Mitochondrial superoxide production in kainate-induced hippocampal damage.
The objective of this study was to determine the role of mitochondrial superoxide radical-mediated oxidative damage in seizure-induced neuronal death. Using aconitase inactivation as an index of superoxide production, we found that systemic administration of kainate in rats increased mitochondrial superoxide production in the hippocampus at times preceding neuronal death. 8-Hydroxy-2-deoxyguanosine, an oxidative lesion of DNA, was also increased in the rat hippocampus following kainate administration. Manganese(III) tetrakis(4-benzoic acid)porphyrin, a catalytic antioxidant, inhibited kainate-induced mitochondrial superoxide production, 8-hydroxy-2-deoxyguanosine formation and neuronal loss in the rat hippocampus. Kainate-induced increases of mitochondrial superoxide production and hippocampal neuronal loss were attenuated in transgenic mice overexpressing mitochondrial superoxide dismutase-2. We propose that these results demonstrate a role for mitochondrial superoxide production in hippocampal pathology produced by kainate seizures.
Liang
L P
LP
Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Ho
Y S
YS
Patel
M
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004827:Epilepsy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D009498:Neurotoxins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D013481:Superoxides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; D000154:Aconitate Hydratase; D003849:Deoxyguanosine; D007608:Kainic Acid