Preventive effect of melatonin against brain mitochondria DNA damage, lipid peroxidation and seizures induced by kainic acid.
The effects of kainic acid on mitochondria DNA (mtDNA) or lipid peroxidation in mice brain and, preventive effects of melatonin against its effects were investigated in vivo. Broad-spectrum limbic and severe sustained seizures were observed in all mice when kainic acid (45 mg/kg) was injected intraperitoneally (ip) to eight mice. These seizures were completely abolished by the simultaneous administration of melatonin (20 mg/kg, ip), a potent scavenger of hydroxyl radical. However, slight limbic seizures or severe sustained seizures were observed when melatonin was injected in animals 30 min before or 15 min after the kainic acid administration. The administration of kainic acid caused damage to mtDNA in brain frontal and middle cortex. These effects were abolished when melatonin was injected in animals 0 or 30 min before, but not 15 min after the kainic acid administration. In vitro or in vivo exposure of kainic acid elicited an increase in lipid peroxidation in a concentration- or dose-dependent manner. The increased lipid peroxidation induced by kainic acid was attenuated by co-treatment with melatonin. These results indicate that there may be a positive relationship among seizures, brain mtDNA damages and increased lipid peroxidation. Hence, our present results suggest that the hydroxyl radicals produced by kainic acid cause damage on mtDNA and the increase of lipid peroxidation in brain, leading to severe seizures. These effects were completely prevented by co-treatment with melatonin, a potent scavenger of hydroxyl radicals.
Mohanan
P V
PV
Institute of Community Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Yamamoto
Hiro-aki
HA
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D004272:DNA, Mitochondrial; D016166:Free Radical Scavengers; D017665:Hydroxyl Radical; D008550:Melatonin; D007608:Kainic Acid