Copper sulfate pretreatment prevents mitochondrial electron transport chain damage and apoptosis against MPP-induced neurotoxicity.

Intrastriatal injection of 1-methyl-4-phenylpyridinium (MPP) is considered a model to reproduce some biochemical alterations observed in Parkinson's disease (PD) patients. Among those alterations, inhibition of mitochondrial complex I activity, increased free radical production and reduced antioxidant responses have been reported. Copper (Cu) plays an important role in the metabolism and antioxidative responses through its participation as a cofactor in the cytochrome c oxidase enzyme (COX), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and metallothioneins. We tested the effect of copper sulfate (CuSO) pretreatment on the mitochondrial electron transport chain (METC) in the striatum after MPP toxicity in rats. The results showed that the MPP intrastriatal injection reduced mitochondrial complex I, II, IV and V activities; while 10 μmol of CuSO pretreatment counteracted this damage. Activities of complexes I, II and IV, were coincident with ATP recovery. Moreover, Cu/Zn-SOD activity was reduced as a consequence of MPP damage; however, copper pre-treatment kept the striatal Cu/Zn-SOD activity unchanged in MPP-damaged animals. We observed that MPP also reduced the metallothionein (MT) content and that CuSO pretreatment maintained baseline values. CuSO pretreatment also reduced the striatal caspase-3 and caspase-9 activities that were increased three days after MPP-induced damage. The present study provided evidence that copper pretreatment reduced MPP-induced apoptotic damage, probably through direct action on copper-dependent proteins or indirectly on proteins in the apoptotic pathway.