ReviewPathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis
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)
- et al.
Mechanisms of glutamate release from astrocytes
Neurochem. Int.
(2008) - et al.
Expression of synaptobrevin II, cellubrevin and syntaxin but not SNAP-25 in cultured astrocytes
FEBS Lett.
(1995) - et al.
P53 has a direct apoptogenic role at the mitochondria
Mol. Cell
(2003) - et al.
JNK and JIP response in rat brain after transient MCAO
Neurosci. Lett.
(2000) - et al.
Cyclin-dependent kinase 5 activity increases in rat brain following ischaemia
Neurochem. Int.
(1997) - et al.
Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischaemia
Brain Res.
(2005) - et al.
Bcl-2 on the endoplasmic reticulum regulates bax activity by binding to BH3-only proteins
J. Biol. Chem.
(2003) - et al.
Continuous lowdose treatment with neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia/ischaemia
Neuroscience
(2003) - et al.
IL-10 reduces rat brain injury following focal stroke
Neurosci. Lett.
(1998) - et al.
G-CSF protects human cerebral hybrid neurons against in vitro ischaemia
Neurosci. Lett.
(2006)
Up-date in spontaneous cerebral hemorrhage
Med. Intensiva
Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children
Atherosclerosis
Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation
J. Am. Coll. Cardiol.
Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment
Blood
Hemorrhagic transformation. The spectrum of ischemia-related brain hemorrhage
Neurosurg. Clin. N. Am.
Early inflammatory response in ischemic stroke
Thromb. Res.
The role of Chlamydia pneumoniae in atherosclerosis—recent evidence from animal models
Trends Microbiol.
Helicobacter pylori infection as an independent risk factor for cerebral ischemia of atherothrombotic origin
J. Neurol. Sci.
Enhancement of immunoreactivity for NF-κB in human cerebral infarctions
Brain Res.
Expression of tumor necrosis factor alpha after focal cerebral ischemia in the rat
Neuroscience
The burden of coronary, cerebrovascular and peripheral arterial disease
PharmacoEconomics
Frequency of thrombolytic therapy in patients with acute ischemic stroke and the risk of in-hospital mortality: the German Stroke Registers Study Group
Stroke
Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: an invited review
Stroke
Atherosclerosis—an inflammatory disease
N. Engl. J. Med.
Genetics and ischaemic stroke
Brain
Early brain temperature elevation and anaerobic metabolism in human acute ischaemic stroke
Brain
Neuroprotection by the NR3A subunit of the NMDA receptor
J. Neurosci.
The complexity of neurobiological processes in acute ischemic stroke
Clin. Neurol. Neurosurg.
Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake
Nature
Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures
J. Neurosci.
Glutamate-mediated astrocyte-neuron signalling
Nature
Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange
J. Physiol.
P2X7 receptor-mediated release of excitatory amino acids from astrocytes
J. Neurosci.
Functional hemichannels in astrocytes: a novel mechanism of glutamate release
J. Neurosci.
Increase in SNAP-25 immunoreactivity in the mossy fibres following transient forebrain ischaemia in the gerbil
Acta Neuropathol.
Vesicular glutamate transporter-dependent glutamate release from astrocytes
J. Neurosci.
Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate
J. Neurosci.
Synaptobrevin2-expressing vesicles in rat astrocytes: insights into molecular characterization, dynamics and exocytosis
J. Physiol.
Synaptotagmin IV regulates glial glutamate release
Proc. Natl. Acad. Sci. U.S.A.
SNARE protein-dependent glutamate release from astrocytes
J. Neurosci.
CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity
Nat. Neurosci.
The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate
Proc. Natl. Acad. Sci. U.S.A.
Astrocytic exocytosis vesicles and glutamate: a high-resolution immunofluorescence study
Glia
Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death
Nature
Apoptosis in neurodegenerative disorders
Curr. Neurovasc. Res.
Caspase pathways, neuronal apoptosis, and CNS injury
J. Neurotrauma
Transcription factor ATF2 regulation by the JNK signal transduction pathway
Science
Therapeutic potential of anti-inflammatory drugs in focal stroke
Expert. Opin. Investig. Drugs
Many mechanisms for HSP70 protection from cerebral ischaemia
J. Neurosurg. Anesthesiol.
Deletion of cellular prion protein results in reduced Akt activation, enhanced postischaemic caspase-3 activation, and exacerbation of ischaemic brain injury
Stroke
Cited by (404)
Tale of two systems: the intertwining duality of fibrinolysis and lipoprotein metabolism
2023, Journal of Thrombosis and HaemostasisCorrelation of covid-19 and Guillain-Barré syndrome: A Mechanistic Perspective
2023, Obesity Medicine