Pharmacological Agents in Post Stroke Recovery

Journal of Neurology & Stroke

Abstract Review Article Stroke is the second commonest cause of death and disability in the world. In Volume 1 Issue 6 - 2014 pathogenesis of stroke, there is unfortunately limited number of agents available in spite of the Amazonian advances in understanding of the pathophysiology and MV Padma Srivastava1, Ashu Bhasin1, novel therapies to target restoration of the damaged brain and not merely protect Tanu Talwar1 and Majaz Moonis2* orthe treat armamentarium in the acute phaseto fight of stroke. the disease. There Byis thereforedeveloping a compellinginterventions need which to develop can be 1Department of Neurology, AIIMS, India administered several days or weeks after the onset of stroke, which can essentially 2Department of Neurology, UMass Memorial medical remodel the intact brain so as to compensate for the infarction, many more patients Centre Worcester, USA can be treated and brought back to their previous level of integration into the society as useful members. A variety of therapeutic approaches that could be considered *Corresponding author: Neuroprotective and Neurorestorative are currently in preclinical and clinical trials of Neurology, UMass Memorial Medical Centre Worcester, Massachusetts,Majaz USA, Tel:Moonis, 5087132183; Department after stroke. There are essentially two varieties of restorative approaches. One is cell- Email: based and includes stem cell transplantation with and without augmentation with growth factor and other variety is the pharmacological approach. Since the current Received: August 12, 2014 | Published: November 21, review deals only with the later, we will deliberate on the several strategies currently 2014

human chorionic gonadotropin, growth factors, and agents that increase cyclic GMP. Recentbeing explored published under literature this banner was searched which include using statins, PubMed erythropoietin and Google for and the analogs, article reporting on Pharmacological approaches in Post stroke recovery.

Keywords Stroke; Neurorestoration; Pharmacological agents

Abbreviations The non regenerating capacity of an injured adult brain has been challenged in the recent past and neural plasticity has been BDNF: Brain Derived Neuro Trophic Factor; HGF: Hepatocyte documented in both global and focal models of animal ischemia Growth Factor; NMDA: N-Methyl- -Aspartate; SVZ: Sub [1] the prospects of repairing an injured nervous system using Ventricular Zone; DTI: Diffusion Tensor Imaging; DRS: Disability d putative restorative therapies seem promising. Numerous pharmacological agents are under investigation RatingIntroduction Scale; MBI: Modified Barthel Index The injury, repair and recovery after stroke have been derived neuro trophic factor [2] (BDNF), hepatocyte growth factorsince a [3] decade (HGF), which granulocyte reflects developmentalmacrophage colony processes. stimulating Brain factor (FM-CSF) [4,5] and other agents such as minocycline has extensively defined. The first epoch is related to acute injury and secondtakes place epoch in is the related first initialto repair, hours which after starts stroke days when after changes stroke preclinical and clinical studies. in blood flow, edema, metabolism rate and diaschisis occurs. A proved to be efficacious in restoring neuro-functional benefits in and lasts for several weeks and is referred to as endogenous Phosphodiesterase 5 inhibitors, statins and agents that repair suggesting a golden period for initiating restorative increase high density lipoproteins and hormones that pioneered therapies. A third epoch occurs weeks to months after stroke the use of thymosin beta 4 and carbamylated erythropoietin when spontaneous recovery gains have plateaued and this for the treatment of stroke and neural injury have been in use representsThe neuro a stable embryology but modifiable of human early lifeand islate governed chronic phase. by the the use of multifactor restorative agent cerebrolysin for stroke principle of ontogeny repeats phylogeny i.e., the injured cerebral therapy.extensively. Chopp et al. [6] published literature recently on tissue reverts to a quasi developmental state, where angiogenesis Pathophysiology of ischemic stroke [7] brain remodeling. These processes remodel the brain and lead toand an synaptogenesis improved neurological are evident function which express throughout proteins the learningthat aid processes of human life. The degree and duration of impaired blood flow determines killsthe extent uniquely and patternvulnerable of cerebrovascular neurons such as damage. pyramidal Ischemia neurons causes in loss of membrane potentials leading to anoxic depolarization and restoration possible and eventual return to normalcy of function. The ultimate aim of any therapeutic strategy is maximum the CA1 and CA4 zones of the hippocampus while sparing other neurons and glial cells. Deprivation of oxygen supply to the brain Submit Manuscript | http://medcraveonline.com J Neurol Stroke 2014, 1(6): 00040 Copyright: Pharmacological Agents in Post Stroke Recovery 2/6  2014 Padma Srivastava et al.

tissue leads to activation of the ischemic cascade with a series Tetracycline derivatives: Minocycline: Minocycline is the of molecular mechanisms being activated. There is depletion of second generation tetracycline derivative known to have anti- adenosine triphosphate and consequent high levels of lactate and unbuffered hydrogen ions. Recent studies have shown that minocycline prevents microglial inflammatory effects independent of its antimicrobial action. Failure of energy dependent mechanisms lead to deterioration models of global and transient focal cerebral ischemia and other of membrane ion gradients, opening of selective ion channels brainactivation, injuries and [10]. also The has proposed notable beneficial mechanisms effects of minocycline in animal Thus potassium ions leave the cell, sodium, chlorine and calcium and equilibration of most intracellular and extracellular ions. include anti-inflammatory effects, reduction of microglial Padmaactivation, et al. MMP [12] reduction, studied the nitric effects oxide of oral production Minocycline and inhibition(200 mg/ intracellularenter and many entry of excitatory calcium is neurotransmitters made largely possible (glutamate, by the dayof apoptotic for 5 days) cell death post stroke[11]. In versus a randomized placebo. single Out ofblinded 50 patients study, activationaspartate) ofare two released types of in receptors, potentially Voltage toxic concentrations.gated (L-type) and/ The included in the trial, patients who received minocycline had or several N-methyl- -aspartate (NMDA) and quisqualate (Q)

d that prevent white blood cells from adhering to vessel walls, significant improvement in stroke outcome as noted on NIHSS, post synaptic receptor/channel complexes by glutamate. Agents limit formation of free radicals, or promote neuronal repair may mBI and mRS scores. Larger trials are needed to confirm the protect the brain from additional injury during reperfusion. Agentsabove findings. for Neurorestoration Neuroprotective agents that work primarily during reperfusion may have a longer window of therapeutic effect than drugs that Augmentation of nitric oxide cascade work earlier in the ischemic cascade. endothelial cell integrity, as well as participating in hemodynamic Agents for neuroprotection homeostasisNitric Oxide [13]. is anNO integral is produced molecule by a involved variety of with cells, maintaining including NMDA receptor modulation [8]: The most commonly vascular smooth muscle cells and neurons suggesting its role in studied neuroprotective agents for acute stroke which block N-methyl- hasneurogenesis been reported by an thatincreased treatment expression with NO of neuronal24 hours NO post synthase stroke d-aspartate (NMDA) receptors. Dextromethorphan, inwithin rat the models sub ventricular augmented zone neurogenesis (SVZ) during and embryogenesis. improvement inIt triala noncompetitive using GV150526 NMDA with antagonist1367 patients was completed the first in NMDA 2000. functional outcome despite no change in infarct volume. NO is also Althoughantagonist the studied drug in was human reported stroke to patients be safe with and a well large tolerated, efficacy a potent activator of soluble guanylate cyclase, which converts no improvement was observed in any of the 3-month outcome GTP to cGMP [14]. Delivery of NO donor increases cGMP levels measures. Magnesium is another agent with actions on the NMDA in both ischemic and non-ischemic rats, suggesting a putative role of NO in neuro-angiogenesis and a downstream mediator of cGMP whose action is increased by inhibiting Phosphodiesterase thewhich NMDA reduce receptor ischemic with injury Magnesium by increasing Phase III regional (FAST-MAG) blood flow,Trial currentlyantagonizing under voltage-sensitive run. calcium channels and blocking mediator cGMP without affecting NO levels may be preferred 5 (PDE5) enzyme. The strategy of increasing the downstream Non NMDA receptor modulation: following alterations in NO levels. A major PDE5 inhibitor is due to the mixed outcomes in stroke reported in animal models by increasing activity of inhibitory Clomethiazole, pathways. In a g-amino Europe, butyric acid agonist, decreases excitatory neurotransmission recovery.sildenafil. Phase Animals I trials treated in humans with sildenafil with acute post stroke stroke are currently achieved have been used for anticonvulsant and sedative effects. The significant and substantial increase in neurological functional clomethiazole’s central nervous system inhibitory properties on going. An improved cerebral blood flow (CBF), neurogenesis [15]. potential efficacy of Clomethiazole as a neuroprotective agent Studiesand synaptogenesis have reported following the improvements experimental in functional stroke, even outcomes when in ischemia was first investigated in Europe as part of the occurredtherapy is despite with Sildenafil no change up in toinfract 1 caged volume, animal nevertheless is delayed these Clomethiazole Acute Stroke Study. Patients received a 24-h IV onset. Nalmefene (Convene) is a narcotic receptor antagonist functional improvement will need to be demonstrated in clinical infusion of Clomethiazole or placebo within 12 h of symptom trials. Functional MRI or diffusion tensor imaging (DTI) may assist to cellular injury in early ischemia. Post hoc analyses of early in answering these questions which demonstrate improvements that reduces levels of excitatory neurotransmitters contributing younger than 70 years. However, a later clinical trial in which the as bio surrogate markers. Other agents such as statins, also studies suggest that the drug may have more benefit in patients drug was administered intravenously (IV) within 6 h of symptom greatlyin structure, enhance organization neurological and recovery functional post connectivity stroke. Drugs via actingwhich increase high density lipoproteins (HDL) such as slow release niacin have also been employed to treat stroke and have shown mayonset block showed sodium no benefit.channels The in cells. exact In mechanism addition, it ofmay action reduce of lubeluzole, a drug effective in animal models, is unclear. The drug after stroke. Other Neurorestorative agents under investigation activation of the NMDA receptors. Free radical agents like NXY- aresubstantial erythropoietin neurological (EPO), benefit carbamylated when treatment EPO is initiated (CEPO) days and 059the are release under of investigation nitric oxide, in a Stroke neurotransmitter trials [9]. generated by Thymosin B4.

Citation: Padma Srivastava MV, Bhasin A, Talwar T, Moonis M (2014) Pharmacological Agents in Post Stroke Recovery. J Neurol Stroke 1(6): 00040. DOI: 10.15406/jnsk.2014.01.00040 Copyright: Pharmacological Agents in Post Stroke Recovery 3/6  2014 Padma Srivastava et al.

Current physical rehabilitation therapies could be enhanced using pharmacological approach thereby helping to re establish lost neuronal connections. It has been elegantly established by andtone functional(modified Ashworth), MRI including Fugl DTIMeyer was (FM) performed scale for atupper baseline, limb, Clarkson et al. [16] that inhibiting tonic GABA (gamma amino 8Edinburgh and 24 weekshandedness of stem inventory, cell infusion. modified Patients Barthel were Index screened (mBI) butyric acid) signaling days improves locomotors function and educated about stem cells and bone marrow aspiration after stroke, suggesting that therapeutic approaches are less technique prior to stem cell infusion [23]. Forty stroke patients time sensitive than acute reperfusion therapies. P13k/Act and were recruited with the above inclusion criteria. Twenty were sonic hedgehog (Shh) pathways are activated by molecular given stem cells followed by 8 weeks of physiotherapy, serving as and signal transduction genes which promote brain plasticity. Various pharmacological agents by means of signal transduction physiotherapy regime alone. 50 -60 million cells in 250 ml of pathways can induce CNS plasticity that enhances functional salineexperimental/stem was infused cell intravenously group and 20 over patients 2-3 hours. were administered The baseline recovery from stroke and neural injury.

Neurotrophic agents and growth factors wasclinical normal and radiologicalwith no mortality scores or between cell related the experimentaladverse reactions and control groups were statistically insignificant. The safety profile In vitro, basic FGF chimeric peptideBasic was fibroblast highly growth effective factor in reducing (FGF) was infarct shown volume to protect in a in stem cell patients. On comparison between experimental and rodentagainst modelexcitatory of permanentamino acid focaltoxicity ischemia [17]. FGF has been control groups, mBI was statistically significant on follow up at investigated in phase II/III trials. The results of the Clinical 24 weeks (p = 0.05). Laterality Index (LI) of BA 4 and BA 6 was Safety Trial of Intravenous Basic Fibroblast Growth Factor in increasedinsignificant number at 8 and of 24 cluster weeks activation follow up, in as Brodmann also in the areasFA ratio, BA Acute Stroke did not report any serious adverse events [18]. The 4,fiber BA length 6 was andobserved fiber number post stem ratio cell between infusion the indicating two groups. neural An plasticity. The study was conclusive for safety and feasibility of intravenous autologous stem cell infusion [24,25]. Stem cells may noted,European-Australian although there phasewas a II/IItrend safety towards and treatment efficacy trialsadvantage were act as “scaffolds” for neural transplantation and may aid in repair [19].terminated in the middle as no significant improvement was mechanism [26]. Recombinant erythropoietin (Epo) was reported to be safe Enhancing recovery with special reference to walking and aphasia after stroke study (522 patients) was negative and showed a higher death Motor weakness and the inability to walk have been the rateand efficacious and complications in a proof-of-concept in patients study receiving [20]. Epo; A phase possible II/III primary targets for testing interventions that may improve after interaction with rTPA was cited as a likely cause of increased stroke. Physical therapeutic interventions enhance recovery after mortality [21]. Intravenous granulocyte colony stimulating factor stroke; however, the timing, duration and type of intervention (G-CSF) has also been investigated in a dose escalation phase II a study [22] (AXIS: 44 subjects, drug administered within 12 particular with dopaminergic and selective serotonin-reuptake hours). The authors reported good tolerability and suggest inhibitors,require clarification shows promise and further in enhancing trials. motor Pharmacotherapy, recovery after in further investigation. stroke; however, further large scale trials are required [27]. Cerebrolysin, a peptide-based rug is another candidate with potential for approval to be used as a restorative agent. Multiple sensory, visual, perceptual and cognitive inputs [28]. Many varied strategiesThe complex and techniques activity of are walking undergoing requires assessment the integration including of pharmacological therapy for aphasia, transcranial magnetic anotherlaboratories potential have agent demonstrated used as a the restorative safety and agent, efficacy which of thisis a stimulation for motor recovery and cognitive rehabilitation for peptide-baseddrug in the treatment rug used of in experimental multiple laboratories stroke. Cerebrolysin, studying its is these techniques may be symbiotic and synergistic. Much of the drug induces neurogenesis and angiogenesis in animal models of researchattention in deficits the area [29]. of Itstroke is possible has focused that when on recoveryused in combination of walking. strokesafety andand efficacyconcomitantly in the treatmentenhances brainof experimental plasticity and stroke. recovery This Walking is a basic human function, often affected by stroke, more from stroke. easily observed, more easily measured and potentially more Clinical trials on autologous bone marrow derived stem cells therapy in chronic stroke loss of power in lower limb, walking also relies on the integrity easily rehabilitated than other functional deficits [30]. Besides walking movements. of the trunk for balance, and the upper extremity for associated This unblinded, non randomized case control study dealt with Currently the only pharmacological agent that has been cellsthe safety in stroke and efficacy [17]. Adult of intravenous patients wereautologous recruited bone with marrow the shown to alter the natural history and recovery after stroke is inclusionderived mononuclear criteria as: 3 and months culture to 2expanded years after mesenchymal stroke, power stem of tissue plasminogen activator given within 4.5 hours after stroke hand muscles of at least 2; Brunnstrom stage 2-5; NIHSS of 4-15, onset. However, a novel era in pharmacotherapeutics for stroke conscious and cooperative with assessments done for strength,

recovery may be in the horizon. Another study [31] randomized Citation: Padma Srivastava MV, Bhasin A, Talwar T, Moonis M (2014) Pharmacological Agents in Post Stroke Recovery. J Neurol Stroke 1(6): 00040. DOI: 10.15406/jnsk.2014.01.00040 Copyright: Pharmacological Agents in Post Stroke Recovery 4/6  2014 Padma Srivastava et al.

patients of severe traumatic brain injury (4-16 weeks) to amantadine (for 4 weeks), or placebo and then assessed at 6 weeks. It was observed that Amantadine, a dopamine agonist impairment and depression; more large randomized trials are increased the speed of recovery during the active treatment Amphetaminesneeded to derive definitive and motor conclusions rehabilitation [42]. phase. Disability Rating Scale (DRS) between baseline and at 6 Amphetamines are potent CNS stimulators of phenethylamine weeks was similar in both groups, a post hoc analysis at the end of 4 weeks showed that more patients on amantadine had an neurotransmitter. Robust animal and human literature suggest improvement in their Disability Rating Scale scores. thatclass amphetamines which increase coupled biogenic with physiotherapy amines acting aid as in functional excitatory recovery via modulation of noradrenergic system. Brain is Dopaminergic agents and selective serotonin-reuptake inhibitors (SSRIs) are known in the in altering the natural history credence through various reports. Changes in catecholaminergic, of recovery after stroke [32]. Dopamine is a neurotransmitter particularlymalleable to nor external epinephrine, and internalfunctioning inputs, after brain which injury has beenhave been correlated with changes in the rate of recovery after injury schemas in brain, via memory and learning principles [33,34] A singlethat may oral promote dose of neuroplasticity100 mg of levodopa in the andcerebral 25 mg cortex of carbidopa through day of treatment initiated 10 days after cortical infarct facilitated can enhance the ability of patients with chronic stroke to the[43]. rate Another of recovery trial reported (AMPH that 68%) a single compared dose of AMPH to saline given (27%) first encode an elementary motor function. Scheidtmann et al. [35] treated animals. The cochraine review [44] of amphetamines off late has suggested that 10 trials with 106 stroke patients either 3 weeks of 100 mg of levodopa with carbidopa or placebo randomized patients (3 weeks and 6 months post stroke) to underwent AMPH therapy and it was found that AM [PH did not in motor recovery and independent ambulation. Subsequent 0.6 to 3.3). Other 6 studies suggested that there was an evidence smalldaily. studiesPatients using receiving levodopa levodopa with hador without significant methylphenidate improvement ofprove a better to be relativebeneficial change in reducing from baselinemortality to (Pero follow OR up1.5, in 95% motor CI- [36] or levodopa with or without amphetamine [37] could function (WMD- 6.1 points, 95% CI -10.4 to -1.9). Schuster et al not show a difference in motor recovery or improvement in 2011 have recently reported increased performance in ADL and functional outcomes with treatment. An ongoing study which arm function in 8 patients who were administered with 10 mg of commenced in 2010, has enrolled 572 patients are to receive 100 AMPH per day [45]. mg of levodopa and 25 mg of carbidopa, or placebo, 1 hour before physiotherapy. The primary outcome will assess the number of Neurorestorative Therapy using Pharmacotherapy: Is there a Hope? patientsAnimal walking studies independently suggest that at 8 SSRIsweeks mayafter berandomization. involved in Is pharmacological restorative therapy post stroke merely a neurogenesis and activation of cortical motor areas modulating chimera? A perusal of clinical trials of neurorestorative agents neuronal plasticity [38]. These drugs are essential in maintaining sleep rhythm, and neurotransmitters levels within the brain and have been tried in stroke rehabilitation trials. A single dose of hascertainly it not been seems replicated depressing in clinical at first domains? glance. Nevertheless, if experimental evidence of neurorestoration is definite, why then Translating restorative agents from bench to bed has to be measured by transmagnetic stimulation. Patients more than 6 citalopram can normalize the balance in cortical excitability, as performed with caution and care, as the failure is evidenced from clinical trials on several previous occasions. For eg; erythropoietin months after stroke, in a single dose cross over experiment with clinical studies for the treatment of stroke, and appeared to patients,citalopram, 2 to showed 3 weeks improvement after stroke showedin hand dexterityimproved as motor measured skills be(EPO) a strong demonstrated candidate in potent for translational therapeutic research. benefits inThe multiple phase onby the none-holenine-hole peg peg test test, [39]. and increasedA single dose activation of fluoxetine of the affectedgiven to III clinical trial was terminated because of high mortality and side on functional resonance imaging [40]. adverse events. Of the stroke patients in the reported trial, 63.4% were administered rTPA, EPO was not tested in the laboratory patients (5-10 days of event) into two arms: one group was in conjunction with rTPA. Another subsequent study clearly Chollet et al. [41] randomized 118 acute ischemic stroke demonstrated adverse events in animals when treated with group placebo. Patients were assessed using the Fugl-Meyer combination of EPO with rTPA which was observed in the clinical motoradministered scale (motor with fluoxetine score varies (20 frommg/day 0 to by 100, mouth) 66 points and another upper trial. limb, 34 points lower limb; movements measured as none, partial or full) at the end of three months (90 days). The mean Criticisms of animal studies include the following improvement in the total Fugl-Meyer motor scale and functional

variations,1) Small 5) sampleConfounding size variables (underpowered), (hypothermia, 2) Lack use of independence measure from baseline to 90 days was significantly anestheticrandomization, agents), 3) 6) Variable Lack of injuryevaluation levels, of the 4) dose-response Inter-species patientshigher in treatedthose patients with an treated SSRI compared with fluoxetine. to usual A carerecent or meta- sham analysis of randomized controlled trials that recruited stroke outcome measures or biomarker end-points and 8) Flawed an improvement in functionality, disability status, neurological statisticalrelationship analysis. and side-effects On the (therapeutic basis of these index), observations, 7) Inadequate the identified 52 trials for analysis. The use of SSRIs is associated with

Stroke Therapy Academic Industry Roundtable (STAIR) recommendations were developed for providing a stronger 11. dose-findingMurata Y, Rosell study. A, StrokeScannevin 41(10): RH, 2283-2287. Rhodes KJ, Wang X, et al. (2008) preclinical database for potential therapeutic agents.

Biomarkers of Restorative Therapy Induced Stroke Extension of the thrombolytic time window with minocycline in Recovery 12. experimental stroke. Stroke 39(12): 3372-3377. of minocycline in acute ischemic stroke: A single-blinded, placebo- A biomarker is an indicator of disease state that is useful controlledPadma MV, trial. Bhasin Neurol A, Bhatia India R, 60(1): Garg A,23-28. Gaikwad S, et al. (2012) Efficacy 13. molecule. Annu Rev Biochem 63: 175-195. [46].clinically A relevant as a biomarker substitute for measure, stroke recovery reflecting is the underlying one that Bredt DS, Snyder SH (1994) Nitric Oxide: A physiologic messenger molecular/cellular events that are difficult to measure directly 14. with behavioral state. Neurorestoration is a concept that has NaturePalmer 327(6122):RM, Ferrige 524-AG, Mocada 526. S (1987) Nitric oxide release accounts reflects a brain event relates to recovery and that correlates for the biological activity of endothelium-derived relaxing factor. stroke. The lack of proof in clinical settings will continue to be 15. Zhang RL, Zhang Z, Zhang L, Wang Y, Zhang C, et al. (2006) Delayed discouragingbeen proven until emphatically the reasons in several for failure experimental in this endeavor models are of functional recovery in aged rats after focal cerebral ischemia. J Neuroscitreatment Res with 83(7): sildenafil 1213-1219. enhances neurogenesis and improves examined. The trials of the past cannot be termed as failures 16. Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST (2010) anas theyimpetus definitely for the have development contributed of superior to our understanding candidate molecules of the complex biology of brain injury. This knowledge must provide functional recovery after stroke. Nature 468(7321): 305-309. and methodological interventions that will enhance drug Reducing excessive GABA-mediated tonic inhibition promotes development as well as clinical testing. 17.

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Citation: Padma Srivastava MV, Bhasin A, Talwar T, Moonis M (2014) Pharmacological Agents in Post Stroke Recovery. J Neurol Stroke 1(6): 00040. DOI: 10.15406/jnsk.2014.01.00040