård AR, Nygård S, et al. Predictors for favorable cognitive

[74] Shen Y, Gao HM. Serum somatostatin and neuron-specific enolase might be biochemical markers of vascular dementia in the early stage. International Journal of Clinical and Experimental Medicine.

2015;**8**(10):19471

Medicine. 2017;**17**(1):73

2001;**57**(7):1216-1222

2010;**23**(3):199-205

2015;**10**(4):513-518

2013;**5**:135

[62] Shao B, Zhou YL, Wang H, Lin YS. The role of calcitonin generelated peptide in post-stroke depression in chronic mild stresstreated ischemic rats. Physiology &

Behavior. 2015;**139**:224-230

[64] Lourenco-Gonzalez Y, Fattori V, Domiciano TP,

Inflammation. 2019;**2019**:1-9

[65] Al-Gareeb AI, Al-Windy S, Al-Kuraishy H. The effects of vinpocetine on the psychomotor performances: Randomized clinical trial, single blind random clinical study. Al-Nahrain Journal of Science.

[66] Chen Q, Li GQ, Li JT. Effect of ganglioside combined with vinpocetine

reconstruction in convalescents with acute cerebral infarction. Journal of Hainan Medical University.

[67] Csillik B, Mihály A, Knyihár-Csillik E. Antinociceptive effect of vinpocetine--a comprehensive survey. Ideggyógyászati Szemle.

therapy on neural functional

2012;**15**(3):129-133

2016;**22**(22):27-30

2010;**63**(5-6):185-192

[63] Greifzu F, Schmidt S, Schmidt KF, Kreikemeier K, Witte OW, Löwel S. Global impairment and therapeutic restoration of visual plasticity mechanisms after a localized cortical stroke. Proceedings of the National Academy of Sciences. 2011;**108**(37):15450-15455

Rossaneis AC, Borghi SM, Zaninelli TH, et al. Repurposing of the nootropic drug Vinpocetine as an analgesic and anti-inflammatory agent: Evidence in a mouse model of superoxide aniontriggered inflammation. Mediators of

**116**

outcome post-stroke: A-seven-year follow-up study. Dementia and Geriatric Cognitive Disorders. 2019;**28**:1-1

[76] Hase Y, Horsburgh K, Ihara M, Kalaria RN. White matter degeneration in vascular and other ageing-related dementias. Journal of Neurochemistry. 2018;**144**(5):617-633

[77] Akinyemi RO, Allan LM, Oakley A, Kalaria RN. Hippocampal neurodegenerative pathology in poststroke dementia compared to other dementias and aging controls. Frontiers in Neuroscience. 2017;**11**:717

[78] McQuown S, Xia S, Baumgärtel K, Barido R, Anderson G, Dyck B, et al. Phosphodiesterase 1b (PDE1B) regulates spatial and contextual memory in hippocampus. Frontiers in Molecular Neuroscience. 2019;**12**:21-33

[79] Ali AA, Ahmed HI, Khaleel SA, Abu-Elfotuh K. Vinpocetine mitigates aluminum-induced cognitive impairment in socially isolated rats. Physiology & Behavior. 2019;**1**:112571-112586

[80] Bitner RS. Cyclic AMP response element-binding protein (CREB) phosphorylation: A mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics. Biochemical Pharmacology. 2012;**83**(6):705-714

[81] Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J. Selective phosphodiesterase inhibitors: A promising target for cognition enhancement. Psychopharmacology. 2009;**202**(1-3):419-443

[82] Jacquin A, Binquet C, Rouaud O, Graule-Petot A, Daubail B, Osseby GV, et al. Post-stroke cognitive impairment: high prevalence and determining factors in a cohort of mild stroke. Journal of Alzheimer's Disease. 2014;**40**(4):1029-1038

## *Edited by Pratap Sanchetee*

Stroke continues to be a major public health issue. It is the third leading cause of death and disability across the globe. Its early identification and treatment along with prevention are major issues that confront a treating physician. We have understood the importance of early intervention and of the quote 'time is brain'. Our endeavor now should be directed to the public at large and paramedics in particular. Although a stroke is a common condition, the availability of neurologists or stroke specialists is quite scarce. Today, management of a suspected case of stroke is done by a specialist team of medical and paramedical personnel. Advances in imaging, newer therapeutic agents, and endovascular management have revolutionized the management. Currently, we are witnessing a new era in the management of strokes and I am hopeful that continued research will get us to a satisfactory solution. This book along with another book from IntechOpen titled 'Ischemic Stroke of Brain' aims to improve the understanding of stroke medicine for postgraduate medical students in medicine and neurology who have an interest in stroke care.

Published in London, UK © 2021 IntechOpen © Sinhyu / iStock

Ischemic Stroke

Ischemic Stroke

*Edited by Pratap Sanchetee*