**2. Repurposed drugs in neurological diseases**

Prior to development of repurposed drugs for neurological diseases therapeutics, it is emphasized how the drug reposition process is carried out. Generally, there are three stages in drug repurposing. First, diverse approaches including serendipitous clinical observation, cellular drug activity assays, in silico drug screens, and data mining of clinical drug interaction are employed to obtain drug candidates [16]. The detailed illustrations in grounds of methodologies are summarized as mentioned above [17]. Second, preclinical investigations including in vivo rodent models and in vitro cell lines for these drugs are conducted in neurological diseases [18]. Finally, large-scale and multicenter clinical trials are implemented for evaluating efficacy and safety of repurposed drugs [19]. Up to date, there are plenty of drugs which are repurposed in neurological diseases through the above approaches. Then, in the following section, we also cite several repurposed drugs to elaborate how they function in neurological diseases. **Table 1** summarizes various repurposed drugs in the treatment of neurological disorders.

#### **2.1 Verapamil**

Verapamil, a classical calcium channel blocker, is mainly used in the treatment of hypertension, angina pectoris, arrhythmia, and other diseases, especially for paroxysmal supraventricular tachycardia [20]. It has been found that administration of verapamil greatly improves seizure control in drug-resistant epileptic patients via inhibiting P-glycoprotein (Pgp). Pgp is responsible for the transport of antiepileptic drug (AED) into the blood vessels through the blood–brain barrier (BBB). And there is evidence supporting that overexpression of Pgp in the brain represents a major mechanism underlying drug resistance in epileptic patients [21]. Verapamil is found to suppress Pgp expression and subsequently facilitates the entry of this

**81**

**Name of drug**

Verapamil

**Original indication**

Hypertension Angina pectoris

Subarachnoid hemorrhage Stroke Resistant depression

Arrhythmia

> Bumetanide

Liver disease Heart failure Stubborn edema

Epilepsy Autism

NKCC1 protein II.

Decreasing neuronal discharge in vitro and in vivo

 Acute and chronic renal failure

Antibacterial

Epilepsy Spinal cord injury

Activated microglia

IL-6, TNF-α TrkB/BDNF PPAR-γ/NF-κB

I.

Reducing seizure duration in rats

 II.Inhibiting inflammatory cytokines and cell death in kainic acid-

Brain inflammation

Neurodegenerative diseases

LKB1/AMPK 5-HT receptors

I. II. I. II. III.

Preventing neuronal necrosis in a pig model of TBI

Penetrating the blood–brain barrier in clinical studies

Reducing mortality within 24 h of admission in patients with TBI

Alleviating headache in patients with angina pectoris

Anticonvulsant effects on photosensitive or induced convulsions

Alleviating epilepsy in patients with Dravet syndrome

induced epilepsy models

Minocycline Fenfluramine

Simple obesity

Epilepsy

Parkinson's disease

Diabetes

Hypertension

Hypertension

Migraine

IL-6

β-adrenergic

Traumatic brain injury

Parkinson's disease

Supraventricular

tachycardia

Prolonged Q-T interval

Thyrotoxicosis

Gastrointestinal stromal

Glioma

Acetylcholinesterase

I. II. in vivo

III.

Preventing neuronal death induced by neurotoxins in vivo

Alleviating glioma progression and glioma-induced neurodegeneration

CGNs, SH-SY5Y

Pheochromocytoma

Alzheimer's disease'

tumor

Non-small-cell lung

cancer

Renal cell carcinoma

Sunitinib

Propranolol

**Novel indication**

Intractable epilepsy

P-glycoprotein II. III.

Showing no adverse effect in patients with stroke

I.Improving anticonvulsant effect of phenobarbital in hypoxic rats

Preventing behavior phenotype in a mouse model of focal ischemia

**Target**

**Summarization of evidence**

I.Improving life quality in drug-resistant epileptic patients

*Drug Repurposing in Neurological Diseases: Opportunities and Challenges*

*DOI: http://dx.doi.org/10.5772/intechopen.93093*


#### *Drug Repurposing in Neurological Diseases: Opportunities and Challenges DOI: http://dx.doi.org/10.5772/intechopen.93093*

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

less toxic CNS targeted drugs.

process.

epilepsy as example, nearly 30% of epileptic patients are unable to obtain seizure control following treatment with marketed drugs [7, 8]. In addition, they have no significant effect on the improvement of cognitive dysfunction in patients with severe epilepsy [9]. Thus, it is essential for investigation of more effective and/or

Drug repurposing, also known as drug reprofiling or drug repositioning, includes the development of new uses and dosage forms for existing drugs or drug candidates. It is regarded as an economic and practical strategy [10]. Drug repurposing avoids the defects of new drug development. Compared to the drug repurposing, development of new drugs consumes much more time and huge investments. It is roughly reported that the cost from basic research for a new drug to clinical trials is 2.6 billion US dollars [11] and it often takes an average of 13–15 years [12]. Although more and more drug candidates are developed, many cases have failed in recent years [13]. Most of new drugs are withdrawn from the market due to unsatisfactory efficacy or intolerable side effects [14, 15]. Therefore, reusing existing drugs, namely, drug repurposing, has attracted great attention, as this approach has the capacity of saving cost and expediting drug development

The purpose of this chapter is to discuss the role of drug repurposing in human diseases especially neurological diseases and summarize repurposing candidates currently in clinical trials for neurological diseases and potential mechanisms as well as preliminary results. Subsequently we also list drug repurposing approaches

Prior to development of repurposed drugs for neurological diseases therapeutics, it is emphasized how the drug reposition process is carried out. Generally, there are three stages in drug repurposing. First, diverse approaches including serendipitous clinical observation, cellular drug activity assays, in silico drug screens, and data mining of clinical drug interaction are employed to obtain drug candidates [16]. The detailed illustrations in grounds of methodologies are summarized as mentioned above [17]. Second, preclinical investigations including in vivo rodent models and in vitro cell lines for these drugs are conducted in neurological diseases [18]. Finally, large-scale and multicenter clinical trials are implemented for evaluating efficacy and safety of repurposed drugs [19]. Up to date, there are plenty of drugs which are repurposed in neurological diseases through the above approaches. Then, in the following section, we also cite several repurposed drugs to elaborate how they function in neurological diseases. **Table 1** summarizes various repurposed

Verapamil, a classical calcium channel blocker, is mainly used in the treatment of hypertension, angina pectoris, arrhythmia, and other diseases, especially for paroxysmal supraventricular tachycardia [20]. It has been found that administration of verapamil greatly improves seizure control in drug-resistant epileptic patients via inhibiting P-glycoprotein (Pgp). Pgp is responsible for the transport of antiepileptic drug (AED) into the blood vessels through the blood–brain barrier (BBB). And there is evidence supporting that overexpression of Pgp in the brain represents a major mechanism underlying drug resistance in epileptic patients [21]. Verapamil is found to suppress Pgp expression and subsequently facilitates the entry of this

and limitations and challenges in the future investigations.

**2. Repurposed drugs in neurological diseases**

drugs in the treatment of neurological disorders.

**80**

**2.1 Verapamil**


**Table 1.** *List of repurposed drugs in neurological disease.*

**83**

*Drug Repurposing in Neurological Diseases: Opportunities and Challenges*

drug into epileptogenic zones. As a marketed drug, verapamil treatment in patients with intractable epilepsy can doubtfully alleviate brain injury caused by repetitive seizures [22]. Actually, in clinical trials, verapamil has previously shown to exhibit great efficacy in intractable depression or mania via inhibiting the function of Pgp [23, 24]. Moreover, it is documented that verapamil has been approved to treat cerebral vasospasm secondary to subarachnoid hemorrhage due to its vasodilatory effects [25]. Intra-arterial (IA) treatment with verapamil, which was physiologically feasible, safe, and neuroprotective as a therapeutic adjunct in stroke, significantly reduces infarct volume and improved functional outcome [26], although there are

As a potent diuretic agent, bumetanide, which is mainly employed to cure liver disease, heart failure, and various kinds of stubborn edema in clinic [27], is a spe-

Minocycline is the second generation of semisynthetic broad-spectrum antibacterial tetracycline analogues. It has immunomodulatory, anti-inflammatory, and anti-apoptosis effects. Minocycline has neuroprotective effects in rodent models of ischemia, spinal cord injury, and infection [37]. It can efficiently penetrate the BBB and has a good effect on activated microglia, which indicates a possible role in the treatment of epilepsy. Minocycline may have synergistic effects with other compounds in manipulating epilepsy. Minocycline has been found to remarkably obviate epileptic conditions and reduce seizure-induced brain impairment at early stage [38]. In addition, minocycline also inhibits pro-inflammatory cytokines through caspase-dependent and caspase-independent pathways, thus inhibiting cell death in kainic acid-induced status epilepticus [39]. An obvious improvement of seizure phenotype is also observed in a rat model of amygdala kindling [40]. Additionally,

NKCC1 significantly modulates the content of intracellular Cl<sup>−</sup>. Upregulation of NKCC1 leads to elevation of intracellular concentration of Cl<sup>−</sup>, which is associated with pathogenesis of neurological diseases. It has been unequivocally proven that many of the available drugs have anti-seizure potential via activating GABAAmediated hyperpolarization due to accumulation of neuronal Cl<sup>−</sup> [29]. Indeed, current investigations have confirmed that bumetanide exerts antiepileptic effect via switching the GABA-mediated inhibitory postsynaptic potential in neurons from depolarization to hyperpolarization, resulting in decreased neuronal discharge [30, 31]. In addition, previous work reinforces that bumetanide can enhance the anticonvulsant effect of phenobarbital in hypoxic rats [32]. It suggests that the combination of phenobarbital and bumetanide may provide a promising therapeutic strategy for ceasing seizures in neonatal epilepsy and may increase the neuroprotective effect of hypothermia on asphyxiated newborns [33]. Persuasively, a current clinically pilot study further demonstrated that bumetanide, as a specific NKCC1 antagonist, considerably reduced seizure frequency in adult patients with temporal lobe epilepsy [34]. Additionally, as a consequence of a randomized controlled trial, bumetanide may also be effective for treatment of autism [35]. It should be considered that there are two obstacles for bumetanide treatment in neurological disorders [31, 36]. It has been shown that the highly potent diuretic effect of bumetanide can lead to hypokalemic alkalosis and the poor penetration into brain exists. This indicates that reuse of bumetanide in neurological diseases


*DOI: http://dx.doi.org/10.5772/intechopen.93093*

still some mysteries about the mechanism.


brings about opportunities and challenges in the future.

**2.2 Bumetanide**

cific inhibitor of Na<sup>+</sup>

**2.3 Minocycline**

#### *Drug Repurposing in Neurological Diseases: Opportunities and Challenges DOI: http://dx.doi.org/10.5772/intechopen.93093*

drug into epileptogenic zones. As a marketed drug, verapamil treatment in patients with intractable epilepsy can doubtfully alleviate brain injury caused by repetitive seizures [22]. Actually, in clinical trials, verapamil has previously shown to exhibit great efficacy in intractable depression or mania via inhibiting the function of Pgp [23, 24]. Moreover, it is documented that verapamil has been approved to treat cerebral vasospasm secondary to subarachnoid hemorrhage due to its vasodilatory effects [25]. Intra-arterial (IA) treatment with verapamil, which was physiologically feasible, safe, and neuroprotective as a therapeutic adjunct in stroke, significantly reduces infarct volume and improved functional outcome [26], although there are still some mysteries about the mechanism.
