Alterations in cytochrome c oxidase activity and energy metabolites in response to kainic acid-induced status epilepticus.
The effects of kainic acid (KA)-induced limbic seizures have been investigated on cytochrome c oxidase (COx) activity, COx subunit IV mRNA abundance, ATP and phosphocreatine (PCr) levels in amygdala, hippocampus and frontal cortex of rat brain. Rats were killed either 1 h, three days or seven days after the onset of status epilepticus (SE) by CO2 and decapitation for the assay of COx activity and by head-focused microwave for the determination of ATP and PCr. Within 1 h COx activity and COx subunit IV mRNA increased in all brain areas tested between 120% and 130% of control activity, followed by a significant reduction from control, in amygdala and hippocampus on day three and seven, respectively. In amygdala, ATP and PCr levels were reduced to 44% and 49% of control 1 h after seizures. No significant recovery was seen on day three or seven. Pretreatment of rats with the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg kg(-1), i.p.) 30 min before KA administration had no effect on SE, but protected COx activity and attenuated changes in energy metabolites. Pretreatment for three days with the endogenous antioxidant vitamin E (Vit-E, 100 mg/kg, i.p.) had an even greater protective effect than PBN. Both pretreatment regimens attenuated KA-induced neurodegenerative changes, as assessed by histology and prevention of the decrease of COx subunit IV mRNA and COx activity in hippocampus and amygdala, otherwise seen following KA-treatment alone. These findings suggest a close relationship between SE-induced neuronal injury and deficits in energy metabolism due to mitochondrial dysfunction.
Milatovic
D
D
Department of Pharmacology, Vanderbilt University, Medical School, Medical Center South, 2100 Pierce Avenue, Nashville, TN 37212, USA.
Zivin
M
M
Gupta
R C
RC
Dettbarn
W D
WD
D000255:Adenosine Triphosphate / Q000378:metabolism; D000679:Amygdala / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D003497:Cyclic N-Oxides; D003576:Electron Transport Complex IV / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D007608:Kainic Acid / Q000494:pharmacology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D009498:Neurotoxins / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010725:Phosphocreatine / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D003497:Cyclic N-Oxides; D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D010725:Phosphocreatine; D014810:Vitamin E; C029217:phenyl-N-tert-butylnitrone; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D007608:Kainic Acid