Mechanisms of ischemic brain damage
Introduction
Each year in the United States approximately 700,000 individuals are afflicted with a stroke. Currently there are approximately 2 million survivors of stroke living in the US with prolonged disability, many unable to work or resume personal relationships. In China 1.5 million people die from stroke each year and in developed nations stroke is the third leading cause of death, only surpassed by heart disease and cancer. In the US health care costs reach 62 billion dollars annually. (Fisher and Bogousslavsky, 1998, Pancioli et al., 1998, Stephenson, 1998, Caplan, 2000, Rosamond et al., 2007; Flynn et al, this issue). There are very few treatments for stroke and the development of new therapeutics is imperative. At present the only FDA approved treatment is to provide tissue plasminogen activator to reopen occluded blood vessels, however, due to a narrow time window this treatment is only appropriate for a very small number of patients.
Section snippets
Stroke pathophysiology
Stroke can be subdivided into 2 categories, ischemic and hemorrhagic. Ischemic strokes are more prevalent than hemorrhagic, making up approximately 87% of all cases, and have been the target of most drug trials (Rosamond et al., 2007). A thrombosis, an embolism or systemic hypo-perfusion, all of which result in a restriction of blood flow to the brain, can cause an ischemic stroke, which results in insufficient oxygen and glucose delivery to support cellular homoestasis. This elicits multiple
Excitotoxcity, acidotoxicity and ionic imbalance
The human brain comprises 2% of body weight but requires 20% of total oxygen consumption (Edvinsson and Krause, 2002). The brain requires this large amount of oxygen to generate sufficient ATP by oxidative phosphorylation to maintain and restore ionic gradients. One estimate suggests that the Na+/K+ATPase found on the plasma membrane of neurons, consumes 70% of the energy supplied to the brain (Edvinsson and Krause, 2002). This ion pump maintains the high intracellular K+ concentration and the
Peri-infarct depolarizations
Cortical spreading depression (CSD) is a self-propagating wave of electrochemical activity that progresses through cortical tissue in intact brain. CSD causes sustained (1–5 min) cellular depolarization, depressed neuro-electrical activity, increased glutamate release and loss of membrane ionic gradients (Gonzalez et al., 1992). Peri-infarct depolarizations (PIDs) are spontaneous waves of depolarization with all of the characteristic features of CSD that propagate through the penumbra following
Oxidative and nitrative stress
High levels of intracellular Ca2+, Na+ and ADP cause mitochondria to produce deleterious levels of reactive oxygen species. Unlike other organs the brain is especially vulnerable to reactive oxygen species due to neurons having relatively low levels of endogenous antioxidants (Coyle and Puttfarcken, 1993). Overly abundant oxygen radicals cause the destruction of cellular macromolecules and participate in signaling mechanisms that result in apoptotic cell death (Halliwell, 1994, Sugawara and
Inflammation
Inflammation contributes to stroke-related brain injury. However, the effect of individual components of the inflammatory cascade can be beneficial depending on the stage of tissue injury, the magnitude of the response and whether the inflammatory component also activates neuroprotective pathways (Bruce et al., 1996, Nawashiro et al., 2000, Zhang et al., 2000). The inflammatory response is a composite process that involves many different cell types, inflammatory mediators and extracellular
Apoptosis
Mild ischemic injury preferentially induces cell death via an apoptotic-like mechanism rather than necrosis. Because the ischemic penumbra sustains milder injury and preserves ATP, apoptosis predominates in this region (Kerr, 1965, Kerr et al., 1972, Gonzalez et al., 2006). Triggers of apoptosis include oxygen free radicals, death receptor ligation, DNA damage, protease activation and ionic imbalance.
The release of cytochrome c from the outer mitochondrial membrane plays a central role in
Conclusion and perspectives
Cell death following stroke results from the complex interplay of excitotoxicity, acidosis, inflammation, oxidative stress, peri-infarct depolarization and apoptosis. On the basis of the complexity of events in cerebral ischemia and the disappointing results from single agent trials, it may be unrealistic to expect that a single neuroprotective drug will demonstrate benefits in human stroke. In light of this complexity, it is likely that effective stroke therapy will require a combinatorial
Acknowledgements
This work was supported by NIH grant NS046827 (MS-P).
References (90)
- et al.
Life or death decisions by the Bcl-2 protein family
Trends in Biochemical Sciences
(2001) - et al.
Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells
Journal of Biological Chemistry
(2001) - et al.
Reduced cerebral ischemia– reperfusion injury in Toll-like receptor 4 deficient mice
Biochemical and Biophysical Research Communications
(2007) - et al.
Reactive oxygen species and the modulation of stroke
Free Radical Biology and Medicine
(2005) - et al.
Cellular localization of tumor necrosis factor alpha following focal cerebral ischemia in mice
Brain Research
(1998) - et al.
Neuroprotection against ischemic brain injury by SP600125 via suppressing the extrinsic and intrinsic pathways of apoptosis
Brain Research
(2006) - et al.
Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N terminal kinase (JNK) via nuclear and non-nuclear pathways
Neuroscience
(2006) Free radicals, antioxidants, and human disease: curiousity, cause, or consequence?
Lancet
(1994)- et al.
Lipopolysaccharide preconditioning induces robust protection against brain injury resulting from deep hypothermic circulatory arrest
Stroke
(2007) - et al.
Inflammation in stroke and focal cerebral ischemia
Surgical Neurology
(2006)
Induction of heat shock hsp 70 mRNA and HSP70 kDa protein in neurons in the ‘penumbra’ following focal cerebral ischemia in the rat
Brain Research
Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke – an MRI study
Experimental Neurology
Enhancing the efficacy of thrombolysis by AMPA receptor blockade NBQX in a rat embolic stroke model
Journal of Neurological Sciences
Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury
Life Science
Neuroprotective effects of TNF binding protein in focal cerebral ischemia
Brain Research
The distinct role of mGlu1 receptors in post-ischemic neuronal death
Trends in Pharmacological Sciences
ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia
Neuron
Peripheral administration of Interleukin-1 Receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat
Experimental Neurology
Evidence of the peripheral inflammatory response in patients with transient ischeimc attack
Journal of Stroke and Cerebrovascular Diseases
Correlations and interactions in the production of IL-6, IL-1, and TNF in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF
Blood
Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion
Journal of Neuroimmunology
Adenovirus mediated transfer of Bcl-X(L) protects neuronal cells from Bax-induced apoptosis
Experimental Cell Research
Effect of ischemic preconditioning on genomic response to cerebral ischemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states
Lancet
Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats
Brain Research
New therapeutic possibility of blocking cytokine-induced neutrophil chemoattractant on transient ischemic brain damage in rats
Brain Research
Tumor necrosis factor alpha is increased in cerebrospinal fluid and serum of ischemic stroke patients and correlates to volume of evolving brain infarct
Biomedical Pharmacotherapy
TLR2 has a detrimental role in mouse transient focal cerebral ischemia
Biochemical and Biophysical Research Communications
Combination therapy with U74006F (tirilazad mesylate), MK-801, insulin and diazepam in transient forebrain ischemia
Neurology Research
Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance
Journal of Cerebral Blood Flow & Metabolism
Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors
Nature, Medicine
Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs
Journal of Cerebral Blood Flow & Metabolism
Caplan's Stroke. A Clinical Approach
Bcl-2 is expressed in neurons that survive focal ischemia in the rat
Neuroreport
Temperature modulation of cerebral depolarization during focal cerebral ischemia in rats, correlation with ischemic injury
Journal of Cerebral Blood Flow & Metabolism
Neutrophil protein kinase C delta as a mediator of stroke reperfusion injury
Journal of Clinical Investigation
Oxidative stress, glutamate, and neurodegenerative disorders
Science
Cerebral Blood Flow and Metabolism
Effects of crowding of mice on humoral antibody formation and protection to lethal antigenic challenge
Psychosomatic Medicine
Shift of the cellular oxidation reduction potential in neural cells expressing Bcl-2
Journal of Neurochemistry
Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex
Brain
Further evolution toward effective therapy for acute ischemic stroke
JAMA
Interleukin-1 receptor antagonsist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion
American Journal of Pathology
The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischemia in the rat
Journal of Cerebral Blood Flow & Metabolism
Somatostatin receptors are expressed by immature cerebellar granule cells
Proceedings of the National Academy of Sciences of the USA
Acute Ischemic Stroke. Imaging and Intervention
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