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-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.
Annepu
J
J
Department of Neurochemistry, National Institute of Mental Health & Neurosciences, Bangalore, India.
Ravindranath
V
V
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004229:Dithiothreitol / Q000494:pharmacology*; D042967:Electron Transport Complex I; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects* / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology
D018696:Neuroprotective Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium; D004229:Dithiothreitol