Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl.
1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.
Behan
W M
WM
Institute of Biomedical & Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ.
McDonald
M
M
Darlington
L G
LG
Stone
T W
TW
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017378:Quinolinic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000494:pharmacology*
D000975:Antioxidants; D018696:Neuroprotective Agents; D012642:Selegiline; D017378:Quinolinic Acid; D008550:Melatonin