**1. Introduction**

Acute ischemic stroke (AIS) remains the second cause of death worldwide [1], despite showing a mortality rate reduction of 1.19% [2]; only in 2017, there were 6 million 167, 291 deaths; 1, 291,000 more with respect to 1997. During the same period, the survival rate increased by 0.02%; this caused an increment in the disability-adjusted life years percentage (DALYs), which went from 4.17 to 5.29% [2].

Data from the World Health Organization (WHO) indicate that stroke represents the third cause of permanent adult disability worldwide [3], and is present in 90% of survivors. Motor deficits after stroke account for the high rates of longlasting disability. The most common impairments are related to speech, or language and communication disorders (aphasia and dysphasia), apraxia [4], swallowing, depression, cognitive impairment, and hemiparesis of the contralateral limb [5] characterized by muscle weakness or spasticity in distal rather than proximal muscles [6]. These deficits ultimately cause chronic disability, affecting the ability to

work and the patient's independence and autonomy for performing daily life activities such as dressing or eating, ensuring they will require long-lasting care, which also deteriorates their quality of life and that of the patients' caregivers.

Stroke complications represent a considerable economic burden both individually and as a society; such complications are associated with a substantial increase in household expenses related to a higher requirement of medical attention, medication, lost workdays, and payment to external or additional caregivers, and in several cases, physical rehabilitation. It is estimated that the United States alone had an annual expenditure of 45.5 billion dollars during the 2014–2015 period, which is only expected to increase through 2035, according to estimations of RTI international [7].

It is therefore fundamental to revisit the procedures regarding basic and clinical research points of view, as well as the most recent recommendations issued by the American Heart Association/American Stroke Association (AHA/ASA), which endorse multiple-component quality improvement initiatives including emergency department education and multidisciplinary teams with neurological management experience, thus increasing the application of fibrinolytic treatment IV.

The strategies that are currently being studied in search of treatments for cerebral ischemia can be categorized into four areas: clinical care, neuroprotection, neurorestoration strategies, and rehabilitation therapy.

The term neuroprotection is defined as the intentional intervention, either inhibition or modulation, that takes place at a certain point during the ischemic cascade, to intervene in a specific mechanism of damage to prevent tissue injury from increasing during the acute phase of ischemia [8]. The neurorestoration is developed through the stimulation of neurogenesis and neuroplasticity to restore the tissue and functional integrity of the neural tissue.

In the clinical setting, several recanalization strategies have been explored to restore blood flow to the injured area of tissue as soon as possible, to assure the lesser damage and decrease secondary sequelae to the original lesion. Finally, physical therapy has become a rehabilitation tactic that has positively impacted the recovery of patients' independence, autonomy, and quality of life, which is worth reviewing.

overproduction of free radicals; such proteins are calpains [14], endonucleases [15], calmodulin [16], and A2 phospholipase (**Figure 1**) [17]. Activation of these proteins leads to a further increase in free radical production and other oxidant species that directly damage structural molecules and activate inflammatory processes [18]. The mitochondria are where the highest production of free radicals takes place;

are produced continuously and eliminated by antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase [19]. Alternatively, under ischemic conditions, reperfusion provides sufficient substrate for different enzymatic oxidation reactions to take place, causing an overproduction of free oxygen radicals (ROS) and the inactivation of antioxidant enzymes [20]. Concurrently, nitric oxide (NO) increases due to the activation of endothelial and neuronal nitric oxide synthases as a result of increased Ca2+ concentration, NO reacts with

Free radicals promote mitochondrial membrane permeability and allow for cytochrome c to be released into the cytosol, where the intrinsic pathway of apoptosis becomes activated, the concentration of free radicals also increases lipid peroxidation and protein denaturalization [22]*,* DNA fragmentation, and activate several signaling pathways that lead to neural death, such as PI3K/AKT [23], Bcl2, p53 [24] and others. From the moment of the occlusion, endothelial cells express damage-associated molecular patterns (DAMPs), produce ROS and adhesion molecules that allow for their activation and that of surrounding mast cells and macrophages, which, as a consequence, release histamine, proteases, TNF-a, and

) and hydrogen peroxide (H2O2)

under normal conditions, superoxide anion (O2

*Available Therapeutics after a Stroke: Current and Promising Options*

*DOI: http://dx.doi.org/10.5772/intechopen.91282*

*Key points to the pathophysiology of stroke.*

**Figure 1.**

**281**

ROS and forms a highly toxic peroxynitric acid (ONOOH) [21].

## **2. Pathophysiology of stroke**

Cerebral ischemia is caused by an abrupt and sustained occlusion of blood flow to a large artery that unties a series of biochemical alterations that are known as the ischemic cascade, **Figure 1** [9]; during the development of such changes, a set of mechanisms that lead to cell death occurs: ionic imbalance and excitotoxicity, oxidative stress, and inflammation [10].

The reduction of blood flow leads to a depletion in levels of glucose and O2, which alters aerobic metabolism, increasing lactic acid accumulation. Simultaneously, astrocytes use stored glycogen to provide energy to the neurons in the form of lactate [11]; but, because aerobic metabolism is interrupted at this time, lactic acid continues to accumulate, causing lactic acidosis, which causes ionic dysfunction [12]. Ionic alterations, together with Na+ /K<sup>+</sup> pump inactivity, give rise to neuronal depolarization, which leads to the opening of the Ca2+ channels and the subsequent release of excitatory neurotransmitters such as glutamate, causing increased activation of ionotropic receptors, especially NMDA, increasing the Ca2+ flux into the cell [13].

Ca2+ is an essential protagonist within the ischemic cascade since it is capable of activating a significant amount of proteins that lead to cell death, and

*Available Therapeutics after a Stroke: Current and Promising Options DOI: http://dx.doi.org/10.5772/intechopen.91282*

work and the patient's independence and autonomy for performing daily life activities such as dressing or eating, ensuring they will require long-lasting care, which also deteriorates their quality of life and that of the patients' caregivers. Stroke complications represent a considerable economic burden both individually and as a society; such complications are associated with a substantial increase in household expenses related to a higher requirement of medical attention, medication, lost workdays, and payment to external or additional caregivers, and in several cases, physical rehabilitation. It is estimated that the United States alone had an annual expenditure of 45.5 billion dollars during the 2014–2015 period, which is

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

only expected to increase through 2035, according to estimations of RTI

experience, thus increasing the application of fibrinolytic treatment IV.

neurorestoration strategies, and rehabilitation therapy.

tissue and functional integrity of the neural tissue.

It is therefore fundamental to revisit the procedures regarding basic and clinical research points of view, as well as the most recent recommendations issued by the American Heart Association/American Stroke Association (AHA/ASA), which endorse multiple-component quality improvement initiatives including emergency department education and multidisciplinary teams with neurological management

The strategies that are currently being studied in search of treatments for cerebral ischemia can be categorized into four areas: clinical care, neuroprotection,

The term neuroprotection is defined as the intentional intervention, either inhibition or modulation, that takes place at a certain point during the ischemic cascade, to intervene in a specific mechanism of damage to prevent tissue injury from increasing during the acute phase of ischemia [8]. The neurorestoration is developed through the stimulation of neurogenesis and neuroplasticity to restore the

In the clinical setting, several recanalization strategies have been explored to restore blood flow to the injured area of tissue as soon as possible, to assure the lesser damage and decrease secondary sequelae to the original lesion. Finally, physical therapy has become a rehabilitation tactic that has positively impacted the recovery of patients' independence, autonomy, and quality of life, which is worth

Cerebral ischemia is caused by an abrupt and sustained occlusion of blood flow to a large artery that unties a series of biochemical alterations that are known as the ischemic cascade, **Figure 1** [9]; during the development of such changes, a set of mechanisms that lead to cell death occurs: ionic imbalance and excitotoxicity,

The reduction of blood flow leads to a depletion in levels of glucose and O2, which alters aerobic metabolism, increasing lactic acid accumulation. Simultaneously, astrocytes use stored glycogen to provide energy to the neurons in the form of lactate [11]; but, because aerobic metabolism is interrupted at this time, lactic acid continues to accumulate, causing lactic acidosis, which causes ionic

to neuronal depolarization, which leads to the opening of the Ca2+ channels and the subsequent release of excitatory neurotransmitters such as glutamate, causing increased activation of ionotropic receptors, especially NMDA, increasing the Ca2+

Ca2+ is an essential protagonist within the ischemic cascade since it is capable of

activating a significant amount of proteins that lead to cell death, and

/K<sup>+</sup> pump inactivity, give rise

international [7].

reviewing.

**2. Pathophysiology of stroke**

flux into the cell [13].

**280**

oxidative stress, and inflammation [10].

dysfunction [12]. Ionic alterations, together with Na+

**Figure 1.** *Key points to the pathophysiology of stroke.*

overproduction of free radicals; such proteins are calpains [14], endonucleases [15], calmodulin [16], and A2 phospholipase (**Figure 1**) [17]. Activation of these proteins leads to a further increase in free radical production and other oxidant species that directly damage structural molecules and activate inflammatory processes [18].

The mitochondria are where the highest production of free radicals takes place; under normal conditions, superoxide anion (O2 ) and hydrogen peroxide (H2O2) are produced continuously and eliminated by antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase [19]. Alternatively, under ischemic conditions, reperfusion provides sufficient substrate for different enzymatic oxidation reactions to take place, causing an overproduction of free oxygen radicals (ROS) and the inactivation of antioxidant enzymes [20]. Concurrently, nitric oxide (NO) increases due to the activation of endothelial and neuronal nitric oxide synthases as a result of increased Ca2+ concentration, NO reacts with ROS and forms a highly toxic peroxynitric acid (ONOOH) [21].

Free radicals promote mitochondrial membrane permeability and allow for cytochrome c to be released into the cytosol, where the intrinsic pathway of apoptosis becomes activated, the concentration of free radicals also increases lipid peroxidation and protein denaturalization [22]*,* DNA fragmentation, and activate several signaling pathways that lead to neural death, such as PI3K/AKT [23], Bcl2, p53 [24] and others. From the moment of the occlusion, endothelial cells express damage-associated molecular patterns (DAMPs), produce ROS and adhesion molecules that allow for their activation and that of surrounding mast cells and macrophages, which, as a consequence, release histamine, proteases, TNF-a, and

chemokines [25]. The production and release of these molecules promote the bloodbrain barrier (BBB) rupturing, thus causing peripheral leukocyte invasion into the injured brain parenchyma [26].

recognition of the symptoms and the time window in which rTPA must be administered is from 3 to 4.5 h from onset of symptoms, and benefits diminish over time [39, 41], which is why the new AHA/ASA guidelines recommend not waiting for clinical improvement before administration [32]. Also, not all patients are eligible, since candidates must be ≤80 years of age, without diabetes or stroke history, with an NIHSS score ≤ 25, not currently taking oral anticoagulation, and without radiologic evidence of ischemic injury involving more than one-third of the MCA

*Available Therapeutics after a Stroke: Current and Promising Options*

*DOI: http://dx.doi.org/10.5772/intechopen.91282*

Complications that are associated with its use are limited: BBB integrity alterations, and hemorrhagic transformation, granting that other studies have shown it to be well tolerated by patients using warfarin or other anticoagulants [38], in controversy with the new AHA/ASA guidelines that suggest it should not be administered if the patient received heparin 24 h before [32, 35, 43]. Other drugs are also available, such as aspirin, which must be delivered within 24–48 h after stroke onset. Although the guidelines emphasize that it should not be used to replace mechanical thrombectomy or IV alteplase, aspirin continues to be the choice for secondary prophylaxis [32, 44], even when the 2018 guidelines find no benefit

Furthermore, the FDA approves of endovascular treatments, which are reported

For patients with large vessel occlusion, less responsive to rTPA, intra-arterial therapy is recommended, since it leads to higher recanalization rates by being able to infuse the drug directly into the occluded area or the clot itself [35, 45]. About 10% of patients with AIS fall into this category, but only a few centers can perform

Also, endovascular mechanical thrombectomy using contact aspiration (CA) [47], which has been described before [48], and stent retrievers (SR), especially those of new generations [49], for clot rupturing and aspiration has shown significant benefits in large vessel occlusion [50] regarding clinical outcomes and lower complication rates [49]. Notwithstanding, CA alone, without the use of a SR, is associated with a greater need for rescue treatment, and thus, worse outcomes [51]; the SR might also increase the risk for hemorrhagic transformation and neurological deficit [52].

Increased costs of endovascular treatments, as well as their complexity and need

In the search to find new alternatives of neuroprotective agents, a great variety of molecules have been explored that affect one or several strategic points of the pathophysiology, and that promise good results; some are mentioned below.

During the onset of AIS, glucose and oxygen concentrations decrease, and this promotes the activation of adenosine monophosphate-activated protein kinase (AMPK). This process upregulates cellular pathways that control energy metabolism through catabolic pathways such as glycolysis and lipid oxidation to increase adenosine triphosphate (ATP) production and decrease its consumption through the inhibition of gluconeogenesis. Observations have been made regarding the fact that the activation of this enzyme for short periods increases neural survival, but its activation for extended periods will lead to cell death through apoptosis, necrosis, and autophagy [53], which is why several drugs that modulate AMPK activation

for trained personnel, cause patients to have less access to them. Therefore,

**4. First neuroprotective pharmacological and non-pharmacological**

exploring new pharmacological therapies should be continued.

have been tested recently in search for beneficial effects.

to have a time window of up to 8 hours from the onset of symptoms [38].

from its use for the treatment of an ongoing AIS [32].

endovascular procedures in proper conditions [46].

territory [42].

**treatments**

**283**

Microglial cells are then activated in the non-perfused region of the brain parenchyma [27], microglial cells acquire phagocytic characteristics and a predominantly pro-inflammatory phenotype (M1), which in turn increases the release of interleukin-6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor-alpha (TNF-α), NO molecules, and prostanoids [28]. Peripheral immune cells such as neutrophils, B lymphocytes, T lymphocytes, and NK are recruited into the injured tissue, this event is thought to contribute both beneficially by inducing the release of antiinflammatory cytokines and growth factors, and negatively by increasing the lesion through a sustained release of proinflammatory cytokines and free radicals [29].

Within the process of the ischemic cascade, three points are identified that could classify as strategic to restore neuroprotection (ionic imbalance, excitotoxicity, and inflammation); nonetheless, most neuroprotective drugs act in many of the phases of the ischemic cascade, which is why they cannot be classified into a single step of neuroprotection.
