International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84 ISSN: 2278-6074

Review Article

The Science of Ischemic Stroke: Pathophysiology & Pharmacological Treatment
*Neema Kanyal

Department of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology & Science, Patel
Nagar, Dehradun 248001, Uttarakhand, India.
ABSTRACT
Over the past two decades, research has heavily emphasized basic mechanisms that irreversibly damage
brain cells after stroke. Much attention has focused on what makes neurons die easily and what strategies
render neurons resistant to ischaemic injury. In the past few years, clinical experience with clot-lysing
drugs has confirmed expectations that early reperfusion improves clinical outcome.Although great
advances have been made in understanding the diverse mechanisms of neuronal cell death induced by
ischemic stroke, clinically effective neuroprotective therapies are limited.Based on the accumulating
evidence that ischemic cell death is a result of series of subsequent biochemical events, new concepts for
prevention and treatment of ischemic stroke may eventually emerge without the hazard of severe
complications.This review focuses on mechanisms and emerging concepts that drive the science of
ischemic 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 by
the interaction of neurons, glia, vascular cells and matrix components, which actively participate in
mechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge that
build 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, the
answers to which may generate a number of treatment strategies and possibly new treatments that could
reduce the impact of this enormous economic and societal burden.

Keywords: Apoptosis, excitotoxicity, ischemia, stroke

Received 26 August 2015 Received in revised form 14 Sept 2015 Accepted 17 Sept 2015

*Address for correspondence:
Neema Kanyal,
Department of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology & Science, Patel
Nagar, Dehradun 248001, Uttarakhand, India.
E-mail:kanyalneema15@gmail.com
_________________________________________________________________________________________________________________________
INTRODUCTION
Stroke is the second leading cause of death as a result of demographic transitions in
worldwide [1-4] and is the major cause of populations [2]. The ultimate result of
morbidity, particularly in the middle aged ischemic cascade initiated by acute stroke is
and elderly population [1,5-6]. Stroke, neuronal death along with an irreversible
according to the American Heart Association loss of neuronal function [9].
(AHA) definition, is a sudden loss of brain According to World Health Organization
function due to disturbance in the cerebral estimates, in 2002, 5.5 million people died of
blood supply with symptoms lasting at least stroke in 2002 and roughly 20% of these
24 hours or leading to death [7]. Stroke is deaths occurred in South Asian Countries
defined as an acute neurologic dysfunction (India, Pakistan, Bangladesh, and Sri Lanka)
[8,9] of vascular origin with sudden (within [3]. The incidence and mortality of stroke
seconds) or at least rapid (within hours) increase with age, and as the elderly
occurrence of signs and symptoms [10,11]. population is rapidly growing in most
Stroke is the rapid loss of brain function due developed countries ischemic stroke is a
to a disturbance in the blood supply to the common societal burden with substantial
brain [12]. Stroke is also the leading cause of economic costs [1,13]. According to the
adult long-term disability [3,8,9] and report from the Centers for Disease Control
represents an enormous burden on society, and Prevention, given in 2013 mortality
which is likely to increase in future decades from stroke was the fourth leading cause of

Neema Kanyal et.al, IJPRR 2015; 4(10) 65

International Journal of Pharma Research & Review, Oct 2015; 4(10):65-84 ISSN: 2278-6074

death in the United States in 2008, and Ischemic stroke is a complex entity with
stroke was a leading cause of long-term multiple etiologies and variable clinical
severe disability. Therefore, it is important manifestations [10,21]. Within 10 seconds
to know the reason for this social burden so after cerebral flow ceases, metabolic failure
that safe and effective therapeutic treatment of brain tissue occurs. The EEG shows
that could be given at medical services slowing of electrical activity and brain
would improve the outcome of millions of dysfunction becomes clinically manifest. If
acute stroke patients [12]. circulation is immediately restored, there is
The two main types of stroke are ischemic abrupt and complete recovery of brain
and hemorrhagic, accounting for function [22].
approximately 85% and 15%, respectively Ischemic stroke is more common in men
[4,9,10,12,14,15]. A third type of stroke, than in women until advanced age, when a
called as transient ischemic attack or TIA is a higher incidence is observed in women
minor stroke that serves as awarning sign [3,23]. When younger patients are
that a more serve stroke may occur [16]. considered, females usually exceed males
Ischemic stroke is caused by focal cerebral under 35, a period that coincides with the
ischemia due to arterial occlusion prime child-bearing years [23].
[1,4,9,10,14] or stenosis [17] whereas The three main pathology of ischemic
hemorrhagic stroke occurs when a blood strokes are:[3,6,12,16,17,22,24]
vessel in the brain bursts, spilling blood into a) Thrombosis
the spaces surrounding the brain cells or b) Embolism and
when a cerebral aneurysm ruptures[18]. c) Global ischemia (hypotensive) stroke
Hemorrhagic stroke includes spontaneous
intracerebral hemorrhage and subarachnoid a) Thrombosis: Cerebral thrombosis refers
hemorrhage [3,8] due to leakage or rupture to the formation of a thrombus (blood
of an artery [17]. Here our main concern is clot) inside an artery such as internal
on ischemic stroke. carotid artery, proximal and intracranial
Ischemic Stroke vertebral arteries which produce
Ischemic stroke occurs when the blood lacunes, small infarcts to typical
supply to a part of the brain is suddenly locations include basal ganglia, thalamus,
interrupted by occlusion [15,18,25]. internal capsule, pons and cerebellum
Ischemic cerebrovascular disease is mainly [25] that develops at the clogged part of
caused by thrombosis, embolism and focal the vessel. Atherosclerosis is one of the
hypoperfusion, all of which can lead to a reasons for vascular obstruction
reduction or an interruption in cerebral resulting in thrombotic stroke [16].
blood flow (CBF) that affect neurological Atherosclerotic plaques can undergo
function due to deprivation of the glucose pathological changes such as thrombosis.
and oxygen [6,8,10,19]. Approximately 45% Disruption of endothelium that can occur
of ischemic strokes are caused by small or in the setting of thispathological change
large artery thrombus, 20% are embolic in initiates a complicated process that
origin, and others have an unknown cause activates many destructive vasoactive
[10]. Focal ischaemic stroke is caused by an enzymes. Platelet adherence and
interruption of the arterial blood flow to a aggregation to the vascular wall follow,
dependent area of the brain parenchyma by forming small nidi of platelets and fibrin
a thrombus or an embolus [11]. In other [15,26]. Thrombosis can form in the
words, Ischemic stroke is defined as acute extracranial and intracranial arteries
onset, (minutes or hours), of a focal when the intima is roughened and
neurological deficit consistent with vascular plaque forms along the injured vessel.
lesion that persisted for more than 24 hour This permits platelets to adhere and
[9]. Ischemic stroke is a dynamic process aggregate, then coagulation is activated
whereby the longer the arterial occlusion and thrombus develops at site of plaque.
persists the larger the infarct size becomes When the compensatory mechanism of
and the higher the risk of post-perfusion collateral circulation fails, perfusion is
hemorrhage [20]. compromised, leading to cell

Neema Kanyal et.al, IJPRR 2015; 4(10) 66

cardiac tumors. it b) Embolism: Cerebral embolism refers results in accumulation of lactic acid and generally to a blood clot that forms at other toxic metabolites that are normally another location in the circulatory removed by the circulation [28]. Thromboembolic recognized and studied being cardiac occlusion of major or multiple smaller arrest due to myocardial infarction intracerebral arteries leads to focal and/or arrhythmia or severe impairment of the downstream blood hypotension (shock) [28. In approximately one. the release embolism to the brain originates from of excessglutamate in the extracellular space the heart. Besides clot. recent acute depletion [8. In the penumbra the most common cause of ischemic region surrounding the infarct core. and to secondary thrombus pyramidal cell layer of the hippocampus formation within the cerebral and the Purkinje cell layer of the microvasculature [4. occult haemorrhage. subacute subsequent biochemical events that bacterial endocarditis. especially in atrial fibrillation which leads to excitotoxicity. or stream and gets wedged in medium. materials known activates multiple intracellular death to embolize into the central circulation pathways such as mitochondrial dysfunction. [16] or a hypokinetic left ischemic cascade is rapidly initiated ventricle [10]. in transient Ischaemic attacks [22]. 10. addition to causing energy failure.Extracranial artery stenoses a generalized loss of arterial pressure are prone to destabilization and plaque [16. tumor or metastasis. IJPRR 2015.International Journal of Pharma Research & Review. neurons and oligodendrocytes stroke: A third mechanism of ischemic seem to be more vulnerable to cell death stroke is systemic hypoperfusion due to than astroglial or endothelial cells. such as fat. events include: ionic imbalance. oxidative bacterial clumps. Oct 2015. eventually lead to disintegration of cell and valvular disorders.27]. Embolic strokes usually however. tissue is preserved for a certain present with a neurologic deficit that is time span depending on whether blood flow maximum at onset [22]. 20% is heralded by one or more hypoglycemia. the area there is limitation of the delivery of Commonly recognized cardiac sources oxygen and metabolic substrates to neurons for embolism include atrial fibrillation.29]. appeared to be due to acute hypotension Embolic stroke occurs when a clot caused by extracranial events such as breaks.14]. 4(10):65-84 ISSN: 2278-6074 death[10]. loose and is carried by the blood heart-failure. stroke [21]. Thrombotic cerebellar cortex areas are greatly strokes occur without warning effected [16]. the most widely thromboembolism [4].31]. 4(10) 67 . This comprises a series of myocardial infarction (AMI). and seizures because. The flow.30. symptoms in 80-90% of patients. both native and membranes and neuronal death at the core artificial [17].31]. and foreign bodies and nitrosative stress and initiate post contribute to this mechanism [10.al. Fatal system. air. a dramatic [2. of the infarction [30].16]. cardioembolism is endothelial cells[4. Several processes can lead to rupture leading to cerebral systemic hypoperfusion. ischemic inflammation which leads According to stroke databases from ultimately to cell death of neurons. and Neema Kanyal et. Consequences after stroke: Active cell Microemboli can break away from a death mechanism sclerosed plaque in the carotid artery or Within seconds to minutes after the loss of from cardiac sources such as atrial blood flow to a region of the brain. Global– Ischemic or Hypotensive In general. Embolism to the brain [30].6. is restored [4]. sized branching arteries [10. multiple pulmonary emboli [29].25]. usually the heart and large strokes in elderly patients often arteries of the upper chest and neck. fibrin. which causes ATP reduction and energy sinoatrial disorder.16]. pieces of increase in intracellular calcium that in turn atheromatous plaque. These biochemical third of ischemic stroke patients. blood-brain barrier dysfunction.Due to the disruption of blood flow to may be arterial or cardiac in origin.4. glia and Western countries. Global ischemia is worse than hypoxia. the fibrillation.

such as mitochondria and leads to disruption of glycogen. This redistribution of ions ATP stimulates the glycolytic metabolism of across plasma membrane causes residual glucose and glycogen. Oct 2015. IJPRR 2015. cortical projection neurons in layer are particularly susceptible [26]. Reduced efflux of K+ . Large reserves of electron transport chain activity within alternative substrates to glucose.32]. reversal of Na+- brain but oxygen is irreplaceable in Ca2+ transporter resulting in increase in mitochondrial oxidative phosphorylation. Cl concentration and the main source of ATP in neurons. which causes depolarization of neurons and astrocytes. Ca2+.[33]Ca2+-H+ ATPase. Neema Kanyal et. 4(10):65-84 ISSN: 2278-6074 among neurons. CA1 hippocampal pyramidal striatum and Purkinje cells of the cerebellum neurons. International Journal of Pharma Research & Review. for both ionic pumps systems like Na+-K+- glycolysis and respiration are present in ATPase.This vessel by a thrombus or embolism. lactate and fatty acids. 4(10) 68 . subsets of neurons in dorsolateral Ischemia to the brain Deprivation of glucose and oxygen Depletion of ATPproduction Decrease glutamate Failure of ionic pump uptake Depolarization Release of excess Glutamate glutamate concentration Opening of voltage dependent increases channels Excessive Ca2+/Na+ Excitotoxicity influx Activation of intracellular signalling system Activation of iNOS Apoptosi s Free radical production Lipid phosphorylation(membrane) (Oxidative and nitrosative stress) Inflammatory response Figure 1: Schematic representation of active cell death mechanism Ionic imbalance: The most common cause an accumulation of protons and lactate and of stroke is the sudden occlusion of a blood therefore intracellular acidification[31]. 3.al. resulting result in further decline in ATP in an immediate loss of oxygen and glucose concentration due to cessation of the to the brain [25. intracellular Na+.

and xanthine oxidase [25]. induction of stroke. and hydrogen depolarization of the postsynaptic neuron by peroxide (H2O2) as well as reactive nitrogen an influx of calcium and sodium.39]. the term ERK. DNA. 3) stimulating also impairs the clearance of glutamate due microglia to produce cytotoxic factors. CREB activation and BDNF production. GluN2BR-induced neuronal death [31.34]. Compared to other tissues and organs in the Synaptic NMDAR conveys the synaptic body. lipid. [33-35] which causes such as superoxide (O2-). and high levels of iron intracellular stores.26. During acute and chronic ischemia.35]. oxidative damage [36] because of high signaling protein extracellular signal. protein BDNF. NMDAR synaptic connections [16.35.Similarly. Neema Kanyal et. 4(10):65-84 ISSN: 2278-6074 leading to excess release of extrasynaptic NMDAR stimulation. into cells.38] Ca2+ and Na+ channels and releases 2)peroxidizing lipids. In contrast. The opening of the NR2. and 5) are complex.31]. elevation of glutamate levels in the ischemic Mitochondria can recover intracellular region of the brain and this is due to calcium concentration by (i) itself taking up dysfunction in the homeostasis of glutamate a huge amount of calcium [33] (ii) [33]. synaptic GluN2AR protects stress occurs when there is an imbalance neurons against excitotoxic neuronal death between the production and quenching of mediated by synaptic GluN2BR.33. coined by Olney in 1969.36]. NR2A and NR2B are the predominant calcium deregulation and induction of NR2 subunits in the adult forebrain. consumption of oxygen under basal regulated kinase (ERK) and triggers an conditions. Oct 2015. free radicals by endogeneous antioxidant extrasynaptic GluN2AR is pro-survival and enzymes such as superoxide dismutase protects neurons against extrasynaptic (SOD). the brain is particularly prone to activity-driven activation of the survival. such as during cerebral ischemia decreases Excitotoxicity: Excitotoxicity. heterotetramer combinations inducing pyknosis (chromatin condensation) of three major subfamilies of subunits: NR1. NMDARs disrupting mitochondrial function. when neurotransmitters (particularly glutamate) there is too much glutamate in the brain. that causes neuronal excitotoxicity [25. 4(10) 69 . [37.36]. high concentrations of increase in nuclear calcium via release from peroxidisable lipids. NR3.36] subtype. occurs due to while there is calcium-dependent activation excess release of excitatory amino acid of death-signaling proteins that triggers a glutamate and excessive activation of their plethora of signaling cascades that work receptors [25]. IJPRR 2015. exaggeration of neuronal excitation NMDAR-mediated dysfunction of sodium- mediated by sodium ions and that any calcium exchanger (NCX) [33] which source of excitation is potentially harmful.al.e. protein. global or NAPDH oxidases. catalase and glutathione [40-42]. The of the transcription factor CREB and the primary sources of ROS in the brain are the production of the survival-promoting mitochondrial respiratory chain (MRC). Under physiological condition release facilitating ATP dependent calcium of glutamate into the synaptic space extrusion. where neuronal death by damaging dendrites and stroke most frequently occur [31].International Journal of Pharma Research & Review. regulate intracellular calcium level explains The first step toward excitotoxicity during the subsequent calcium overload that occurs an acute episode of stroke is the rapid following an excitotoxic stimulus [35].[35] which disrupt excitatory glutamate in the synaptic cleft and membrane integrity. which results in the production of stimulates glutamate receptors of the NMDA reactive oxygen species (ROS) [33. NMDA species (RNS)[35] such as nitric oxide (NO) receptors (NMDARs) revert to the inactive and peroxinitrite (ONOO-) [34. NR2 (GluN2AR-GluN2DR) permeability transition pore results in subtypes appear to play a pivotal role in mitochondrial depolarization . 4) to transporter dysfunction [25. which opens voltage-gated i. [31. and RNS induce cell death by: 1) activating ATP depletion causes neuronal membrane proteases that damage cellular architecture depolarization. Excitotoxicity is an synergistically to induce neuronal death. ROS. subtypes can confer neuronal survival and Oxidative and nitrosative stress: Oxidative neuronal death.34. leading to the activation that act as a pro-oxidant during stress. High state as transporters sequester glutamate concentrations of intracellular calcium.

Pro-oxidant glutathione peroxidase and peroxiredoxin) enzymes such as xanthine oxidase and or dismuted to water and oxygen (by NADPH oxidase (NOX) also catalyze the Catalase)[25. and hydroxyl radicals enzymatic antioxidants by dismutation of (·OH). ATP generation by oxidative their derivatives are generated after stroke. O2·− are formed within the superoxide to hydrogen peroxide by mitochondria when oxygen acquires an superoxidedismutase which is then additional electron. O2 levels superoxide as a by-product of their primary are depleted before glucose. Under normal cellular mitochondria to act as an intracellular conditions. phosphorylation through the MRC [25]. mitochondria produce messenger. hydrogen Superoxide concentration is regulated by peroxide (H2O2). IJPRR 2015.International Journal of Pharma Research & Review. favouring a Neema Kanyal et.e.43]before leaving the generation of O2·−[43]. 4(10):65-84 ISSN: 2278-6074 Figure 2: NMDA receptors with synaptic and extrasynaptic location and their role in neuronal survival and death [31] Several oxygen free radicals (oxidants) and function i. Oct 2015. 4(10) 70 . leaving the molecule converted to water (by peroxidases such as with only one unpaired electron. In the ischaemic cell.al. including superoxide anions (O2·−).

Hydroxyl radical. IJPRR 2015. stressing conditions including DNA damage. and therefore are contributes to oxidative stress by providing potentially recoverable for some time after H+ for the conversion of •O2− into H2O2 or the the onset of stroke [46]. Bid.43]. Bad [Bcl-2-antagonist of protein heme sites (e. Under of apoptosis. 4(10):65-84 ISSN: 2278-6074 switch to the glycolytic pathway of anaerobic core is surrounded by a zone of less severely ATP production.al.L-α-amino-3- proteins and DNA. reperfusion after ischaemia leads to apoptotic protease-activating factor 1. carbonate Cerebral ischemia elevates cytosolic calcium radical and nitrogen dioxide) all have the levels through the stimulation of N-methyl- potential to react and damage lipids. Either Bax or Bak is enzymes which generate ROS for biological required for all instances of apoptosis functions such as blood pressure regulation.51].This results in lactic acid affected tissue which is rendered and H+ production within the mitochondria functionally silent by reduced blood flow but and the subsequent reversal of the remains metabolically active. overproduction and ROS imbalance[45]. Oct 2015. 8 and 9. The normal human more reactive hydroxyl radical (•OH). the transcription factor p53. (tBid). death production of superoxide and hydroxyl receptors. peroxynitrite and peroxynitrite-derived oxidative stress and many others [50] products (hydroxyl radical. mediated via the intrinsic pathway [49]. d-aspartate (NMDA) and D. 4(10) 71 .e. This necrotic opening in the inner membrane of the Neema Kanyal et. This occur at the mitochondrial outer Another source of ROS production is membrane (MOM) where the Bcl-2 protein nicotinamide adenine dinucleotide family plays a pivotal role in the regulation phosphate-oxidases (NOXs) enzyme. Proapoptotic protein are subdivided into (a) In addition. flow reduction is injured and subsequently Another mechanism is the result of the undergoes necrotic cell death. an important enzyme in the implicated in apoptosis [47. Increased increases intracellular NO and subsequent intracellular calcium activates calpains and ONOO− production in the ATP depleted post. the core of brain force that is required for oxidative tissue exposed to the most dramatic blood phosphorylation and ATP generation. inhibit the antiapoptotic normal physiological conditions NOX proteins and activate the pro-apoptotic enzymes function as membrane bound proteins[49. This region is H+uniporter on the mitochondrial known as “ischemic penumbra” and neurons membrane which causes excess cytosolic H+ in this area may undergo apoptosis after accumulation and acidosis [44]. activation of nitric oxide multidomainproapoptotics (eg.The intrinsic pathway is that causes protein nitration and activated in response to a number of dysfunction[25. cytochrome c) and of cell death] etc [49. tBid microbial killing and otoconia formation but interacts with apoptotic proteins such as in pathological conditions NOXs are Bad and Bax[49] at the mitochondrial significant contributors to pathological membrane.g. and a number scavenging mechanism. tricarboxylic acid cycle [25. mitochondrial transition pores (MTP) are Apoptosis Cell Death:Within minutes after open [50] and dissipates the proton motive a focal ischemic stroke.26].50].Superoxide can cause of proteins(i. DNA radicals which overwhelms endogenous fragmentation factor (DFF45). The brain expresses caspases 1.International Journal of Pharma Research & Review. Bax [Bcl-2– synthase (NOS) during ischaemia might lead associated X protein] and Bak [Bcl-2– to excessive nitric oxide production which antagonist/killer]) and (b) BH3-only leads to nitrosative damage bynitrosylation proapoptotics (eg.pro-apoptotic proteins) oxidative damage of iron/sulfur clusters of belonging to Bcl2 family and all these are aconitase. 3. mediates cleavage of Bid to truncated Bid synaptic cell [25]. by its reaction products with oxygen or There are two general pathways for other nitrogen oxides[25]. Acidosis several hours or days. Activation of NMDA hydroxy-5-methyl-isoxazolpropionic acid receptors (NMDARs) by glutamate also (AMPA) receptors by glutamate.O2·− can react with activation of apoptosis: The Intrinsic and nitric oxide (NO) to produce peroxynitrite Extrinsic pathway ONOO− which is a strong oxidative radical Intrinsic pathway. After heterodimerization of damage by oxidative stress from •O2− proapoptotic proteins with tBid.48].

The second group of pro-apoptotic proteins within the inner and outer proteins. The first (AIF)[50. After releasing after the cell has committed to die [53]. It into the cytosol. IJPRR 2015.The extrinsic pathway factor receptor (TNFR) superfamily.al. such as poly Dependent Anion Channel (VDAC) [50].Smac/DIABLO. but this is a late event that occurs protease HtrA2/Omi[53].50. Cytc binds with apoptotic mediates large-scale DNA fragmentation and protein-activating factor-1 (Apaf-1) and cell death in a caspase-independent manner procaspase-9 to form an “apoptosome.International Journal of Pharma Research & Review. 4(10):65-84 ISSN: 2278-6074 permeability transition pore complex (PTPC) which activates caspase-9 and subsequently that would require the Adenine Nucleotide caspase-3 [50.52]. initiated extracellularly via activation of cell surface receptors CD95/FasR and DR4.53.56]. mitochondria release their leads to nDNA damage and apoptosis constituents including apoptosis-related [50.52]and endonuclease G[52] are group of apoptosis-related protein include released from the mitochondria during cytochrome c.50. conformational changes allowing the The ligand may be an integral membrane assembly of a large multi-protein complex protein on the surface of a second cell (eg. Oct 2015. known as Death Initiation Signalling Fas [CD95/Apo-1] ligand) or a soluble Complex (DISC) that leads to activation of extracellular protein (eg.54]. DR Upon ligand binding several receptor by specific molecules known as lethal molecules are brought together and undergo ligands or death ligand trimer [49. 4(10) 72 . tumor necrosis the caspase cascade [49. As a (ADP-ribose) polymerase (PARP). and the serine apoptosis. Figure 3: Schematic representation of the main molecular pathways leading to apoptosis [50] receptors belong to the tumor necrosis Extrinsic pathway. which result. Taking the factor-α)[49].This pathway is also known as example of Fas ligand. Activated caspase-3 Transporter (ANT) and the Voltage cleaves nDNA repair enzymes.52].extracellular Fas death receptor pathway [50] because these ligand (FasL) binds to Fas death receptors Neema Kanyal et.55. apoptosis-inducing factor mitochondrial membranes [26.55].” [53].

63].60] causing microvascular Fas-associated protein with a DD (FADD) occlusion [59.56]. nicotinamide adenine ischemia and stroke [57-59]. As the ischemic Once activated. in turn.26]. 4(10):65-84 ISSN: 2278-6074 (FasR) and once activated.[57.55. eg. apoptotic signaling from death receptors dendritic cells. in turn. cell death leads to a new activates downstream procaspase-3 and Bid. Treatment is required if BP is Microglial transformed into phagocytes and >140/90mmHg. Stroke triggers dinucleotide phosphate (NADPH) oxidase- this inflammatory response as a result of derived ROS. associated molecular patterns (DAMPs) such Cleavage of Bid to truncated Bid (tBid).IL-1β.[32] IL-17. and platelets[59. ischemic insult [59. IJPRR 2015. Meta-analyses of are responsible for relase of various randomized controlled trials confirm an substances like pro-inflammatory cytokines approximate 30% to 40% stroke risk (TNH-α. prostanoids) or cytoprotectives  Diabetes Mellitus (DM): Diabetes has [15.necrotic cells debris and reactive contribute to brain injury by producing pro- oxygen species (ROS)[59. results in brain parenchyma.62. selectins (in particular. Arterial hypertension such as intercellular adhesion molecule-1 (HTN) contributes to 60% of all strokes by (ICAM-1). ventricular dysfunction and atrial leukocytes.60]. the death the infarct’s border.60. Activated fibrillation. P-selectin carotids.60]. such as hypoxia. Adhesion molecules domains of these receptors recruits a highly mediate adhesion of leukocytes (especially conserved 80 amino acid domain. [46. Oct 2015. A result pathways. such as the potent oxygen free radicals triggers the expression cytokines interferon-γ (IFN-γ).63] and alteration of [49. which leads to factors.59. Both CD4+ and CD8+ T lymphocytes stress.61]hypoxia inducible disruption of the blood-brain barrier (BBB) factor 1.IL-6 cytotoxic molecules like reduction with BP lowering. 11% of strokes and 9. uridine triphosphate (UTP)[60] and pathways at the mitochondrial checkpoint of high-mobility group protein B1 apoptosis. NO. especially around the penumbra. Chemokine upregulation stimulates been clearly established as a risk factor for inflammatory cell chemotaxis into ischemic first stroke but not as one for recurrent brain. left LFA-1) on the surface of endothelial cells. or stroke.The increase in inflammatory mediators. tBid binds to the mitochondrial (HMGB1)[64] or alarm molecules released membrane to facilitate the release of from the necrotic brain to activate cytochrome c and initiate the intrinsic infiltrating immune cells [60. and T and B lymphocytes. Altered BBB procaspase-8 through death effector leads to infiltration of immune cells into the domains into the DISC this.55.[32] of a number of pro-inflammatory genes by interleukin-6 (IL-6). recruits permeability of BBB [60.64]. caspase-8 cleaves and cascade progresses.1% of Neema Kanyal et. vertebral arteries and aortic arch. ROS. This lead to granule exocytosis and release Post ischemic inflammation: Brain of a variety of pro-inflammatory molecules inflammation has been implicated as a such as nitric oxide (NO) derived from secondary injury mechanism following inducible NO synthase. interferon regulator factor 1 and and extracellular matrix [57. as nucleotides adenosine triphosphate which integrates the different death (ATP). These triggering factors lead to Modifiable risk factors [66-70] microglial(main immune cell in CNS) [57]  High blood pressure: High BP is the activation. and E-selectin).55]. IL-1β. expression of adhesion molecules factor for stroke. known as neutrophils) to endothelia in the periphery death domain (DD). which links the endogenous molecules are called danger- extrinsic and intrinsic pathways [49. FADD. all within 24 hours of the procaspase-8 dimerization and activation. phase of the inflammatory response.65]. Certain a proapoptotic Bcl-2 protein.50. NF-κB.62. and tumor inducing the synthesis of transcription necrosis factor (TNF). upregulation of chemokins and single most important modifiable risk cytokines. vascular adhesion molecules several mechanism such as atheroma in (VCAMs).62. and integrins ( Mac-1 and friability of small cerebral arteries. shear (MMPs). STAT3 [15]. 4(10) 73 . and matrix metalloproteinases several factors. This allows “cross-talk” between of these processes is a time-dependent the two main pathways and amplifies the infiltration of neutrophils.56].International Journal of Pharma Research & Review. macrophages.al. an adaptor molecule of the infarct [15.62].

and atrial higher rate of recanalization. The primary aim of association between serum cholesterol thrombolysis in acute ischemic stroke is levels and both incident and recurrent recanalization of an occluded intracranial stroke rate has not been clearly artery.Risk of stroke At present. outcome according to Dose Escalation of 1. AF is present in 15– thrombolysis in acute ischemic 21% of patients affected by stroke. There is an association Intra-arterial(IA) thrombolysis has been between alcohol and stroke. 4(10) 74 .Obesity. primary ischemic stroke. intravenous thrombolysis [73.73-77]. IJPRR 2015. more 5. Desmoteplase appeared to improve clinical Treatment of acute ischemic stroke. and oral saliva of vampire bat. Free radical scavengers a stroke.9 mg/kg (maximum 90 mg) given vascular stenosis.al. hypercoagulable state.e. An drugs”[71]. Plasmin is well-established risk factor for stroke. in both sexes. Antiplatelets study in patients treated within 3 to 9 hour 3.Thrombolytics: Thrombolytic drugs stroke patients. Intravenous tissue plasminogen occurance may be double in smokersas activator (IV-TPA) i. illicit drug use. compare to th non-smokers. However.Desmoteplase is a fibrin-specific and  Other risk factors . Thrombolytics Desmoteplase in Acute Stroke (DEDAS) 2. ranging from shown effective until 6 hours after middle a definite independent effect to no effect. streptokinase. contraceptive use . and among different treatment of ischemic stroke [71. Glutamate and the NMDA receptor be attributable to diabetes.Physical nonneurotoxic protein derived from the activity. reduced systemic exposure and therefore reduced cerebral blood flow. While  Atrial fibrillation: Patients with there are currently no FDA-approved IA nonvalvular atrial fibrillation (AF) are at 4. Anticoagulants time window. thrombolytic agents. reteplase remains the only FDA- associated with smoking is present at all approved therapeutic agent for the ages.International Journal of Pharma Research & Review. GABA antagonists severe disability. as well as higher rates of stroke 7. compared with fibrillation (AF). The risk alteplase. dissolve blood clot by activating  Abnormal lipid level: Dyslipidemia is a plasminogen. stroke. ischemic strokes. the vessel. cerebral artery occlusion and basilar artery The deleterious risk mechanism for the occlusion.78].Because of this action it is also known epidemiological association between as “plasminogen activator” and “fibrinolytic cholesterol and stroke is controversial. It offers a higher concentrations of same may include alcohol-induced thrombolytic delivered to the clot with hypertension.alteplase) in a includes changes in blood dynamicsand dose of 0. several uncontrolled 5% annual risk of stroke particularly and anecdotal studies have evaluated IA cardioembolicstroke . 4(10):65-84 ISSN: 2278-6074 recurrent strokes have been estimated to 4. and slower recovery after 6. Apoptosis inhibitors recurrence compared to nondiabetic 1.which form plasmin . Patients with antagonists diabetes have higher mortality. The pathological Intravenous recombinant tissue pathway contributing to increased risk plasminogen activator (rt-PA. over one hour has been licensed in the USA  Alcohol consumption: Heavy alcohol use since 1996 was safe and effective when has been associated with an increased rate given within 3 hours from symptoms onset of stroke in patients with previous [77-79]. Oct 2015. Ancrod (Viprinex) is an Neema Kanyal et. At a dose of 125 μg/kg. a proteolytic enzyme that break cross-links Cholesterol levels represent an important between fibrin molecules and restricts the and modifiable risk factor for coronary damage caused by the blockage in the blood artery disease (CAD). predictor of stroke outcome as timely  Tobacco/Cigarette smoking: Smoking restoration of regional cerebral perfusion and exposure to passive smoke are helps salvage threatened ischemic tissue established independent risk factors for [72]. Recanalization is an important demonstrated. racial/ethnic groups.

International Journal of Pharma Research & Review. The superiority of recommended for some specific clinical combination therapy compared to situations. Therapy the setting of acute ischemic stroke [81]. Thus. IJPRR 2015. Indications currently proposed monotherapy may be due to the synergy by many experts for early full-dose i. thrombin. particularly for patients stroke is modest [76]. therefore NMDA receptor antagonists can be Intravenous antiplatelet therapy with used for the treatment. and yet to be assessed properly [88].86]. etc.Another study hours) because the evidence indicates it is showed that early initiation of aspirin plus not efficacious and may be associated with extended release dipyridamole leads to no or increased bleeding complications [81].Two GPIs in clinical use include Abciximab clinical trial studies. The benefit of weight heparin is not recommended in acute aspirin when used in early phase of ischemic ischemic stroke.81].78. or early recurrent stroke in days was significantly lower for dual therapy patients with acute stroke (i.91]. non-responsive. The Chinese Acute (ReoPro). combined 4.Antiplatelet drugs: Early antiplatelet GP IIb-IIIa receptors on the platelet surface treatment is recommended to treat most and block the final common pathway to patients with acute ischemic stroke because platelet aggregation by preventing the few patients can be treated with binding of fibrinogen molecules that form thrombolysis due to the limit of strict bridges between adjacent platelets[85. GP IIb/IIIa have failed due to unwanted side effects of receptors are found on the platelet surface the drugs.82]. whether alone or in combination.v. other antiplatelet agents may be intracranial hemorrhagic complications used as an alternative. clopidogrel. endpoint of a recurrent stroke within 90 mortality.Tirofiban (Aggrastat) and Stroke Trial (CAST) and the International Eptifibatide (Integrillin) [71.. finally induce neurotransmission. effects of different antiplatelet mechanisms heparin after stroke [90]. or daily within 48 hours of symptom onset other antiplatelet agents during ischemic provided contraindications such as allergy stroke. has and gastrointestinal bleeding are absent.e. in reducing vascular events. Another (CHANCE) [90. indications. since the receptors also play an for fibrinogen. TXA2. should be encouraged in the activation is implicated in excitotoxicity treatment of acute ischemic stroke [78]. mild disability at 90 day compared with late However. In patients who were with moderate to extensive cerebral allergic. Oct 2015. while oral GPIIb/IIIa receptor trials involving NMDA receptor antagonists inhibitors appear hazardous [83]. Many NMDA Glycoprotein (GP) IIb/IIIa receptor receptors antagonist are presently in phase inhibitors for acute stroke appears II and phase III clinical trials.76. the patient has or will not be treated with 3. such as a time window[80].al. (GP) IIb-IIIa inhibitors act by antagonising 2. The rate of the primary recommended for reducing morbidity.85. The data Stroke Trial (IST) showed a significant are insufficient at this time to recommend benefit of aspirin as to the reduction of the use of any other platelet antiaggregant in morbidity and mortality rates. blocking them causes Neema Kanyal et. conducted in 5170 patients with minor Dose-adjusted.87]. 4(10):65-84 ISSN: 2278-6074 enzyme derived from pit viper venom with platelet aggregation [84-86]. dipyridamole. unfractionated heparin is not ischemic stroke. which compared clopidogrel (300 mg unfractionated heparin is not recommended loading followed by 75 mg once daily for 90 for decreasing the risk of death or stroke- days) plus aspirin (75 mg once daily for the related morbidity or for preventing early first 21 days) versus aspirin monotherapy stroke recurrence because of concomitant (75 mg once daily for 90 days) was increase in the occurrence of hemorrhage. such as aspirin and antagonist: Since NMDA receptor over clopidogrel.Glutamate and the NMDA receptor antiplatelet therapy. or intolerant to infraction due to increased risk of severe aspirin.80. Most clinical promising.Anticoagulants: Routine anticoagulation recombinant tissue-type plasminogen with unfractionated or low-molecular- activator [71. anticoagulation continues to be initiation [80. The use of fixed dose subcutaneous trial. 4(10) 75 . through which agonists like important role in normal glutamatergic collagen. Glycoprotein defibrinating properties is under study [73]. in the first 48 than for aspirin monotherapy. Use should be initiated with aspirin160-325mg of ticlopidine.

IJPRR 2015. protecting neurovascular receptor antagonist. through its action as an open-channel Ebselen.C and E) impairment in GABA (γ-aminobutyric acid) supplements is another choice [45]. Experimental receptor antagonist . a free radical Amonophospho-novalerate (APV) a selective scavenger. transporter (GAT-3/GAT-4) function. Memantine. ischemia in rats and reduced stroke Tirilazadmesylate (U-74006F). blocks the receptor in units. has been clinically available in NMDA receptor antagonist prevente the Japan since 2001 and has been reported to excitoxic action of L –glutamate on cortical improve clinical outcomes in patients neurons.BQ-869. Oct 2015. Edaravone. Strategies Tonically active extrasynaptic GABA-A to silence caspases or suppress apoptosis- receptors set an excitability threshold for related gene products using antisense neurons[97]. The neuroprotective effect of BQ.Free radical scavengers: Free radicals the intensity and duration of ischaemia. the therapeutic window seems produced an early and sustained recovery of to be temporally related to the onset of motor function [96]. however [92]. MK 801 is use to studies have revealed that the possible prevent NMDA receptor dependent influx of mechanisms of Edaravoneare decreasing calcium[93]. Mitoquinone (mitoQ) a derivative of 5. 4(10):65-84 ISSN: 2278-6074 side-effects. an inhibitor mortality. The increased amount of independent or redundant cell death free radicals in ischemic stroke condition pathways and/or shortcomings of the damages all cellular components.al. upregulation of caspase- brain cell injury. This treatment [105]. In fact. 4(10) 76 . DNA. and proteins. A non –competetive NMDA exhibiting ischemic strokes. These results have not yet been of neurons. glial cells. caspase activation. This increased tonic protecting mitochondria from oxidative inhibition is mediated by extrasynaptic damage and apoptosis caused by H2O2. synaptic transmission [95]. caspase performance on learning and memory tasks inhibitors do not reduce infarct size in all [98.GABA antagonist: Tonic neuronal ubiquinone. Across derivative.Apoptosis inhibitor: Cell death in the Benzodiazepine inverse agonist specific for a penumbral region of the lesion can be 5-subunit containing extrasynaptic GABA-A suppressed by administering caspase receptors can be used to counteract the inhibitors during and after vessel occlusion heightened inhibition. attenuate ischaemic brain injury and A receptors is divided into synaptic (phasic) neurological function when administered up and extrasynaptic (tonic) components. vessels [100. and caspase inhibitors Cortical GABAergic signalling through GABA. The GABA-A receptors and is caused by an use of antioxidant vitamin (Vit.103]. reduced to ubiquinol and has inhibition is increased in the peri-infarct been found to be an effective antioxidant zone after a stroke. 7. an inhibitor of glutathione blocker and its off-rate is relatively fast so peroxidase-like activity. have been implicated in stroke robustness of caspase expression and pathophysiology as pivotal contributors to cleavage. nerve fibers. a potent NMDA oxidative stress. leading to injuries Neema Kanyal et. to the point of protease activation. an adamantane following transient focal ischaemia. Pharmacological andgenetic oligonucleotides or viral vector-mediated knockdown of a 5-GABA-A receptors gene transfer substantiate these enhance long term potentiationand improve observations [106]. may be a promising that it does not substantially accumulate in neuroprotective agent and improve the the channel to interfere with normal outcome of acute ischemic stroke [104].101]. and blood reproduced in humans. Memantine does this and improve neurological score by 48% [45]. of lipid peroxidation was studied extensively 869 provide new insights with potential in pre-clinical models in the mid-1990s and therapeutic applications for the treatment of was shown to reduce infarct size in rats stroke[94].International Journal of Pharma Research & Review. tirilazad was demonstrated NMDA receptor activity without disrupting to reduce lesion size by an average of 29% normal activity.99].This might relate to 6. lipids. preferentially blocks excessive 19 publications. However. and reducing the activation of concentration-dependent in focal cerebral microglia after ischemic stress [102. brain ischaemia models. including administered agent [107].

may benefit from risk factor modification. patient's age and comorbidities. or chronic kidney converting enzyme inhibitors are the drug of disease and very high (≥10%).113]. BP reduction was associated with a study involving over 20. People with cholesterol clearly beneficial. followed for 5 years showed a benefit of In case of arterial hypertention the target for simvastatin versus placebo in reducing systolic blood pressure is under140mmHg. thus primary-care physicians have a 2. Here the area of in older patients (over 80 years of focus is pharmacological treatment. are infarction.Statins. high-dose diuretics were effective in The main aim of primary prevention is to preventing stroke [111]. initiation of primary in patients with coronary heart disease have prevention strategies may have the greatest been supported by several meta-analyses impact on the disease and its enormous toll [111]. anti- of 18 long-term randomized trials found that inflammatory.International Journal of Pharma Research & Review. Thiazide diuretics and angiotensin- with microalbuminuria.112. The Heart protection is uncertain. Although some of the Outcomes Prevention Evaluation (HOPE) stroke reduction may be due to lipoprotein trial suggested the ACE inhibitor ramipril alterations. 4(10):65-84 ISSN: 2278-6074 Primary preventionof ischemic stroke. A large randomized prospective risk. Oct 2015. (CARE) study found patients with average 1. stroke and myocardial infarction except for older patients (>160-150 mmHg) in high-risk vascular patients regardless of [109].In demonstrated a 36% reduction in the asymptomatic individuals. mortality. 4(10) 77 . the best drug regimen to levels above 200 mg/dl and cardiovascular achieve this is unclear. The choice of an (SCORE) project. type 2 diabetes or type 1 diabetes patients. Of all age).68 relative risk of stroke improved endothelial function. Elevated cholesterol levels treated with pravastatin systolic pressure.Calcium channel blokers can be another strokes. other mechanisms unrelated to reduced the risk of stroke and myocardial their lipid-lowering properties.000 patients 32% risk reduction in stroke incidence[111]. To prevent smoking habits . Although lowering blood pressure is cholesterol levels. The exact than angiotensin-converting enzyme (ACE) mechanism how statins provide stroke inhibitors or α-blockers. A meta-analysis stabilization. IJPRR 2015.Antihypertensive drugs. with hypertension should be treated The risk is high (≥5%) for symptomatic aggressively to the same target blood individuals with manifested cardiovascular pressures which is identified for younger disease. which evaluates the age. it is necessary to treat older adults a value over 5% is considered a high risk . with or without an after a myocardial infarction had a lower accompanying elevation in diastolic risk of stroke than patients receiving pressure. approximately 70% are first-time choice [108. In The benefits of statins in stroke prevention these settings.al. LDL. The Cholesterol and Recurrent Events on the healthcare system [110]. and antithrombotic. and neuroprotective both β-blocker therapy and treatment with properties [111]. events. if there are a choice from which therapy may be initiated combination of factors[109]. The Antihypertensive risk factors should have a complete lipid and Lipid-Lowering Treatment to Prevent analysis (total cholesterol. this value is incidence of total stroke with determined by using nomograms from the antihypertensive treatment (chlorthalidone Systematic Coronary Risk Evaluation or atenolol) [111]. The Systolic Hypertension hypertension (AH). HDL and Heart Attack Trial (ALLHAT) showed that a triglycerides) and most likely would benefit thiazide diuretic was more effective at from cholesterol-lowering regimens. Angiotensin II reduce the risk of ischemic stroke (IS) in receptor blockers (Losartan) may also have asymptomatic patients and focuses on a beneficial effect on cardiovascular events managing known risk factors such as arterial and stroke [112].114]. To date. antihypertensive agent depends on the gender. the largest trials Neema Kanyal et. has been shown to increase stroke placebo. with a 0. diabetes mellitus (DM) in the Elderly Program (SHEP) trial and lipid metabolism disorders[108]. total cholesterol levels and stroke. plaque for ramipril versus placebo.109.Lipid management remains vital great opportunity to identify patients who component of primary stroke prevention. systolic blood pressure (SBP). reducing the risk of cardiovascular events including statins [109.

interaction prevention has been studied in two medium- with other drugs along with serious sized trials. show 9% reduction in recurrent (AF). This led to the quest for an Ticlopidine Study) which show a reduction alternative approach to prevention of of 30. dose adjustment.114]. includes careful [90. management of diabetes mellitus diabetic complications. National Stroke Association and American yet the relative effect is only modest [117].112. Ticlopidine's role in stroke monitoring. However. Both hyperglycemia and such as hypertension.Treatment with among both type 1 and type 2 diabeticswith an antiplatelet agent is an essential part of targets of <130/80 mm Hg. Angiotensin.108]. Timing for initiation of secondary type 2 diabetics is charecterised by preventative treatment depends upon the hyperinsulinemia and insulin resistance clinical scenario. the disadvantages reasonable for patients allergic to aspirin of warfarin treatment. Oct 2015. peripheral neuropathy [111]. IJPRR 2015.al. CATS (Canadian American bleeding. In minor stroke. The relative risk reduction of stroke and other atherothrombotic events as thromboembolic strokes ranged from 42 to compare to aspirin [114] and may be 86% for warfarin versus placebo considered over aspirin alone and it is [111. 4(10) 78 . including stroke and carotid stenosis are important in [111]. 3. and Extended Release (ER) onset insulin-dependent (type 1) diabetes Dipyridamole (200mg twice daily) mellitus was shown to reduce microvascular monotherapy provide comparable benefit complications. increased secondary preventative measures can be very-low-density lipoprotein cholesterol. A meta- first-choice medications for patients with analysis based on individual patient data DM. mainly obesity compared to the general population.For hypercholesterolemia. hyperlipidemia. Intensive therapy to achieve suggests that aspirin (50–325 mg daily) tight control of hyperglycemia with ≥3 doses monotherapy.2% in the risk of vascular events at two ischemic stroke in patients with AF.Antidiabetic drugs. dabigatran [112. atrial hypertension increase the frequency of fibrillation. An years and TASS (Ticlopidine Aspirin Stroke antithrombotic agent that might be used Study) show a 21% reduction in the risk of Neema Kanyal et. and for the prevention of recurrent stroke [119]. According to Primary stroke secondary stroke prevention [116]. nephropathy.114]. Treatment of risk factors hypertension. 4(10):65-84 ISSN: 2278-6074 suggest a beneficial effect of statins for (once it has been approved) instead of stroke prevention in high-risk elderly warfarin is the oral direct thrombin subjects aged 82 years or younger [108].Type 1 diabetics have Secondary prevention of ischemic stroke- both an increased susceptibility to Patients with an initial stroke are known to atherosclerosis and an increased prevalence be at high risk for further stroke(s) of atherogenic risk factors.hypertension.retinopathy. initiated almost immediately after decreased HDL cholesterol.Numerous large clinical Stroke Prevention Study). Six clinical trials have investigated the converting enzyme inhibitors or angiotensin benefit of dipyridamole in the secondary receptor antagonists are recommended as prevention of ischaemic stroke. Clopidogrel is more patients with nonvalvular atrial fibrillation effective.111-113]. and presentation [78]. clopidogrel (75mg daily) per day of insulin in patients with recent. therefore secondary prevention is necessary Syndrome X. Heart Association recommend rigorous Long term anti-platelet therapy should be comprehensive control of blood sugar levels prescribed to all people who are not for adherent patients with type 1 or type 2 prescribed anticoagulant therapy [118].Anticoagulants. . result from ESPS-II (the second European 4. significantly secondary prevention of strokein Non- lowers the risk of stroke [109. finding that trials have demonstrated the efficacy of dipyridamole reduces the risk of stroke warfarin for preventing stroke among recurrence by 18% [83].a metabolic risk factor in some [115]. The cardioembolics(atherothrombotic) patients. most which results in hyperglycemia. inhibitor.Antiplatelet treatment.113]. and abnormal blood lipids.International Journal of Pharma Research & Review. monotherapy.statin are from five of the six trials confirmed the generally recommended [109. diabetes to prevent microvascular Evidence from randomized clinical studies complications. prevention guidelines rigorous control of BP 1.

and diuretic with or without an angiotensin- systemic embolism after minor stroke [78]. with or without the diuretic may be of benefit [90. The LIFE trial suggested for secondary prevention but is the therapy that an ARB (losartan) was superior to a β- of choice and are significantly more effective blocker (atenolol) for prevention of stroke than antiplatelets therapy in reducing the [108]. The angiotensin converting enzyme risk of recurrent ischemic stroke in patient (ACE) inhibitor ramipril significantly with atrial fibrillation or cardioembolic reduces the risk of stroke and acute stroke[90.120] with 23% reduction of Antihypertensive therapy is effective in risk of recurrent stroke [78. However. Current reducing the risk of recurrent stroke.al. however its were approved in the USA in 2012 and 2013 side effects limit its use [120].120]. The definitive role of Dabigatran for aspirin alone is the combination of secondary stroke prevention needs further aspirin(25mg) plus Extended Release (ER) evaluation [114]. Warfarin is treatment of coronary syndromes in patients with choice if the benefit outweighs the risk of vascular disease and at least one recognised hemorrhage. 4(10):65-84 ISSN: 2278-6074 fatal and non-fatal stroke as compared with cardioembolic stroke [121].123].108. Careful AHA/ASA (American Heart Association/ identification of hypertensive patients with American Stroke Association) guidelines for stroke and initiation of single or secondary stroke prevention do not support combination therapy.21 days) perindopril.e. The PROGRESS and ACCESS mg/day). diuretic and an ACEI are useful [113.direct Xa inhibitors secondary stroke prevention. Combination of indapamide.108]. prevention. Oct 2015.low molecular-weight heparin that a diuretic or the combination of a (Tinzaprin) and Danaparoid [108. the only therapy required careful compliance with treatment that has been shown to be better than [109].108. myocardial infarction.120]. antihypertensive agents is provided by the the preliminary results of the CHANCE trial seventh report of the Joint National suggest that use of dual antiplatelet therapy Committee (JNC7) guidelines. 4(10) 79 .Antihypertensive treatment— [80. Ticlopidine may direct thrombin inhibitor and rivaroxaban. The agentbecause it is presumed that the short half-life and rapid onset and decrease individual effects on platelets will be in efficacy are important aspects that additive [117]. a aspirin at three years [83].114].114]. In the in the acute post-ischemic period for a PROGRESS study. agent for secondary prevention of Neema Kanyal et. is essential for the routine use of combination of clopidogrel secondary stroke prevention [122. Currently. Data suggests heparin.108.117.114. there is no compelling patient specific factors and comorbities reason to treat patients with an antiplatelet [114].Drug selection should be based on options are untenable. irrespective of blood pressure anticoagulant are unfractionated and other treatments [78].other generally used risk factor. The advantage of NOAs over One strategy that has been adopted in warfarin is their fixed dosage with no need secondary prevention is the use of aspirin in for regular monitoringand lower quantity of combination with another antiplatelet clinically significant drug interactions. IJPRR 2015. and edoxaban. Dabigatran.114]. Dipyridamole (200 mg twice daily) 3. clopidogrel (75 stroke by 28%. be more efficacious than aspirin in apixaban.119. converting enzyme inhibitor is Result from ACTIVE-A and the ACTIVE-W recommended. Other-CCBs or B- trials suggest that Unless all anticoagulant blokers. Warfarin significantly reduces risk of On the basis of PROGRESS study thiazide recurrent stroke. The HOPE trial also confirmed a 2. active treatment with limited duration (short course i.International Journal of Pharma Research & Review.Anticoagulates—Oral Anticoagulant is benefit of the ACE inhibitor ramipril in not routinely recommended within 24 hrs preventing strokes. respectively. dipyridamole (modified release trials suggest that ACE inhibitors or 200 mg twice daily) can also be used in angiotensin II receptor blockers (ARBs) may patients who were resistant to single or dual be especially effective in secondary stroke antiplatelet therapy [117]. + aspirin due to increase hemorrhagic Information on the use of specific complications [90. reduced the risk of recurrent aspirin (75mg/day).

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