Elsevier

Neuroscience Letters

Volume 289, Issue 3, 11 August 2000, Pages 209-212
Neuroscience Letters

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

https://doi.org/10.1016/S0304-3940(00)01300-8Get rights and content

Abstract

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

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Acknowledgements

We are grateful to Eisai Pharmaceutical (Japan) for providing ubiquinone 1. This research was funded by a grant from the US-India fund for Cultural, Educational and Scientific Cooperation.

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