3-Nitrotyrosine-dependent dopaminergic neurotoxicity following direct nigral administration of a peroxynitrite but not a nitric oxide donor

The presence of 3-nitrotyrosine (3-NT) adducts in Lewy bodies in Parkinson's disease suggests a role for nitrative stress in dopaminergic cell death. Whether this is a direct effect of increased nitric oxide (NO) formation or requires its reaction with superoxide to form peroxynitrite is not clear. In the present study, we show that direct nigral administration of a NO donor, SNOG, in the rat produced only local toxicity to dopaminergic neurones pre-labeled with fluorogold with no 3-NT formation. However, administration of a peroxynitrite donor, SIN-1, caused widespread damage to dopaminergic neurones and marked expression of 3-NT immunoreactivity. Importantly, dopaminergic cell loss and the expression of 3-NT were completely prevented when SIN-1 was co-administered with the NO/peroxynitrite scavenger, carboxy-PTIO. The results suggest that increased NO formation is not inherently toxic to dopaminergic neurons, but when both oxidative and nitrative stress combine to cause peroxynitrite formation, neurotoxicity occurs.