Manganese: a transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of parkinsonism.

It has been suggested that transition metals such as iron and manganese produce oxidative injury to the dopaminergic nigrostriatal system. which may play a critical role in the pathogenesis of Parkinson's disease. Intranigral infusion of ferrous citrate (0 to 8.4 nmol, i.n.) acutely increased lipid peroxidation in the substantia nigra and dopamine turnover in the caudate nucleus. Subsequently, it caused a severe depletion of dopamine levels in the rat caudate nucleus. In contrast to iron's pro-oxidant effect, manganese (up to 30 nmol, i.n.) causes neither lipid peroxidation nor nigral injury/dopamine depletion. Manganese (1.05 to 4.2 nmol, i.n.) dose-dependently protected nigral neurons from iron-induced oxidative injury and dopamine depletion. Manganese also suppressed acute increase in dopamine turnover and contralateral turning behaviour induced by iron. In brain homogenates manganese (0 to 10 microM) concentration-dependently inhibited propagation of lipid peroxidation caused by iron (0 to 5 microM). Without the contribution of manganese-superoxide dismutase manganese was still effective in sodium azide and/or heat-pretreated brain homogenates. Surprisingly, iron but not manganese, catalysed the Fenton reaction or the conversion of hydrogen peroxide to hydroxyl radicals. The results indicate that iron and manganese are two transition metals mediating opposite effects in the nigrostriatal system, as pro-oxidant and antioxidant, respectively. In conclusion, intranigral infusion of iron, but not manganese, provides an animal model for studying the pathophysiological role of oxidant and oxidative stress in nigrostriatal degeneration and Parkinsonism. The present results further suggest that the atypical antioxidative properties of manganese may protect substantia nigra compacta neurons from iron-induced oxidative stress.