ROLE OF IRON AND IRON CHELATION IN DOPAMINERGIC-INDUCED NEURODEGENERATION - IMPLICATION FOR PARKINSONS-DISEASE

Recent studies in Parkinson's disease suggest that the degeneration of the nigrostriatal melanin-containing dopaminergic neurons results from toxic effects of free radicals, which are generated during dopamine metabolism in the substantia nigra (SN). This has been linked to the selective accumulation of iron, a known catalyst of radical formation, in the zona compacta of the SN. We have shown that interaction of iron with melanin may result in a high affinity binding of iron to melanin (K(D) = 13.0 +/- 0.15 nM). Indeed, x-ray analysis of melanized dopamine neurons of parkinsonian SN has shown an interaction of iron with melanin that is absent in control brains. In the presence of excess Fe3+, melanin potentiates iron-induced lipid peroxidation. Since iron chelators prevent lipid peroxidation, we have ascertained the ability of the iron chelator deferoxamine to prevent the lesion of the nigrostriatal dopamine neuron induced by 6-hydroxy dopamine (6-OHDA). Our results demonstrated that intraventricular injection of 130 ng deferoxamine to rats prior to 250-mu-g of 6-OHDA partially prevented the decrease in striatal dopamine content caused by 6-OHDA (56% reduction vs 90%, respectively). This protection was sufficient to produce normal dopamine-related behavioral responses. These results suggest that iron and iron chelators play a crucial role in the process of dopaminergic neurodegeneration and neuroprotection. The latter is further supported by our recent findings that intranigral injection of iron (50-mu-g) resulted in a substantial selective decrease of striatal dopamine (95%) and impaired dopamine-related responses.