**2.3 Minocycline**

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,

increasing studies have reported the neuroprotective effects of minocycline in neurologic diseases, such as ischemic stroke, multiple sclerosis (MS), and traumatic brain injury (TBI) [41–43]. In in vivo animal model, minocycline promotes M2 microglia polarization via activation of tyrosine kinase receptor B (TrkB)/ brain-derived neurotrophic factors (BDNF) pathway and facilitates neurogenesis after intracerebral hemorrhage (ICH) [44]. In the process of acute cerebral infarct, minocycline also effectively inhibits oxidative stress via elevating the activity of superoxide dismutase (SOD) and activating the liver kinase B1 (LKB1)/adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway [45]. However, repurposing of minocycline in treating neurological diseases requires to be re-evaluated as there is a clinical study showing serious neurodegeneration TBI [46].

#### **2.4 Fenfluramine**

Fenfluramine, which has been successfully applied in obesity, diabetes, and hypertension [47], is a potent 5-hydroxytryptamine (5-HT) releaser activating multiple 5-HT receptor subtypes. Of note, elevation of extracellular 5-HT levels inhibits focal and generalized seizures, while depletion of 5-HT lowers the threshold of epileptic seizures [48]. Therefore, 5-HT agonist fenfluramine is assessed for treatment of epilepsy. In a small-scale retrospective study, it has reported that adjuvant treatment with fenfluramine has evidently obtained seizure control in patients with Dravet syndrome. As the side effects is not serious, it does not lead to the termination of treatment [49]. This drug may have anticonvulsant effects on other severe epilepsy syndromes, especially those characterized by photosensitive or induced convulsions [50, 51]. Encouragingly, a recent investigation has unveiled that fenfluramine significantly reduces convulsive seizure frequency compared with placebo and exhibits good tolerance [52]. It indicates that fenfluramine could be functioned as a potent novel therapeutic regime for patients with Dravet syndrome. It is noteworthy that fenfluramine also alleviates L-DOPA-induced dyskinesia via stimulation of 5-HT1A receptor in PD [53].

## **2.5 Propranolol**

Propranolol as a β-adrenoceptor antagonist (b-blocker) has been commonly used in hypertension, supraventricular tachycardia, prolonged Q-T interval, and thyrotoxicosis in clinic [54]. Since 1996, in patients who were being treated for angina pectoris, Rabkin et al. has disclosed the therapeutic effect of propranolol on migraine headache [55]. Meanwhile, further clinical studies have noted that administration of propranolol within 24 h of admission after TBI triggers lower mortality [56]. The evidence also arises from a recent study that propranolol blocks the upregulation of IL-6 and prevents neuronal cell necrosis in CA1 and CA3 hippocampus in a pig model of TBI [57]. Given that propranolol has neuroprotective potential in neuropathological conditions, it is likely to serve as a neuroprotective drug in epilepsy. Additionally, both clinical and experimental studies have demonstrated the potential of propranolol to resist dyskinesia in PD, as modulation of β-adrenergic receptors (βAR), which is abundantly, expressed in striatum, is involved L-DOPAinduced dyskinesia (LID) [58, 59].

#### **2.6 Sunitinib**

Sunitinib, which is an oral, small molecule receptor tyrosine kinase inhibitor approved by the US Food and Drug Administration, has been currently implemented in the treatment of various cancers such as gastrointestinal stromal tumor

**85**

*Drug Repurposing in Neurological Diseases: Opportunities and Challenges*

with low potassium or 1-methyl-4-phenylpyridinium ion (MPP+

further deserved to identify the most suitable dosage in clinic.

(GIST), non-small-cell lung cancer, and renal cell carcinoma [60]. Clinical evidence has revealed that oral administration of sunitinib penetrates the BBB and subsequently facilitates the entry into central nervous system [61]. Furthermore, on the basis of its potent antiangiogenic and antitumoral characteristics, it has discovered that sunitinib can alleviate glioma-induced neurodegeneration and glioma progression in vivo models [60]. Meanwhile, sunitinib has been found to exert therapeutic effects on learning and memory deficits in a mouse model of AD through inhibition of acetylcholinesterase (AChE) [62]. Additionally, sunitinib has also demonstrated to prevent neuronal death induced by neurotoxins via inhibiting NO overproduction in cerebellar granule neurons (CGNs) and SH-SY5Y cells following exposure

apoptosis [63]. It indicates that sunitinib may improve brain dysfunction via inhibi-

In in vitro studies, angiotensin receptor blockers (ARBs) are generally known to treat essential hypertension by influencing the level of angiotensin II (Ang II) via two distinct pathways, namely, through interrupting the AT1 receptor and augmentation of Ang II processing which plays a critical role in cognition regulation [64]. For example, valsartan, which has previously been found to penetrate BBB and elicit antihypertensive responses in the brain, has been demonstrated to reduce Aβ accumulation and aggregation in vivo and in vitro [65]. Actually, similar situation exists in losartan and telmisartan, which are also classical ARBs [66, 67]. Overall, it indicates ARBs are potential candidates for treating AD. Significantly, several clinically epidemiological studies and RCTs certify the efficacy of ARBs in AD. A large-scale retrospective cohort study has revealed an obvious reduction of dementia in patients treated with ARBs compared with other cardiovascular agents [68]. Likewise, the further UK-based study also reports a similar trend, with a 50% reduction in AD after ARBs treatment [69]. In brief, ARBs, the conventional cardiovascular medicine, have been confirmed to exert a vital effect in AD, and it is

Amantadine is a classic antiviral compound which has been found to moderately ameliorate impaired motor behavior in Parkinson's disease [70]. Intriguingly, in 1969, it was coincident that Schwab et al. found an improvement of motor symptoms in a female PD patient, who took 200 mg amantadine daily for antiviral prophylaxis [71]. Subsequently, three potential mechanisms have been proposed to explain the efficacy of amantadine in PD. Several preclinical data demonstrate an activation of the dopamine system's both presynaptic and postsynaptic actions [72], and amantadine also inhibits the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors [72, 73]. The mild anticholinergic effect is also involved [74]. Surprisingly, PD is well known to be frequently associated with depression, and antagonism of NMDA receptors is also a promising target for new antidepressants, although there is no definite evidence to certify its efficacy in depressive disorder.

There are three important stages in the field of drug repurposing: generation of candidate compounds, preclinical investigation, and clinical trial. Determination

)-induced neuronal

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

tion of oxidative stress.

**2.8 Amantadine**

**3. Approaches to drug repurposing**

**2.7 Angiotensin receptor blockers**

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

(GIST), non-small-cell lung cancer, and renal cell carcinoma [60]. Clinical evidence has revealed that oral administration of sunitinib penetrates the BBB and subsequently facilitates the entry into central nervous system [61]. Furthermore, on the basis of its potent antiangiogenic and antitumoral characteristics, it has discovered that sunitinib can alleviate glioma-induced neurodegeneration and glioma progression in vivo models [60]. Meanwhile, sunitinib has been found to exert therapeutic effects on learning and memory deficits in a mouse model of AD through inhibition of acetylcholinesterase (AChE) [62]. Additionally, sunitinib has also demonstrated to prevent neuronal death induced by neurotoxins via inhibiting NO overproduction in cerebellar granule neurons (CGNs) and SH-SY5Y cells following exposure with low potassium or 1-methyl-4-phenylpyridinium ion (MPP+ )-induced neuronal apoptosis [63]. It indicates that sunitinib may improve brain dysfunction via inhibition of oxidative stress.

## **2.7 Angiotensin receptor blockers**

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

increasing studies have reported the neuroprotective effects of minocycline in neurologic diseases, such as ischemic stroke, multiple sclerosis (MS), and traumatic brain injury (TBI) [41–43]. In in vivo animal model, minocycline promotes M2 microglia polarization via activation of tyrosine kinase receptor B (TrkB)/ brain-derived neurotrophic factors (BDNF) pathway and facilitates neurogenesis after intracerebral hemorrhage (ICH) [44]. In the process of acute cerebral infarct, minocycline also effectively inhibits oxidative stress via elevating the activity of superoxide dismutase (SOD) and activating the liver kinase B1 (LKB1)/adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway [45]. However, repurposing of minocycline in treating neurological diseases requires to be re-evaluated as there is a clinical study showing serious neurodegeneration TBI [46].

Fenfluramine, which has been successfully applied in obesity, diabetes, and hypertension [47], is a potent 5-hydroxytryptamine (5-HT) releaser activating multiple 5-HT receptor subtypes. Of note, elevation of extracellular 5-HT levels inhibits focal and generalized seizures, while depletion of 5-HT lowers the threshold of epileptic seizures [48]. Therefore, 5-HT agonist fenfluramine is assessed for treatment of epilepsy. In a small-scale retrospective study, it has reported that adjuvant treatment with fenfluramine has evidently obtained seizure control in patients with Dravet syndrome. As the side effects is not serious, it does not lead to the termination of treatment [49]. This drug may have anticonvulsant effects on other severe epilepsy syndromes, especially those characterized by photosensitive or induced convulsions [50, 51]. Encouragingly, a recent investigation has unveiled that fenfluramine significantly reduces convulsive seizure frequency compared with placebo and exhibits good tolerance [52]. It indicates that fenfluramine could be functioned as a potent novel therapeutic regime for patients with Dravet syndrome. It is noteworthy that fenfluramine also alleviates L-DOPA-induced dyskinesia via stimulation

Propranolol as a β-adrenoceptor antagonist (b-blocker) has been commonly used in hypertension, supraventricular tachycardia, prolonged Q-T interval, and thyrotoxicosis in clinic [54]. Since 1996, in patients who were being treated for angina pectoris, Rabkin et al. has disclosed the therapeutic effect of propranolol on migraine headache [55]. Meanwhile, further clinical studies have noted that administration of propranolol within 24 h of admission after TBI triggers lower mortality [56]. The evidence also arises from a recent study that propranolol blocks the upregulation of IL-6 and prevents neuronal cell necrosis in CA1 and CA3 hippocampus in a pig model of TBI [57]. Given that propranolol has neuroprotective potential in neuropathological conditions, it is likely to serve as a neuroprotective drug in epilepsy. Additionally, both clinical and experimental studies have demonstrated the potential of propranolol to resist dyskinesia in PD, as modulation of β-adrenergic receptors (βAR), which is abundantly, expressed in striatum, is involved L-DOPA-

Sunitinib, which is an oral, small molecule receptor tyrosine kinase inhibitor approved by the US Food and Drug Administration, has been currently implemented in the treatment of various cancers such as gastrointestinal stromal tumor

**84**

**2.6 Sunitinib**

**2.4 Fenfluramine**

of 5-HT1A receptor in PD [53].

induced dyskinesia (LID) [58, 59].

**2.5 Propranolol**

In in vitro studies, angiotensin receptor blockers (ARBs) are generally known to treat essential hypertension by influencing the level of angiotensin II (Ang II) via two distinct pathways, namely, through interrupting the AT1 receptor and augmentation of Ang II processing which plays a critical role in cognition regulation [64]. For example, valsartan, which has previously been found to penetrate BBB and elicit antihypertensive responses in the brain, has been demonstrated to reduce Aβ accumulation and aggregation in vivo and in vitro [65]. Actually, similar situation exists in losartan and telmisartan, which are also classical ARBs [66, 67]. Overall, it indicates ARBs are potential candidates for treating AD. Significantly, several clinically epidemiological studies and RCTs certify the efficacy of ARBs in AD. A large-scale retrospective cohort study has revealed an obvious reduction of dementia in patients treated with ARBs compared with other cardiovascular agents [68]. Likewise, the further UK-based study also reports a similar trend, with a 50% reduction in AD after ARBs treatment [69]. In brief, ARBs, the conventional cardiovascular medicine, have been confirmed to exert a vital effect in AD, and it is further deserved to identify the most suitable dosage in clinic.

#### **2.8 Amantadine**

Amantadine is a classic antiviral compound which has been found to moderately ameliorate impaired motor behavior in Parkinson's disease [70]. Intriguingly, in 1969, it was coincident that Schwab et al. found an improvement of motor symptoms in a female PD patient, who took 200 mg amantadine daily for antiviral prophylaxis [71]. Subsequently, three potential mechanisms have been proposed to explain the efficacy of amantadine in PD. Several preclinical data demonstrate an activation of the dopamine system's both presynaptic and postsynaptic actions [72], and amantadine also inhibits the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors [72, 73]. The mild anticholinergic effect is also involved [74]. Surprisingly, PD is well known to be frequently associated with depression, and antagonism of NMDA receptors is also a promising target for new antidepressants, although there is no definite evidence to certify its efficacy in depressive disorder.

## **3. Approaches to drug repurposing**

There are three important stages in the field of drug repurposing: generation of candidate compounds, preclinical investigation, and clinical trial. Determination

of appropriate drugs for potential indications is crucial for production of candidate compounds. At present, two approaches are widely used for drug repurposing including experimental screening approaches and molecular docking by computer. In the following items, we make a detailed description of these two methods in drug repurposing process.

#### **3.1 Experimental approaches**

Experimental screening approaches are usually regarded as the first stage in the process of drug discovery and drug repurposing. Proteomic techniques such as affinity chromatography and mass spectrometry have been widely employed to identify drug candidates [75]. Nowadays, drug target analysis and drug repurposing are inseparable. Drug repurposing is distinct from drug discovery in terms of alteration of drug target. Cellular thermo stability assay technique can predict the affinity of drug ligands by mapping the contact patterns of intracellular targets [76]. The molecular on and off targets have been disclosed for many clinically approved drugs via this method. Especially in the field of kinases, new targets of well-known drugs are obtained through affinity matrices [77, 78]. For example, imatinib, a tyrosine kinase inhibitor, has been successfully reused in the treatment of gastrointestinal stromal tumors [79].

In addition, chemical compounds with disease-related effects can be defined in the model through phenotype screening [80]. Phenotype screening has always been more successful than target screening in the facet of drug development [81, 82]. In the case of drug repurposing, if the compounds selected through phenotypical assays are approved clinical drugs or ongoing clinical trials, they are probable to reuse. Several drugs approved for tobacco dependence have been evaluated, and it has been found that topiramate changes nicotine- or ethanolinduced behavior in zebrafish models [83]. However, there are some challenges that the efficacy of drug candidates in in vitro experiments require to be validated in human diseases [84].

#### **3.2 Computational approaches**

Molecular docking by a computer is also an important method for evaluating drug target binding kinetics and drug residence times of existing drugs or drug candidates [85]. Large amounts of computational drug repositioning methods choose transcriptomic data to identify potential new indications for drugs. Furthermore, these methods have applied techniques such as comparison of gene expression profiles between a disease model and drug-treated condition [86], network integration [87], prediction of drug-protein interactions [88], and utilization of genotype–phenotype associations. Recently, a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation Score/Class (DRPS/C) for Alzheimer's disease occurs on the basis of inverse associations between disease-induced or drug-induced gene and protein perturbation patterns [89]. Briefly, these approaches can be applicable to discovery of drug targets or biomarkers.

It should be considered that for many neurological disorders, drugs require good penetration into BBB. Then, the therapeutic approaches of targeting brain have been classified as invasive and noninvasive categories [90, 91]. The invasive approaches contain the temporary increase of BBB permeability, and noninvasive approaches involve modification of drug molecule via physiological, chemical, or colloidal carrier system approach. Meanwhile, these methods are also related

**87**

post marketing data.

*Drug Repurposing in Neurological Diseases: Opportunities and Challenges*

to computational approaches. Influx clearance into the brain (*K*in), which is the unidirectional influx constant from the blood to brain, can be used to calculate the transport of drugs in the brain. Similar computational approaches conclude the permeability surface area (PS), brain/plasma ratio (*K*p), brain uptake index (BUI), and apparent permeability (*P*app) [92–95]. Consequently, drug repurposing in neurological diseases covers various manners to participate in integrating the role of transporters and pathophysiological complexity of BBB to establish a

Drug repurposing is a vital strategy for developing new therapeutic values of existing drugs or drug candidates due to its ability to save time and reduce cost [96]. This type of innovative concept will undoubtedly expedite the drug development process. Meanwhile, some limitations need to be considered during drug repurposing process in neurological diseases. Owing to complex molecular and cellular signaling mechanisms in neuropathological states, drug repurposing may be difficult. Additionally, drugs not only respond to a single target but also affect multiple targets [97], causing a variety of adverse reactions. A comprehensive assessment of the advantages and disadvantages of these side effects can help us understand drug

In order to overcome limitations faced during drug repurposing, we make proposals in the following descriptions. Firstly, it is foremost to establish a comprehensive data analysis platform to maximize data sharing. Information science services and artificial intelligence can help unlock and reanalyze the large amount of data accumulated by approved drugs or drug candidates to clinical trials. These data may be stored in a diversified way. Storage locations, formats, and types may vary, including different storage locations, formats, and types. The data obtained from clinical trials and biological databases are too large and complex that the traditional data processing methods cannot deal with it, which leads to the bottleneck in the research process [99]. Big data can significantly improve our understanding of the disease and make more accurate disease-related strategies. However, there is a big gap between generating biomedical data and data analysis [99, 100]. To ensure the efficiency of research, it takes time, energy, and expertise to find technical solutions to integrate them. Secondly, it is encouraged to provide more financial support for clinical trials of drug repurposing, including technical support. The preclinical research of drug repurposing requires financial support to obtain the data in clinical trials. In this case, drugs that can be developed to treat rare diseases are more likely to apply in clinical neurological diseases therapeutics [101]. Finally, in order to facilitate drug repurposing process, we advocate it is indispensable to solve patent restrictions and take reasonable supervision. All applications of drug repurposing should be accompanied by a risk management plan. Drug's safety can be supported by clinical trial data or

In conclusion, drug repurposing is a novel approach for expediting drug development process in neurological diseases. Repurposed drugs may provide an efficient avenue for improving a plethora of pathological conditions including neurological disorders. In the future, it is essential to exploit molecular mechanisms during drug repurposing processes due to the possibility that targets of repurposed drugs in neurological diseases are distinct from original targets in treating other

diseases, in order to make these drugs more effective and safe.

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

suitable model for high-throughput screening.

**4. Concluding remarks and perspectives**

repositioning from a more all-round perspective [98, 99].

to computational approaches. Influx clearance into the brain (*K*in), which is the unidirectional influx constant from the blood to brain, can be used to calculate the transport of drugs in the brain. Similar computational approaches conclude the permeability surface area (PS), brain/plasma ratio (*K*p), brain uptake index (BUI), and apparent permeability (*P*app) [92–95]. Consequently, drug repurposing in neurological diseases covers various manners to participate in integrating the role of transporters and pathophysiological complexity of BBB to establish a suitable model for high-throughput screening.
