Future Neuroprotective Approach In Strokes Biology Essay

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Stroke is the third largest cause of death next to heart disease and cancer in the western world. About 5.5 million people died from stroke in 1999. In USA, the incidence of stroke is estimated approximately 750,000 per annum (www.stroke.org), with a mortality of 150,000 per annum. The changing pattern of diseases occurring in India due to efforts in control of communicable diseases have brought in a sharp focus, stroke as one of the major health problems.

Recent community surveys from many regions of India show a prevalence rate presumed to be in the range of 40 to 270/100,000 in rural population as compared to the reported prevalence of 400-800/100,000 in metropolitan cities [1-3]. Males are more susceptible to ischemia as compared to females with a ratio of 1.7.

Stroke occurs as a result of interruption of blood supply to a part of brain typically by a thrombus occlusion or embolus or hemorrhage due to rupture of blood vessels. The symptoms of stroke ranges from blurred vision to vertigo, dizziness, convulsion, and loss of consciousness depending on the area of the nervous system affected. There are wide ranges of motor and sensorimotor deficits, including tremor, lack of co-ordination and partial or complete paralysis. Major disability results from lose of ability to communicate, ambulate, coordinate or reason. Many risk factors have been identified as the probable cause for ischemia. The non-modifiable factors include age, gender, positive family history, ethnicity, previous transient ischemic attack or stroke whereas, the modifiable factors include hypertension, diabetes, smoking, lipid disorders - hypercholestrolemia, alcohol intoxication and physical inactivity.

Treatment options are limited to supportive care and the management of complications. Currently only approved drug for stroke is intravenous recombinant tissue plasminogen activator (rtPA) and is effective within 3 hours of onset of stroke. Because of narrow therapeutic window, it can be used in a very small percentage of acute stroke patients. Despite substantial research into neuroprotection, there is no approved therapy, which can reduce stroke size or neurological disability. The pathophysiology involved in ischemic stroke is complex and not yet fully understood [4-6]. The development of new therapeutic approaches thus remains a crucial challenge. Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke [7]. Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established (Fig. 1). Several therapeutic strategies both in vitro and in vivo inhibiting excitatory amino acid receptor activation, calcium overload and oxidative stress have been explored. A number of experimental agents reduce infarction size in well-controlled animal stroke models have failed to show efficacy in clinical studies. The failure of neuroprotective drugs in the clinic has been tentatively attributed to several factors such as toxicity, narrow therapeutic time window, difficulty in finding a clinically relevant delivery system to administer compounds intracerebrally over a long period of time and difficulty in transposing standardized experimental settings to human situations. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. These targets includes free radicals, poly (ADP ribose) polymerase, apoptotic, mitogen activated protein kinases, growth factors and gene activations.

Fig. 1: Mechanisms of neuronal death in stroke: Interruption of cerebral blood flow results in decreased energy production, which causes failure of ionic pumps, release of excitatory neurotransmitter such as glutamate from presynaptic terminals and generation of free radicals. These events activate downstream signaling cascade such as PARP and MAP kinases leading to cell death. ROS-reactive oxygen species, PARP - poly (ADP ribose) polymerase, MAP kinases-mitogen activated protein kinases.

Antioxidants and Poly (ADP-ribose) polymerase inhibitors

The central nervous system is particularly vulnerable to oxidative damage caused by free radicals and their toxic effects on the brain are diverse. Levels of endogenous antioxidant enzymes fall during ischemia where as free radical production increases during reperfusion. Free radicals such as superoxide, hydroxyl, and nitric oxide are involved in the pathophysiology of cerebral ischemia. Nitric oxide, which is a weak radical that can combine with superoxide to form a more toxic species Peroxynitrite [8]. Peroxynitrite is a potent oxidant that induces an array of deleterious events including peroxidation of membrane lipids, depletion of glutathione, DNA single strand breakage, and mitochondria dysfunction and cell death [9]. Peroxynitrite production depends on the stage of evolution of the ischemic process and on the cell type producing nitric oxide. Recent evidence report that peroxynirite may also act as signaling molecule by promoting phospholipase A2 and release of arachadonic acid. Antioxidants such as tirilazad mesylate and ebselen have been tried in animals and humans. We have demonstrated the neuroprotective effects of antioxidants {metalloporphyrin catalytic antioxidants (FeTMPyP and FeTPPS) and Curcumin} in cerebral ischemia model [10-13].

Free radicals induced DNA nicks can lead to over activation of Poly (ADP-ribose) polymerase (PARP). Though PARP play role in maintaining genomic integrity and in the repair of DNA strand breaks. However, overactivation of PARP in stroke utilizes NAD leading to depletion of NAD and consequently ATP depletion [14]. Energy depletion in already energy starved ischemic neuron results in cellular dysfunctions leading to cell death. Therefore inhibiting PARP may be beneficial effects in the treatment of stroke. There are several reports indicating the therapeutic potential of PARP inhibitors in neuronal injury [15,16]. We have demonstrated neuroprotective effect of PARP inhibitors such as nicotinamide, 3-aminobenzamide, 4-Amino 1, 8-Napthalimide [17] and 1, 5-isoquinolidiol in focal cerebral ischemia model. These agents have shown to protect cells against N-methyl-D-aspartate, nitric oxide, and peroxynitrite induced cytotoxicity and DNA damage. They can prevent depletion of NAD and protect against decreased production of ATP in ischemic brain. 4- nicotinamide and 4-amino 1, 8-napthalimide have shown to protect against necrosis and apoptotic cell death. There are several PARP inhibitors, which are under clinical development for neurological disorders.

MAP Kinase Inhibitors

Mitogen-activated protein kinase (MAPK) pathways are major signaling cascade controlling complex programmes such as embryogenesis, differentiation, and cell death in addition to short-term changes required for homeostasis and hormonal response. There are three pathways consist of kinase cascades leading to activation of ERKs (Extracellular signal Regulated protein Kinases), JNKs (c-Jun N-terminal kinases) and p38/CSBP protein kinases. Both JNKs and p38 pathways are involved in relaying stress type extracellular signals.

The ERK pathway is primarily responsible for transducing mitogenic differential signals to the cell nucleus. ERKs family protein kinase includes mainly ERK1, ERK2. Activation of ERK1/2 is important for the several neuronal functions like neuronal differentiation, and survival during development and adaptive response of mature neurons. There are evidences of activation of ERK1/2 after cerebral ischemia [18]. Several inhibitors of MAPK cascade such as PD98059 and U0126 have been tried for neuroprotection and showed neuroprotective in animal models.

Activation of the JNK/SAPK pathway has also been shown to be increased after transient cerebral ischemia and global ischemia. Three isoforms of JNK viz JNK1, JNK2 and JNK3 have been identified. JNK1 and JNK2 are found in all tissues, whereas JNK3 is found most abundant in brain, heart and testis. JNK activity is increased as early 3 hours after transient MCAO and further increased up to 72 hours. The translocation of activated JNKs into the nucleus is controlled by JIPs (JNK-interacting proteins The regulator of JIP-1 has been shown to prevent neuronal cell death. Under experimental condition PD98059, U0126 inhibit both ERK and JNK. The activity of p38 inhibitor such as SB-203580 may be explained by inhibition of JNK2 and/or JNK3. CEP1347 inhibits JNK pathway however activates ERK pathway. Recently more selective JNK inhibitors have been generated, which includes SP600125 and SP69766.

p38 is widely distributed in mammalian tissue including brain. p38 pathway plays important role in transducing signals involved in cell survival, apoptosis and inflammatory cytokine production. Sustained activation of p38 has been shown to be associated with neuronal cell death/apoptosis and selective p38 inhibitors have been shown to promote cell survival. The p38 pathway is strongly activated by factors such as TNF-µ and interleukin-1b, which is known to be increased after stroke and have been shown to be involved in the mechanism underlying ischemia, induced cell death. Increased p38 activity is reported after cerebral ischemia. Extensive study has been done on p38 inhibitors induced neuroprotection in ischemia [19]. More convincing data supporting the theory that p38 inhibition provides neuroprotection after CNS injury using new generation potent p38 inhibitor SB-239063 have been reported.

Antiapoptotic agents

Despite an intuitive link between ischemic insults and necrosis, growing evidence indicates that programmed cell death culminating in apoptosis may also contribute to ischemia induced delayed neuronal loss [20]. Apoptosis is highly orchestrated form of cell death in which cells neatly commit suicide by chopping themselves into membrane-packed bits. The bcl-2 family of protein is a main protein regulating apoptosis. In Bcl-2 family, BCL-X is the ant-apoptotic proteins where as Bax, Bid, Bad are proapoptotic in nature. Bcl-2 protects the cortical neurons in mice from ischemic insult induced by permanent middle cerebral artery occlusion [21]. Bad, a proapoptotic protein displaces bax from bcl-2 or bcl-xl heterodimer, allowing free Bax to carry out its death promoting functions [22]. Bid promotes apoptosis through its binding to Bax. Bid is cleaved by caspase-8 and cleavage fragment translocates from cytosol to mitochondrial membrane where it induces a structural changes to bax confirmation leading to cytochrome c release, leading to activation of execution caspase. The transgenic mice that overexpressed bcl-2 in neurons had significantly smaller infarction. Bid deficient mice showed less infarction volume in which caspase, cytochrome-c expression is severely impaired. The inhibitor of apoptosis (IAP) family of proteins, which includes the neuronal apoptosis inhibitory protein (NAIP), the X-chromosome-linked IAP (XIAP), and human IAP-1 and -2, constitute cellular regulators of cell death that are very well-conserved across species. XIAP is the most potent inhibitor in the family, and protects against apoptosis by binding to caspases.

Caspases (cysteine proteases) are proteolytic enzymes plays key role in the initiation and execution of the apoptotic program. All caspases are expressed as pro-caspases. Once activated caspases cleaves proteins in a relatively substrate specific manner. Caspases are activated by a) cytokine mediated receptor activation and b) via alteration of mitochondrial membrane potential. Caspase activation is naturally controlled by a set of endogenous molecules residing in the cytosol and in the mitochondria. A dozen of caspases are found till now, amongst caspase 3 plays a major role in apoptosis. Caspase 3 has highest homology to ced-3, the key protease found in programmed cell death, is expressed in CA-1 neurons after cerebral ischemia. Activation of caspase-3 has been demonstrated in IR injury. Inhibitors of caspases were found to reduce the infarction suggests that blocked of the apoptotic pathway prevents the neurons from apoptotic cell death. Caspase irreversible inhibitors z-VAD and z-devd significantly decrease cortical infarction in moderately severe but transient forebrain and focal ischemic insults in rat. Z-VAD fmk (z-Val-Ala-Dl-Asp-fluoromethyl ketone) a broad-spectrum caspase inhibitor showed neuroprotection in animal model of focal and global ischemia. Caspase inhibition holds tremendous neuroprotective potential. Small molecule inhibitors are actively being developed by the pharmaceutical industry. Peptide-based inhibitors may preserve cellular functionality, but only in the short period following ischemic shock, and not in all cases. Other obstacles include safety, brain penetration, and caspase selectivity, potency, and pharmacokinetic properties. Broad-range inhibitors may interact with vital cysteine proteases, resulting in the deregulation of apoptosis, but may also affect critical functions, overloading the cell death pathways and switching the outcome from apoptosis to necrosis.

Inhibiting Phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) pathway

Recently it has been demonstrated that PI3-K/Akt and downstream phosphorylated Bad and proline-rich Akt substrate survival signaling pathways are upregulated in surviving neurons in the ischemic brain that overexpresses copper-zinc superoxide dismutase activity. Studies of Chan group [23] have provided another novel therapeutic targets in neuroprotective strategies in stroke.

Growth factors

In nervous system growth factors stimulate differentiation (during development), support neuronal survival and generally considered to be neuroprotective. Several growth factors are expressed during cerebral ischemia including BDNF, NGF, bFGF, PDGF, TGFb and VEGF. Upregulation of mRNA encoding BDNF and NGF have been observed in dentate granule cells even after brief ischemia. Many preclinical proved the prominent improvement on treatment with growth factors after ischemic insult [24]. The mechanism by which growth factors protect neurons after stroke has been debated. Basic fibroblast growth factor has been reported to protect neurons in in vitro and in vivo against excitotoxicity, ROS and toxins induced insults. Clinical trials were conducted to evaluate the neuroprotective potential of bFGF in stroke patients based on the preclinical reports. Nevertheless, in clinical studies the treatment seems to be worthless and did not alter the mortality rate in patients. In some studies the inherent antigenic property of growth factors resulted in immune reactions (reduction in mean blood pressure and leukocytosis).

Gene therapy

Accumulation of glutamate in the extracellular space and [Ca++]i overload in neurons activates many downstream processes including gene transcription. Distribution and cellular specificity of these responses strongly depend on the duration and severity of the IR insult. More than 100 genes which are denoted as immediate early genes (IEG) have been reported to be expressed within 15 min. of the insult. These include many proteins (eg. cytokines, enzymes, transcription factors etc.). Transcription factors c-fos, fos-B, c-jun and junD are oncogenes, which are involved in the transcriptional activation of other genes. Heat shock genes are activated continuously or immediately after the IEG expression to stabilize the stressed cells. As number of potential gene candidates such as calbindin D28K, glucose transporter, HSP72, interleukin-1 receptor antagonist, interleukin-10, transforming growth factor-β1, glial cell line derived neurotrophin factor, hepatocyte growth factor, Bcl2, neural apoptosis inhibitory protein and redox inducible antioxidant protein have been implicated in cerebral infarction indicating that gene therapy could be one of the most promising therapy and will have several advantage over classical drug therapies. There has been a problem that drug proteins are unable or difficult to pass through blood brain barrier. In gene therapy, however, drug proteins are expressed in the brain with transgene transfer technique. Moreover, the development of new vectors and gene delivery systems has been studied. Herpes Simplex is considered to as one of the common vector systems used to deliver the genes to nervous system. Many proteins have been experimented to evaluate the neuroprotective potential in in vitro and in vivo models of IR injury. Upregulation of glucose transporter-1 as a result of transient transfection using herpes simplex vector system resulted in significant improvement in neuronal survival after focal ischemia. The other proteins that are tried include heat shock protein (HSP70) [25] and calmodulin (Ca++ binding protein). Gene therapy aimed to upregulate these proteins produced conflicting results. HSP70 over expression failed to produce protection against excitotoxicity induced neuronal loss in primary neuronal cultures. Nevertheless it produced neuroprotection on treatment 20 min. after MCAO induced ischemia model of stroke in rat. Herpes simplex virus mediated transfection of calmodulin gene resulted in reduction of neuronal loss. In similar approach many other genes that are involved in apoptotic neuronal loss have also been experimented. The safety of the vectors is considered to an important limiting factor for the gene therapy in human beings. Gene therapy would be a strong strategy for treatment of cerebral infarction in the future.


Despite the significant number of neuroprotective drugs that have been developed to limit ischemic brain damage and improve the outcome for stroke patients, ischemic stroke is still a leading cause of death and long-term disability. Several clinical studies with neuroprotective agents are still in progress and we are waiting for these studies outcome (Table 1). The pathophysiological mechanisms leading to the neuronal death are so complex that single mechanism based neuroprotective agent has never been shown sufficiently reduce cerebral infarction in human. A strategy of using the combination of the neuroprotective agents in the treatment of stroke needs to be explored [26]. Therefore, it would be a candid approach to target drugs, which act by different mechanism simultaneously to limit ischemic injury. In addition to neuroprotective drugs and their combination, strategies aimed at enhancing endogenous neuronal plasticity or replacing dead cells or damaged neurons using stem cell transplantation may be explored for stroke.

Table 1: Ongoing clinical trials for stroke

Sr. No

Drug Name


Development Status



Protease inhibitor

Phase I


Neural cells

Stem cell

Phase I



ADP receptors antagonist

Phase I



Anti-factor IX MAb

Phase I


NPS 1506(delucemine)

NMDA antagonist

Phase I


Troxoprodil (CP-101,606)

NMDA antagonist

Phase II



Endothelin A antagonist

Phase II


737004 (S-0139)

Endothelin A antagonist

Phase II


Zonampanel (YM872)

AMPA antagonist

Phase II


ReoPro (abciximab)

GPIIa/IIIb antagonist

Phase II completed


Repinotan HCI

5HT1 antagonist

Phase II/III


Cerovive (NXY-059)

Free radical scavenger

Phase II/III



Phasphaticholine precursor

Phase IIIReferences

[1] Anand, K.; Chowdhury, D.; Singh, K.B.; Pandav, C.S.; Kapoor, S.K. Estimation of mortality and morbidity due to strokes in India. Neuroepidemiology. 20: 208-11.; 2001.

[2] Dhamija, R.K.; Dhamija, S.B. Prevalence of stroke in rural community--an overview of Indian experience. J Assoc Physicians India. 46: 351-4.; 1998.

[3] Dalal, P.M. Stroke in India : issues in primary and secondary prevention. Neurol India. 50 Suppl: S2-7.; 2002.

[4] Lo, E.H.; Dalkara, T.; Moskowitz, M.A. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 4: 399-415.; 2003.

[5] Fisher, M.; Brott, T.G. Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke. 34: 359-61.; 2003.

[6] Onteniente, B.; Rasika, S.; Benchoua, A.; Guegan, C. Molecular pathways in cerebral ischemia: cues to novel therapeutic strategies. Mol Neurobiol. 27: 33-72.; 2003.

[7] Koroshetz, W.J.; Moskowitz, M.A. Emerging treatments for stroke in humans. Trends Pharmacol Sci. 17: 227-33.; 1996.

[8] Forman, L.J.; Liu, P.; Nagele, R.G.; Yin, K.; Wong, P.Y. Augmentation of nitric oxide, superoxide, and peroxynitrite production during cerebral ischemia and reperfusion in the rat. Neurochem Res. 23: 141-8.; 1998.

[9] Virag, L.; Szabo, E.; Gergely, P.; Szabo, C. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett. 140-141: 113-24.; 2003.

[10] Thiyagarajan, M.; Kaul, C.L.; Sharma, S.S. Neuroprotective efficacy and therapeutic time window of peroxynitrite decomposition catalysts in focal cerebral ischemia in rats. Br J Pharmacol. 142: 899-911. Epub 2004 Jun 14.; 2004.

[11] Thiyagarajan, M.; Sharma, S.S. Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci. 74: 969-85.; 2004.

[12] Gupta, S.; Kaul, C.L.; Sharma, S.S. Neuroprotective effect of combination of poly (ADP-ribose) polymerase inhibitor and antioxidant in middle cerebral artery occlusion induced focal ischemia in rats. Neurol Res. 26: 103-7.; 2004.

[13] Gupta, Y.K.; Chaudhary, G.; Sinha, K. Enhanced protection by melatonin and meloxicam combination in a middle cerebral artery occlusion model of acute ischemic stroke in rat. Can J Physiol Pharmacol. 80: 210-7.; 2002.

[14] Endres, M.; Wang, Z.Q.; Namura, S.; Waeber, C.; Moskowitz, M.A. Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab. 17: 1143-51.; 1997.

[15] Virag, L.; Szabo, C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 54: 375-429.; 2002.

[16] Pieper, A.A.; Verma, A.; Zhang, J.; Snyder, S.H. Poly (ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol Sci. 20: 171-81.; 1999.

[17] Kabra, D.G.; Thiyagarajan, M.; Kaul, C.L.; Sharma, S.S. Neuroprotective effect of 4-amino-1,8-napthalimide, a poly(ADP ribose) polymerase inhibitor in middle cerebral artery occlusion-induced focal cerebral ischemia in rat. Brain Res Bull. 62: 425-33.; 2004.

[18] Hu, B.R.; Liu, C.L.; Park, D.J. Alteration of MAP kinase pathways after transient forebrain ischemia. J Cereb Blood Flow Metab. 20: 1089-95.; 2000.

[19] Legos, J.J.; McLaughlin, B.; Skaper, S.D.; Strijbos, P.J.; Parsons, A.A.; Aizenman, E.; Herin, G.A.; Barone, F.C.; Erhardt, J.A. The selective p38 inhibitor SB-239063 protects primary neurons from mild to moderate excitotoxic injury. Eur J Pharmacol. 447: 37-42.; 2002.

[20] Graham, S.H.; Chen, J. Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab. 21: 99-109.; 2001.

[21] Kane, D.J.; Sarafian, T.A.; Anton, R.; Hahn, H.; Gralla, E.B.; Valentine, J.S.; Ord, T.; Bredesen, D.E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 262: 1274-7.; 1993.

[22] Yin, X.M.; Luo, Y.; Cao, G.; Bai, L.; Pei, W.; Kuharsky, D.K.; Chen, J. Bid-mediated mitochondrial pathway is critical to ischemic neuronal apoptosis and focal cerebral ischemia. J Biol Chem. 277: 42074-81. Epub 2002 Aug 27.; 2002.

[23] Chan, P.H. Future targets and cascades for neuroprotective strategies. Stroke. 35: 2748-50. Epub 2004 Sep 23.; 2004.

[24] Kawamata, T.; Dietrich, W.D.; Schallert, T.; Gotts, J.E.; Cocke, R.R.; Benowitz, L.I.; Finklestein, S.P. Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. Proc Natl Acad Sci U S A. 94: 8179-84.; 1997.

[25] Yenari, M.A.; Giffard, R.G.; Sapolsky, R.M.; Steinberg, G.K. The neuroprotective potential of heat shock protein 70 (HSP70). Mol Med Today. 5: 525-31.; 1999.

[26] Schmid-Elsaesser, R.; Hungerhuber, E.; Zausinger, S.; Baethmann, A.; Reulen, H.J. Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke. 30: 1891-9.; 1999.

Ravinder K. Kaundal and Shyam S. Sharma *

Department of Pharmacology and Toxicology , National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali)-160062, Punjab, INDIA

Dr. Sharma is currently Associate Professor, Pharmacology and Toxicology at National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India. Before joining NIPER he worked as Senior Research Associate in 1997 at Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi. He worked as postdoctoral fellow at Department of Pharmacodynamics College of Pharmacy, The University of Illinois at Chicago, Chicago, USA. He did his PhD from AIIMS, New Delhi in 1998 and M. Pharm. (Pharmacology) from College of Pharmacy, New Delhi in 1991.

Dr. Sharma is currently involved in drug discovery research with major interests in diseases areas such as stroke, diabetic neuropathy and Leishmania. He has worked extensively on involvement of oxidative stress, poly (ADP ribose) polymerase and MAP kinase pathway in stroke and diabetic neuropathy. He has more than 20 papers in peer-reviewed scientific journals and presented 40 papers in several national and international conferences. He has guided more than 15 masters and PhD students.

He is editor of Current Research and Information on Pharmaceutical Sciences (CRIPS) and a life member of the Indian Pharmacological Society (IPS). *corresponding author e-mail:sssharma@niper.ac.in, shyamsharma14@yahoo.com


Stroke: The Neglected Epidemic, an Indian perspective

PK Sethi 

Department of Neurology

Sir Ganga Ram Hospital, Rajinder Nagar  

I Anand 

Department of Neurology

Sir Ganga Ram Hospital, Rajinder Nagar  

R Ranjan 

Department of Neurology

Sir Ganga Ram Hospital, Rajinder Nagar  

NK Sethi 

Department of Neurology

Weill Cornell Medical Center  

J Torgovnick 

Department of Neurology

Saint Vincent's Hospital and Medical Centers  

Citation: P. Sethi, I. Anand, R. Ranjan, N. Sethi & J. Torgovnick : Stroke: The Neglected Epidemic, an Indian perspective . The Internet Journal of Neurology. 2007 Volume 8 Number 1

Table of Contents

Stroke in India

Address for correspondence


It is well known that in most developed countries cerebrovascular disease (CVD) or stroke is a common cause of death and disability. In U.S.A. and U.K., stroke ranks third as a cause of death after heart disease and cancer. The annual economic consequence due to CVD has been estimated to exceed 7 billion dollars in USA1, 2. Prevalence rates reported for cerebrovascular accident (CVA) worldwide vary between 500 to 800 per 100,000 population. Oriental studies have shown higher prevalence and incidence rates.1 Precious little is known about the epidemiology of stroke in India and of the Indian subcontinent in general. Is this burden same as in the West? Expectation rate of 600 in the occident and perhaps 900 in orient for the prevalence seems pausible1.

Do we have enough data to estimate the burden of stroke in India? India's population is one billion plus, taking a prevalence rate of 900 per 100,000 into account, stroke is then indeed occurring in epidemic proportions in India. It is a matter of regret that our knowledge about epidemiology of stroke in India is so poor. So if stroke is occurring in epidemic proportions, then indeed it is a neglected epidemic.

Stroke in India

Epidemiology, originally signified the study of epidemics, but it is now used more broadly for the study of groups: epi=among; demos= people; logos=study. India is a vast country with diverse geographic variation. The population stands above one billion and life style of people varies in different parts of the country. It is a multi-ethnic, multi-cultural, multi-religious society. There are many religions sects with different life styles. Food habits vary in different religious groups. Some like the Jains and Buddhists are strict vegetarians while meat and meat products are an integral part of the diet of the Sikhs and Punjabis. Some literally drink "Ghee" a native cooking oil rich in saturated fats. Some till recently have not used salt in cooking as people from Mizoram. Some don't smoke but instead eat tobacco. It would be interesting and highly educative to study the epidemiology of stroke in such a diverse group.

Unfortunately in India, epidemiological information on annual incidence, prevalence rates, morbidity and mortality trends in well defined populations is not available. Most of data published is from retrospective analysis of subjects admitted to urban medical hospitals though the majority of Indian population lives in small towns and villages. Some of the studies lack proper stroke terminology and baseline investigations.

Despite these limitations, analysis of data collected from major urban hospitals suggests that nearly 2% of all hospital admissions; 4-5% of medical and 20% of neurological admission have CVD. The incidence of stroke in the young (< 40 years of age) is high (13 to 32%) when compared to similar data from the west. Literature is available suggesting that risk of coronary artery disease (CAD) is higher in Indians specially in the young population.3,4,5,6 We know that the risk factors for stroke and coronary artery disease are same. We also know that coronary artery disease is being reported more and more in people of Indian origin, whether staying in India or abroad, as compared to Western population. Will it then be fair to assume that incidence of stroke and its prevalence may be higher in Indians too? 3, 4, 5

Many studies on epidemiology of stroke in India are deficient with respect to randomization of data, making comparison between them difficult. In addition, many of these studies are published in local journals, which are not indexed and therefore difficult to retrieve from, or have been only published as abstracts. Table I presents a summary of crude prevalence rate by survey of hemiplegia presumed to be CVD from different parts of India namely the north, south, west and east7,8,9,10,11,12,13,14,15,16 This data show prevalence of CVD in the range of 52 to 843 per 100,000 population. Only data from the Paris Community (Bombay), (843/100,000) comes somewhere near the expected rate of 900/100,000 in the oriental population. Lower rate reported in other studies may be due to several factors. In some only hemiplegia was taken as a crude indicator of stroke. Further, perhaps the method of collection of public health data was faulty.

In India, particularly in rural areas, the health care delivery system is still deficient, both in quality and coverage. Accurate and current census data is not available, and the number of well trained physicians and health workers are limited, rendering the proper study of neuroepidemiology of CVD difficult. As we do not know the real burden of various diseases, planning of health services and distribution of resources is difficult and at times an educated guess at the best.


Table 1: India: Crude Prevalence Rate By Survey Of Hemiplegia Presumed To Be CVA.

Another striking thing in India is the lack of awareness about stroke and stroke prevention. The biggest thing which has happened to stroke and its management In India is not tPA rather coining of the word "Brain Attack". For a change neurologists left their ivory towers and spoke in a layman's language. Unless people know what disease we are talking about, one cannot collect any meaningful epidemiological data or talk about prevention of the disease. The best treatment of stroke still remains its prevention. For every lecture a neurologist gives on tPA he should give at least ten on primary and secondary prevention of stroke. We are already paying a heavy price for negligence of this simple fact. What about negligence on part of the patient? Indians, by large, are not health conscious. There is no social security system and no worthwhile health insurance. The feeling is that some how their "Karma" will save them from disease or if unfortunately they fall sick, God shall look after them.

India may be a poor country but it is rich in computer hardware and software technology. Computers are rapidly spreading to towns and villages. Medical authorities with the help of the mass-media should make interesting programs to educate people about stroke, its warning signs and how to prevent it. Educating of the masses should be the primary goal. Neurological associations and societies should have a patient forum to convey this message to the public. Once this is achieved, we shall be in an excellent position to study the epidemiology of this epidemic, till then this epidemic remains largely neglected.

Address for correspondence

NK Sethi, MD

Department of Neurology

Weill Cornell Medical Center

New York, NY 10021

Email: [sethinitinmd@hotmail.com]