Wmh. Behan et al., Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl, BR J PHARM, 128(8), 1999, pp. 1754-1760
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 s
tudy was designed to examine the effect of a potent antioxidant, melatonin,
and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic a
cid-induced brain damage. Injections were made into the hippocampus of anae
sthetized 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, w
hich was prevented by the co-administration of melatonin (5 nmols locally p
lus 2 x 20 mg kg(-1) i.p.). This protective effect was not prevented by the
melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (12
0 nmols) was not prevented by melatonin.
3 Quinolinic acid increased the formation of lipid peroxidation products fr
om hippocampal tissue and this effect was prevented by melatonin.
4 Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nm
ols but not 10 nmols plus 2 x 1.0 mg kg(-1) i.p. The non-selective monoamin
e oxidase inhibitor nialamide(10 and 50 nmols plus 2 x 25 mg kg(-1)) did no
t afford protection.
5 The results suggest that quinolinic acid-induced neuronal damage can be p
revented by a receptor-independent action of melatonin and deprenyl, agents
which can act as a potent free radical scavenger and can increase the acti
vity of endogenous antioxidant enzymes respectively. This suggests that fre
e radical formation contributes significantly to quinolinic acid-induced da
mage in vivo.