Melatonin protects against MPTP/MPP+‐induced mitochondrial DNA oxidative damage in vivo and in vitro

Abstract: The effects of melatonin on the mitochondrial DNA (mtDNA) damage induced by 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) and 1‐methyl‐4‐phenylpyridine ion (MPP + ) were investigated both in vivo and in vitro. MPTP (24 mg/kg, s.c.) induced a rapid increase in the immunoreactivity of 8‐hydroxyguanine (8‐oxoG), a common biomarker of DNA oxidative damage, in the cytoplasm of neurons in the Substantia Nigra Compact of mouse brain. Melatonin preinjection (7.5, 15 or 30 mg/kg, i.p.) dose‐dependently prevented MPTP‐induced DNA oxidative damage. In SH‐SY5Y cells, MPP + (1 m m ) increased the immunoreactivity of 8‐oxoG in the mitochondria at 1 hr and in the nucleus at 3 hr after treatment. Melatonin (200 μ m ) preincubation significantly attenuated MPP + ‐induced mtDNA oxidative damage. Furthermore, MPP + time‐dependently increased the accumulation of mitochondrial oxygen free radicals (mtOFR) from 1 to 24 hr and gradually decreased the mitochondrial membrane potential (Ψ m) from 18 to 36 hr after incubation. At 72 hr after incubation, MPP + caused cell death in 49% of the control. However, melatonin prevented MPP + ‐induced mtOFR generation and Ψ m collapse, and later cell death. The present results suggest that cytoprotection of melatonin against MPTP/MPP + ‐induced cell death may be associated with the attenuation of mtDNA oxidative damage via inhibition of mtOFR generation and the prevention of Ψ m collapse.