Hypoxia in presence of blockers of excitotoxicity induces a caspase-dependent neuronal necrosis.
When excitotoxic mechanisms are blocked, severe or prolonged hypoxia and hypoxia-ischemia can still kill neurons, by a mechanism which is poorly understood. We studied this "non-excitotoxic hypoxic death" in primary cultures of rat dentate gyrus neurons. Many neurons subjected to hypoxia in the presence of blockers of ionotropic glutamate receptors developed the electron microscopic features of necrosis. They showed early mitochondrial swelling, loss of mitochondrial membrane potential and cytoplasmic release of cytochrome c, followed by activation of caspase-9, and by caspase-9-dependent activation of caspase-3. Caspase inhibitors were neuroprotective. These results suggest that "non-excitotoxic hypoxic neuronal death" requires the activation in many neurons of a cell death program originating in mitochondria and leading to necrosis.
Niquet
J
J
Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, West Los Angeles, CA 90073, USA. jniquet@ucla.edu
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Allen
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Wasterlain
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016253:Microscopy, Immunoelectron / Q000379:methods; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D012966:Sodium Cyanide / Q000633:toxicity
D018696:Neuroprotective Agents; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016291:Dizocilpine Maleate; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D020169:Caspases; D012966:Sodium Cyanide