title: Kainate-induced mitochondrial oxidative stress contributes to hippocampal degeneration in senescence-accelerated mice.
abstract: We have demonstrated that kainate (KA) induces a reduction in mitochondrial Mn-superoxide dismutase (Mn-SOD) expression in the rat hippocampus and that KA-induced oxidative damage is more prominent in senile-prone (SAM-P8) than senile-resistant (SAM-R1) mice. To extend this, we examined whether KA seizure sensitivity contributed to mitochondrial degeneration in these mouse strains. KA-induced seizure susceptibility in SAM-P8 mice paralleled prominent increases in lipid peroxidation and protein oxidation and was accompanied by significant impairment in glutathione homeostasis in the hippocampus. These findings were more pronounced in the mitochondrial fraction than in the hippocampal homogenate. Consistently, KA-induced decreases in Mn-SOD protein expression, mitochondrial transmembrane potential, and uncoupling protein (UCP)-2 expression were more prominent in SAM-P8 than SAM-R1 mice. Marked release of cytochrome c from mitochondria into the cytosol and a higher level of caspase-3 cleavage were observed in KA-treated SAM-P8 mice. Additionally, electron microscopic evaluation indicated that KA-induced increases in mitochondrial damage and lipofuscin-like substances were more pronounced in SAM-P8 than SAM-R1 animals. These results suggest that KA-mediated mitochondrial oxidative stress contributed to hippocampal degeneration in the senile-prone mouse.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Guoying
authors.initials: G
authors.lastname: Bing
authors.forename: Eon Sub
authors.initials: ES
authors.lastname: Park
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Chae
authors.forename: Tran Phi Hoang
authors.initials: TP
authors.lastname: Yen
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Myung-Bok
authors.initials: MB
authors.lastname: Wie
authors.forename: Bae-Dong
authors.initials: BD
authors.lastname: Jung
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sung-Youl
authors.initials: SY
authors.lastname: Lee
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D007473:Ion Channels / Q000378:metabolism; D007608:Kainic Acid; D015227:Lipid Peroxidation / Q000187:drug effects; D008062:Lipofuscin / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D008062:Lipofuscin; D024101:Mitochondrial Proteins; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D045304:Cytochromes c; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005978:Glutathione; D007608:Kainic Acid; D019803:Glutathione Disulfide