Elsevier

Pathophysiology

Volume 17, Issue 3, June 2010, Pages 197-218
Pathophysiology

Review
Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis

https://doi.org/10.1016/j.pathophys.2009.12.001Get rights and content

Abstract

Stroke is a serious neurological disease, and constitutes a major cause of death and disability throughout the world. The pathophysiology of stroke is complex, and involves excitotoxicity mechanisms, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis, angiogenesis and neuroprotection. The ultimate result of ischemic cascade initiated by acute stroke is neuronal death along with an irreversible loss of neuronal function. Therapeutic strategies in stroke have been developed with two main aims: restoration of cerebral flow and the minimization of the deleterious effects of ischemia on neurons. Intense research spanning over the last two decades has witnessed significant therapeutic advances in the form of carotid endarterectomy, thrombolytics, anticoagulant therapy, antiplatelet agents, neuroprotective agents, and treating associated risk factors such as hypertension and hyperlipidemia. However, the search for an effective neuroprotectant remains frustrating, and the current therapeutic protocols remain suboptimal. Till date only one FDA-approved drug is available for ischemic stroke; i.e., the serine protease tissue-type plasminogen activator (tPA), utility of which is limited by short therapeutic window. The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, with emphasis on potential novel targets for designing newer therapeutic modalities.

Introduction

Stroke is the leading cause of disability worldwide, the second most common cause of dementia and the third leading cause of death [1]. It has enormous clinical, social, and economic implications and demands a significant effort from both basic scientists and clinicians in the quest for understanding the underlying pathogenetic mechanisms, and thereby adopting suitable preventive measures and successful therapies, beyond thrombolysis, which is but available to <5% of all patients [2].

Owing to its high prevalence, high burden of illness and economic cost, well-defined modifiable risk factors, and effective prevention measures stroke is well suited for prevention. However, unfavourable trends in stroke risk factor profile; lack of awareness among public and medical fraternity; misapplication or underutilization of stroke preventative programmes; and lack of emphasis on preventive training in medical school and postgraduate programmes throughout the world, have precipitated high stroke rates and culminated into widening the stroke prevention gap [3].

There is increasing evidence that an inflammatory process is the central dogma in the development and progression of atherosclerosis, a common entity underlying the pathogenesis of cerebral and cardiac ischemia [4]. This, coupled with the realization that only part of the disease risk can be explained by conventional risk factors, has ushered the search for newer pathogenetic mechanisms in stroke, which possibly may have therapeutic ramifications beyond conventional thrombolysis.

Though strong epidemiological and animal studies have implicated genetic influences in the pathogenesis of multifactorial ischemic stroke, identification of individual causative mutations remains handicapped due to limited number of approaches currently available [5], [164].

The primary objectives of this review are: (A) to summarize the pathophysiology of stroke, with respect to atherosclerosis; (B) to outline the inflammatory and infective conditions associated with clinical stroke, along with role of various inflammatory mediators; (C) current status and understanding of role of genetics in stroke; (D) unifying the proposed mechanisms linking various pathogenetic processes; and (E) to discuss the emerging opportunities for novel therapeutic strategies.

Section snippets

Ischemic stroke

Ischemic stroke may manifest in the form of thrombotic stroke (large vessel and small vessel types); embolic stroke (with/without known cardiac and/or arterial factor); systemic hypoperfusion (Watershed or Border Zone stroke); or venous thrombosis. Irrespective of the cause, compromised vascular supply to the brain is the primary event in majority (85–90%) of acute strokes. Low respiratory reserve and complete dependence on aerobic metabolism make brain tissue particularly vulnerable to effects

Atherosclerosis and stroke

Atherogenesis is a decade-long process which involves luminal obstruction by cellular and extracellular substances. The pathogenetic process from onset of atherosclerotic changes in cerebrovascular or extracranial circulation to precipitation of acute ischemic stroke with its consequent cell damage is complex and many of the intermediary steps are not fully understood.

Changes may manifest in the form of: (a) fatty streak, earliest lesions seen as yellowish areas of discoloration of intima, due

Inflammation and stroke

Currently there is increasing evidence that some form of inflammatory mechanism plays a role in development and progression of stroke, especially in the setting of cerebral ischemia due to subarcahnoid hemorrhage, head injury or cardiac arrest. It has been reported that low grade inflammation with raised levels of C-reactive protein (CRP) is an independent risk factor for stroke and TIA [81]. In pediatric population, inflammation without significant atherosclerosis has been associated with

Gentics and stroke

Ischemic stroke can be a manifestation of a number of single-gene disorders, where it is usually part of a multisystem disorder. While classical forms of inheritance cannot be demonstrated, epidemiological and animal studies strongly suggest importance of genetic factors.

Proposed interactions unifying various pathophysiologic mechanisms

A wide range of mechanisms have been proposed for unifying and linking inflammation, infection, atherosclerosis and vascular risk factors in the pathogenesis of stroke.

Implications for therapeutic intervention beyond thrombolytics

Current protocols of primary stroke management and secondary prevention focuses on modifiable vascular risk factors such as hypertension, smoking, carotid stenosis, atrial fibrillation, physical inactivity, diabetes mellitus, and dyslipidemia, with usage of drugs like antiplatelet agents, antihypertensive drugs, lipid-lowering agents, and anticoagulant drugs. A recent addition to this armamentarium was intravenous tissue plasminogen activator in cases of acute ischemic stroke, the efficacy of

Conclusion

The complex pathophysiology stroke encompasses various excitotoxicity mechanisms, inflammatory pathways, oxidative damage and ionic imbalances. Despite significant therapeutic advances in the form of carotid endarterectomy, thrombolytics, anticoagulant therapy, antiplatelet agents, neuroprotective agents, and treating associated risk factors such as hypertension and dyslipidemia have failed to reduce the burden of stroke. Current understanding of inflammation and ischemia has caused a paradigm

References (168)

  • D. Escudero Augusto et al.

    Up-date in spontaneous cerebral hemorrhage

    Med. Intensiva

    (2008)
  • H.C. Stary

    Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children

    Atherosclerosis

    (1987)
  • J.H. Ip et al.

    Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation

    J. Am. Coll. Cardiol.

    (1990)
  • G. Stoll et al.

    Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment

    Blood

    (2008)
  • P.A. Teal et al.

    Hemorrhagic transformation. The spectrum of ischemia-related brain hemorrhage

    Neurosurg. Clin. N. Am.

    (1992)
  • M. Di Napoli

    Early inflammatory response in ischemic stroke

    Thromb. Res.

    (2001)
  • L.A. Campbell et al.

    The role of Chlamydia pneumoniae in atherosclerosis—recent evidence from animal models

    Trends Microbiol.

    (2000)
  • A.J. Grau et al.

    Helicobacter pylori infection as an independent risk factor for cerebral ischemia of atherothrombotic origin

    J. Neurol. Sci.

    (2001)
  • K. Terai et al.

    Enhancement of immunoreactivity for NF-κB in human cerebral infarctions

    Brain Res.

    (1996)
  • M. Buttini et al.

    Expression of tumor necrosis factor alpha after focal cerebral ischemia in the rat

    Neuroscience

    (1996)
  • A. Bakhai

    The burden of coronary, cerebrovascular and peripheral arterial disease

    PharmacoEconomics

    (2004)
  • P.U. Heuschmann et al.

    Frequency of thrombolytic therapy in patients with acute ischemic stroke and the risk of in-hospital mortality: the German Stroke Registers Study Group

    Stroke

    (2003)
  • P.B. Gorelick

    Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review

    Stroke

    (2002)
  • R. Ross

    Atherosclerosis—an inflammatory disease

    N. Engl. J. Med.

    (1999)
  • A. Hassan et al.

    Genetics and ischaemic stroke

    Brain

    (2000)
  • B. Karaszewski et al.

    Early brain temperature elevation and anaerobic metabolism in human acute ischaemic stroke

    Brain

    (2009)
  • N. Nakanishi et al.

    Neuroprotection by the NR3A subunit of the NMDA receptor

    J. Neurosci.

    (2009)
  • R. Brouns et al.

    The complexity of neurobiological processes in acute ischemic stroke

    Clin. Neurol. Neurosurg.

    (2009)
  • M. Szatkowski et al.

    Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake

    Nature

    (1990)
  • H.K. Kimelberg et al.

    Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures

    J. Neurosci.

    (1990)
  • V. Parpura et al.

    Glutamate-mediated astrocyte-neuron signalling

    Nature

    (1994)
  • O. Warr et al.

    Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange

    J. Physiol.

    (1999)
  • S. Duan et al.

    P2X7 receptor-mediated release of excitatory amino acids from astrocytes

    J. Neurosci.

    (2003)
  • Z.C. Ye et al.

    Functional hemichannels in astrocytes: a novel mechanism of glutamate release

    J. Neurosci.

    (2003)
  • E. Marti et al.

    Increase in SNAP-25 immunoreactivity in the mossy fibres following transient forebrain ischaemia in the gerbil

    Acta Neuropathol.

    (1998)
  • V. Montana et al.

    Vesicular glutamate transporter-dependent glutamate release from astrocytes

    J. Neurosci.

    (2004)
  • L. Pasti et al.

    Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate

    J. Neurosci.

    (2001)
  • D. Crippa et al.

    Synaptobrevin2-expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis

    J. Physiol.

    (2006)
  • Q. Zhang et al.

    Synaptotagmin IV regulates glial glutamate release

    Proc. Natl. Acad. Sci. U.S.A.

    (2004)
  • A. Araque et al.

    SNARE protein-dependent glutamate release from astrocytes

    J. Neurosci.

    (2000)
  • P. Bezzi et al.

    CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity

    Nat. Neurosci.

    (2001)
  • R.T. Fremeau et al.

    The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • E. Anlauf et al.

    Astrocytic exocytosis vesicles and glutamate: a high-resolution immunofluorescence study

    Glia

    (2005)
  • N. Joza et al.

    Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death

    Nature

    (2001)
  • O. Ekshyyan et al.

    Apoptosis in neurodegenerative disorders

    Curr. Neurovasc. Res.

    (2004)
  • B.A. Eldadah et al.

    Caspase pathways, neuronal apoptosis, and CNS injury

    J. Neurotrauma

    (2000)
  • S. Gupta et al.

    Transcription factor ATF2 regulation by the JNK signal transduction pathway

    Science

    (1995)
  • F.C. Barone et al.

    Therapeutic potential of anti-inflammatory drugs in focal stroke

    Expert. Opin. Investig. Drugs

    (2000)
  • R.G. Giffard et al.

    Many mechanisms for HSP70 protection from cerebral ischaemia

    J. Neurosurg. Anesthesiol.

    (2004)
  • J. Weise et al.

    Deletion of cellular prion protein results in reduced Akt activation, enhanced postischaemic caspase-3 activation, and exacerbation of ischaemic brain injury

    Stroke

    (2006)
  • Cited by (404)

    View all citing articles on Scopus
    View full text