Reactive oxidative and nitrogen species in the nigrostriatal system following striatal 6-hydroxydopamine lesion in rats

Oxidative stress is a major contributing factor in the pathogenesis of Parkinson's disease. We therefore investigated the effect of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) on hydroxyl-free radical and peroxynitrite formation in the intrastriatal 6-OHDA rat model of Parkinson's disease. The hydroxylation product of salicylate (2,3-dihydroxy-benzoic acid) as well as the hydroxylation and nitration products of D-phenylalanine (2- and 3-hydroxyl-phenylalanine, nitrotyrosine and nitrophenylalanine) were assessed in tissue samples of the striatum and, for the first time, the substantia nigra of adult rats at four different time points (25 min, 2 h, 4 h and 7 days) after unilateral stereotaxic intrastriatal injection of 6-OHDA. In the striatum, maxima of hydroxylating and nitrating markers were found at early time points after 6-OHDA lesion. These results suggest a direct interrelation between 6-OHDA-autoxidation and/or the increased dopamine turnover and hydroxyl-free radical and peroxynitrite formation. In the Substantia nigra, i.e., at a distance from the injection site of the neurotoxin, an increase in hydroxyl-free radical formation was observed at 7 days after 6-OHDA lesion, with this modification possibly being independent of 6-OHDA autoxidation and rather representing a long-term effect of the toxin. Furthermore, we conclude that apart from the formation of reactive oxygen species, the production of reactive nitrogen species occurs in this experimental Parkinson's disease model. Finally, the similarity between the 6-OHDA model and Parkinson's disease supports the notion that reactive oxygen species as well as reactive nitrogen species may play an important role in the pathogenesis of this neurodegenerative disorder. (c) 2005 Elsevier B.V. All rights reserved.