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

Abstract

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 (CuSO4) 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 CuSO4 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 CuSO4 pretreatment maintained baseline values. CuSO4 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.