1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced complex I inhibition is reversed by disulfide reductant, dithiothreitol in mouse brain

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes dopaminergic cell loss in mice by inhibiting mitochondrial complex-1 through its metabolite, MPP+, which binds to specific sites on complex-1. Since complex-1 is highly vulnerable to oxidative stress, we have examined the nature of inhibition of complex-1 by MPTP. Both MPTP and MPP+ inhibited complex-1 activity, in vitro, in mouse brain slices, which was abolished by prior exposure of brain slices to glutathione. Further, the inhibited complex-1 activity rebounded after incubation with disulfide reductant, dithiothreitol. Systemic administration of MPTP to mice resulted in inhibition of complex-1 in striatum and midbrain which was also reversed by treatment of mitochondria with dithiothreitol. Inhibition of complex activity by MPTP may be due to oxidation of thiol group(s) in complex-1, which may be reversed by thiol antioxidants. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.