Molecular mechanisms of cerebral ischemia-induced neuronal death.
The mode of neuronal death caused by cerebral ischemia and reperfusion appears on the continuum between the poles of catastrophic necrosis and apoptosis: ischemic neurons exhibit many biochemical hallmarks of apoptosis but remain cytologically necrotic. The position on this continuum may be modulated by the severity of the ischemic insult. The ischemia-induced neuronal death is an active process (energy dependent) and is the result of activation of cascades of detrimental biochemical events that include perturbion of calcium homeostasis leading to increased excitotoxicity, malfunction of endoplasmic reticulum and mitochondria, elevation of oxidative stress causing DNA damage, alteration in proapoptotic gene expression, and activation of the effector cysteine proteases (caspases) and endonucleases leading to the final degradation of the genome. In spite of strong evidence showing that brain infarction can be reduced by inhibiting any one of the above biochemical events, such as targeting excitotoxicity, up-regulation of an antiapoptotic gene, or inhibition of a down-stream effector caspase, it is becoming clear that targeting a single gene or factor is not sufficient for stroke therapeutics. An effective neuroprotective therapy is likely to be a cocktail aimed at all of the above detrimental events evoked by cerebral ischemia and the success of such therapeutic intervention relies upon the complete elucidation of pathways and mechanisms of the cerebral ischemia-induced active neuronal death.
Hou
Sheng T
ST
Experimental Stroke Group, Institute for Biological Sciences, National Research Council Canada, Ottawa, Ontario, KIA 0R6, Canada.
MacManus
John P
JP
D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
D009498:Neurotoxins