The Science Of Ischemic Stroke: Pathophysiology .

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International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84ISSN: 2278-6074Review ArticleThe Science of Ischemic Stroke: Pathophysiology & Pharmacological Treatment*Neema KanyalDepartment of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology & Science, PatelNagar, Dehradun 248001, Uttarakhand, India.ABSTRACTOver the past two decades, research has heavily emphasized basic mechanisms that irreversibly damagebrain cells after stroke. Much attention has focused on what makes neurons die easily and what strategiesrender neurons resistant to ischaemic injury. In the past few years, clinical experience with clot-lysingdrugs has confirmed expectations that early reperfusion improves clinical outcome.Although greatadvances have been made in understanding the diverse mechanisms of neuronal cell death induced byischemic stroke, clinically effective neuroprotective therapies are limited.Based on the accumulatingevidence that ischemic cell death is a result of series of subsequent biochemical events, new concepts forprevention and treatment of ischemic stroke may eventually emerge without the hazard of severecomplications.This review focuses on mechanisms and emerging concepts that drive the science ofischemic stroke in a therapeutic direction. Once considered exclusively a disorder of blood vessels,growing evidence has led to the realization that the biological processes underlying stroke are driven bythe interaction of neurons, glia, vascular cells and matrix components, which actively participate inmechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge thatbuild on an appreciation of acute cellular events acting in a broader context of ongoing destructive,protective and reparative processes. This review then poses a number of fundamental questions, theanswers to which may generate a number of treatment strategies and possibly new treatments that couldreduce the impact of this enormous economic and societal burden.Keywords: Apoptosis, excitotoxicity, ischemia, strokeReceived 26 August 2015Received in revised form 14 Sept 2015Accepted 17 Sept 2015*Address for correspondence:Neema Kanyal,Department of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology & Science, PatelNagar, Dehradun 248001, Uttarakhand, roke is the second leading cause of deathworldwide [1-4] and is the major cause ofmorbidity, particularly in the middle agedand elderly population [1,5-6]. Stroke,according to the American Heart Association(AHA) definition, is a sudden loss of brainfunction due to disturbance in the cerebralblood supply with symptoms lasting at least24 hours or leading to death [7]. Stroke isdefined as an acute neurologic dysfunction[8,9] of vascular origin with sudden (withinseconds) or at least rapid (within hours)occurrence of signs and symptoms [10,11].Stroke is the rapid loss of brain function dueto a disturbance in the blood supply to thebrain [12]. Stroke is also the leading cause ofadult long-term disability [3,8,9] andrepresents an enormous burden on society,which is likely to increase in future decadesNeema Kanyal, IJPRR 2015; 4(10)as a result of demographic transitions inpopulations [2]. The ultimate result ofischemic cascade initiated by acute stroke isneuronal death along with an irreversibleloss of neuronal function [9].According to World Health Organizationestimates, in 2002, 5.5 million people died ofstroke in 2002 and roughly 20% of thesedeaths occurred in South Asian Countries(India, Pakistan, Bangladesh, and Sri Lanka)[3]. The incidence and mortality of strokeincrease with age, and as the elderlypopulation is rapidly growing in mostdeveloped countries ischemic stroke is acommon societal burden with substantialeconomic costs [1,13]. According to thereport from the Centers for Disease Controland Prevention, given in 2013 mortalityfrom stroke was the fourth leading cause of65

International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84death in the United States in 2008, andstroke was a leading cause of long-termsevere disability. Therefore, it is importantto know the reason for this social burden sothat safe and effective therapeutic treatmentthat could be given at medical serviceswould improve the outcome of millions ofacute stroke patients [12].The two main types of stroke are ischemicandhemorrhagic,accountingforapproximately 85% and 15%, respectively[4,9,10,12,14,15]. A third type of stroke,called as transient ischemic attack or TIA is aminor stroke that serves as awarning signthat a more serve stroke may occur [16].Ischemic stroke is caused by focal cerebralischemia due to arterial occlusion[1,4,9,10,14] or stenosis [17] whereashemorrhagic stroke occurs when a bloodvessel in the brain bursts, spilling blood intothe spaces surrounding the brain cells orwhen a cerebral aneurysm ruptures[18].Hemorrhagic stroke includes spontaneousintracerebral hemorrhage and subarachnoidhemorrhage [3,8] due to leakage or ruptureof an artery [17]. Here our main concern ison ischemic stroke.Ischemic StrokeIschemic stroke occurs when the bloodsupply to a part of the brain is suddenlyinterrupted by occlusion [15,18,25].Ischemic cerebrovascular disease is mainlycaused by thrombosis, embolism and focalhypoperfusion, all of which can lead to areduction or an interruption in cerebralblood flow (CBF) that affect neurologicalfunction due to deprivation of the glucoseand oxygen [6,8,10,19]. Approximately 45%of ischemic strokes are caused by small orlarge artery thrombus, 20% are embolic inorigin, and others have an unknown cause[10]. Focal ischaemic stroke is caused by aninterruption of the arterial blood flow to adependent area of the brain parenchyma bya thrombus or an embolus [11]. In otherwords, Ischemic stroke is defined as acuteonset, (minutes or hours), of a focalneurological deficit consistent with vascularlesion that persisted for more than 24 hour[9]. Ischemic stroke is a dynamic processwhereby the longer the arterial occlusionpersists the larger the infarct size becomesand the higher the risk of post-perfusionhemorrhage [20].Neema Kanyal, IJPRR 2015; 4(10)ISSN: 2278-6074Ischemic stroke is a complex entity withmultiple etiologies and variable clinicalmanifestations [10,21]. Within 10 secondsafter cerebral flow ceases, metabolic failureof brain tissue occurs. The EEG showsslowing of electrical activity and braindysfunction becomes clinically manifest. Ifcirculation is immediately restored, there isabrupt and complete recovery of brainfunction [22].Ischemic stroke is more common in menthan in women until advanced age, when ahigher incidence is observed in women[3,23]. When younger patients areconsidered, females usually exceed malesunder 35, a period that coincides with theprime child-bearing years [23].The three main pathology of ischemicstrokes are:[3,6,12,16,17,22,24]a) Thrombosisb) Embolism andc) Global ischemia (hypotensive) strokea) Thrombosis: Cerebral thrombosis refersto the formation of a thrombus (bloodclot) inside an artery such as internalcarotid artery, proximal and intracranialvertebral arteries which producelacunes, small infarcts to typicallocations include basal ganglia, thalamus,internal capsule, pons and cerebellum[25] that develops at the clogged part ofthe vessel. Atherosclerosis is one of thereasons for vascular obstructionresulting in thrombotic stroke [16].Atherosclerotic plaques can undergopathological changes such as thrombosis.Disruption of endothelium that can occurin the setting of thispathological changeinitiates a complicated process thatactivates many destructive vasoactiveenzymes. Platelet adherence andaggregation to the vascular wall follow,forming small nidi of platelets and fibrin[15,26]. Thrombosis can form in theextracranial and intracranial arterieswhen the intima is roughened andplaque forms along the injured vessel.This permits platelets to adhere andaggregate, then coagulation is activatedand thrombus develops at site of plaque.When the compensatory mechanism ofcollateral circulation fails, perfusion iscompromised,leadingtocell66

International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84death[10].Extracranial artery stenosesare prone to destabilization and plaqueruptureleadingtocerebralthromboembolism [4]. Thromboembolicocclusion of major or multiple smallerintracerebral arteries leads to focalimpairment of the downstream bloodflow, and to secondary thrombusformationwithinthecerebralmicrovasculature [4,14]. Thromboticstrokesoccurwithoutwarningsymptoms in 80-90% of patients. 1020% is heralded by one or moretransient Ischaemic attacks [22].b) Embolism: Cerebral embolism refersgenerally to a blood clot that forms atanother location in the circulatorysystem, usually the heart and largearteries of the upper chest and neck.Embolic stroke occurs when a clotbreaks, loose and is carried by the bloodstream and gets wedged in mediumsized branching arteries [10,25].Microemboli can break away from asclerosed plaque in the carotid artery orfrom cardiac sources such as atrialfibrillation, [16] or a hypokinetic leftventricle [10]. Embolism to the brainmay be arterial or cardiac in origin.Commonly recognized cardiac sourcesfor embolism include atrial ial infarction (AMI), subacutebacterial endocarditis, cardiac tumors,and valvular disorders, both native andartificial [17]. In approximately onethird of ischemic stroke patients,embolism to the brain originates fromthe heart, especially in atrial fibrillation[2,4,16]. Besides clot, fibrin, pieces ofatheromatous plaque, materials knownto embolize into the central circulationsuch as fat, air, tumor or metastasis,bacterial clumps, and foreign bodiescontribute to this mechanism [10,16].According to stroke databases fromWestern countries, cardioembolism isthe most common cause of ischemicstroke [21]. Embolic strokes usuallypresent with a neurologic deficit that ismaximum at onset [22].Global– Ischemic or Hypotensivestroke: A third mechanism of ischemicstroke is systemic hypoperfusion due toNeema Kanyal, IJPRR 2015; 4(10)ISSN: 2278-6074a generalized loss of arterial pressure[16,27]. Several processes can lead tosystemic hypoperfusion, the most widelyrecognized and studied being cardiacarrest due to myocardial infarctionand/orarrhythmiaorseverehypotension (shock) [28,29]. Thepyramidal cell layer of the hippocampusand the Purkinje cell layer of thecerebellar cortex areas are greatlyeffected [16].Global ischemia is worse than hypoxia,hypoglycemia, and seizures because, inaddition to causing energy failure, itresults in accumulation of lactic acid andother toxic metabolites that are normallyremoved by the circulation [28]. Fatalstrokes in elderly patients oftenappeared to be due to acute hypotensioncaused by extracranial events such asheart-failure, occult haemorrhage, ormultiple pulmonary emboli [29].Consequences after stroke: Active celldeath mechanismWithin seconds to minutes after the loss ofblood flow to a region of the brain, theischemic cascade is rapidly initiated[30].Due to the disruption of blood flow tothe area there is limitation of the delivery ofoxygen and metabolic substrates to neuronswhich causes ATP reduction and energydepletion [8,31]. This comprises a series ofsubsequentbiochemicaleventsthateventually lead to disintegration of cellmembranes and neuronal death at the coreof the infarction [30]. These biochemicalevents include: ionic imbalance, the releaseof excessglutamate in the extracellular spacewhich leads to excitotoxicity, a dramaticincrease in intracellular calcium that in turnactivates multiple intracellular deathpathways such as mitochondrial dysfunction,blood-brain barrier dysfunction, oxidativeand nitrosative stress and initiate postischemicinflammationwhichleadsultimately to cell death of neurons, glia andendothelial cells[4,6,30,31]. In the penumbraregion surrounding the infarct core,however, tissue is preserved for a certaintime span depending on whether blood flowis restored [4].In general, neurons and oligodendrocytesseem to be more vulnerable to cell deaththan astroglial or endothelial cells, and67

International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84among neurons, CA1 hippocampal pyramidalneurons, cortical projection neurons in layer3, subsets of neurons in dorsolateralISSN: 2278-6074striatum and Purkinje cells of the cerebellumare particularly susceptible [26].Ischemia to the brainDeprivation of glucoseand oxygenDepletion ofATPproductionFailure of ionic pumpDecrease glutamateuptakeDepolarizationRelease of excessglutamateOpening of voltage cessive Ca2 /Na influxActivation of intracellularsignalling systemApoptosisExcitotoxicityActivationof iNOSFree radical production(Oxidative and flammatoryresponseFigure 1: Schematic representation of active cell death mechanismIonic imbalance: The most common causeof stroke is the sudden occlusion of a bloodvessel by a thrombus or embolism, resultingin an immediate loss of oxygen and glucoseto the brain [25,32]. Large reserves ofalternative substrates to glucose, such asglycogen, lactate and fatty acids, for bothglycolysis and respiration are present inbrain but oxygen is irreplaceable inmitochondrial oxidative phosphorylation,the main source of ATP in neurons. ReducedATP stimulates the glycolytic metabolism ofresidual glucose and glycogen, which causesNeema Kanyal, IJPRR 2015; 4(10)an accumulation of protons and lactate andtherefore intracellular acidification[31].Thisresult in further decline in ATPconcentration due to cessation of theelectron transport chain activity withinmitochondria and leads to disruption ofionicpumps systemslike Na -K ATPase,[33]Ca2 -H ATPase, reversal of Na Ca2 transporter resulting in increase inintracellular Na , Ca2 , Cl concentration andefflux of K . This redistribution of ionsacrossplasmamembranecausesdepolarization of neurons and astrocytes,68

International Journal of Pharma Research & Review, Oct 2015; rs (particularly glutamate)that causes neuronal excitotoxicity [25,31].Excitotoxicity: Excitotoxicity, the termcoined by Olney in 1969, occurs due toexcess release of excitatory amino acidglutamate and excessive activation of theirreceptors [25]. Excitotoxicity is anexaggerationofneuronalexcitationmediated by sodium ions and that anysource of excitation is potentially harmful.The first step toward excitotoxicity duringan acute episode of stroke is the rapidelevation of glutamate levels in the ischemicregion of the brain and this is due todysfunction in the homeostasis of glutamate[33]. Under physiological condition releaseof glutamate into the synaptic spacestimulates glutamate receptors of the NMDAsubtype,[33-35]whichcausesdepolarization of the postsynaptic neuron byan influx of calcium and sodium. NMDAreceptors (NMDARs) revert to the inactivestate as transporters sequester glutamateinto cells. During acute and chronic ischemia,ATP depletion causes neuronal membranedepolarization, which opens voltage-gatedCa2 and Na channels and releasesexcitatory glutamate in the synaptic cleft andalso impairs the clearance of glutamate dueto transporter dysfunction [25,34]. NMDARsare complex, heterotetramer combinationsof three major subfamilies of subunits: NR1,NR2, NR3. NR2 (GluN2AR-GluN2DR)subtypes appear to play a pivotal role instroke. NR2A and NR2B are the predominantNR2 subunits in the adult forebrain, wherestroke most frequently occur [31]. NMDARsubtypes can confer neuronal survival andneuronal death, synaptic GluN2AR protectsneurons against excitotoxic neuronal deathmediated by synaptic GluN2BR.Similarly,extrasynaptic GluN2AR is pro-survival andprotects neurons against extrasynapticGluN2BR-induced neuronal death [31,36].Synaptic NMDAR conveys the synapticactivity-driven activation of the survivalsignaling protein extracellular signalregulated kinase (ERK) and triggers anincrease in nuclear calcium via release fromintracellular stores, leading to the activationof the transcription factor CREB and theproduction of the survival-promotingprotein BDNF. In contrast, global orNeema Kanyal, IJPRR 2015; 4(10)ISSN: 2278-6074extrasynaptic NMDAR stimulation, whenthere is too much glutamate in the brain,such as during cerebral ischemia decreasesERK, CREB activation and BDNF production,while there is calcium-dependent activationof death-signaling proteins that triggers aplethora of signaling cascades that worksynergistically to induce neuronal death.NMDAR-mediated dysfunction of sodiumcalcium exchanger (NCX) [33] whichregulate intracellular calcium level explainsthe subsequent calcium overload that occursfollowing an excitotoxic stimulus [35].Mitochondria can recover intracellularcalcium concentration by (i) itself taking upa huge amount of calcium [33] (ii)facilitatingATPdependentcalciumextrusion, which results in the production ofreactive oxygen species (ROS) [33,35,36]such as superoxide (O2-), and hydrogenperoxide (H2O2) as well as reactive nitrogenspecies (RNS)[35] such as nitric oxide (NO)and peroxinitrite (ONOO-) [34,36]. Highconcentrations of intracellular calcium, ROS,and RNS induce cell death by: 1) activatingproteases that damage cellular izing lipids,[35] which disruptmembraneintegrity,3)stimulatingmicroglia to produce cytotoxic factors, 4)disrupting mitochondrial function, and 5)inducing pyknosis (chromatin condensation)[31,33,34,39]. The opening of thepermeability transition pore results inmitochondrial depolarization , induction ofcalcium deregulation and induction ofneuronal death by damaging dendrites andsynaptic connections [16,26,35].Oxidative and nitrosative stress: Oxidativestress occurs when there is an imbalancebetween the production and quenching offree radicals by endogeneous antioxidantenzymes such as superoxide dismutase(SOD), catalase and glutathione [40-42].Compared to other tissues and organs in thebody, the brain is particularly prone tooxidative damage [36] because of highconsumption of oxygen under basalconditions,highconcentrationsofperoxidisable lipids, and high levels of ironthat act as a pro-oxidant during stress. Theprimary sources of ROS in the brain are themitochondrial respiratory chain (MRC),NAPDH oxidases, and xanthine oxidase [25].69

International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84ISSN: 2278-6074Figure 2: NMDA receptors with synaptic and extrasynaptic location and their role inneuronal survival and death [31]Several oxygen free radicals (oxidants) andtheir derivatives are generated after stroke,including superoxide anions (O2· ), hydrogenperoxide (H2O2), and hydroxyl radicals(·OH). O2· are formed within themitochondria when oxygen acquires anadditional electron, leaving the moleculewith only one unpaired electron. Pro-oxidantenzymes such as xanthine oxidase andNADPH oxidase (NOX) also catalyze thegeneration of O2· [43]. Under normal cellularconditions,mitochondriaproducesuperoxide as a by-product of their primaryNeema Kanyal, IJPRR 2015; 4(10)function i.e. ATP generation by oxidativephosphorylation through the MRC [25].Superoxide concentration is regulated byenzymatic antioxidants by dismutation ofsuperoxide to hydrogen peroxide bysuperoxidedismutasewhichisthenconverted to water (by peroxidases such asglutathione peroxidase and peroxiredoxin)or dismuted to water and oxygen (byCatalase)[25,43]beforeleavingthemitochondria to act as an intracellularmessenger. In the ischaemic cell, O2 levelsare depleted before glucose, favouring a70

International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84switch to the glycolytic pathway of anaerobicATP production.This results in lactic acidand H production within the mitochondriaand the subsequen

The three main pathology of ischemic strokes are:[3,6,12,16,17,22,24] a) Thrombosis b) Embolism and c) Global ischemia (hypotensive) stroke a) Thrombosis: Cerebral thrombosis refers to the formation of a thrombus (blood clot) inside an artery s