Melatonin protects against MPTP/MPP super(+)-induced mitochondrial DNA oxidative damage in vivo and in vitro

• Published in: Journal of pineal research Vol. 39; no. 1; pp. 34 - 42
• Main Authors: Chen, Liu-Ji, Gao, Yan-Qin, Li, Xue-Jun, Shen, Di-Han, Sun, Feng-Yan
• Format: Journal Article
• Language: English
• Published: 01.08.2005
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/j.1600-079X.2005.00209.x

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 super(+)) 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 super(+) (1 mm) increased the immunoreactivity of 8-oxoG in the mitochondria at 1 hr and in the nucleus at 3 hr after treatment. Melatonin (200 mu m) preincubation significantly attenuated MPP super(+)-induced mtDNA oxidative damage. Furthermore, MPP super(+) time-dependently increased the accumulation of mitochondrial oxygen free radicals (mtOFR) from 1 to 24 hr and gradually decreased the mitochondrial membrane potential ( psi m) from 18 to 36 hr after incubation. At 72 hr after incubation, MPP super(+) caused cell death in 49% of the control. However, melatonin prevented MPP super(+)-induced mtOFR generation and psi m collapse, and later cell death. The present results suggest that cytoprotection of melatonin against MPTP/MPP super(+)-induced cell death may be associated with the attenuation of mtDNA oxidative damage via inhibition of mtOFR generation and the prevention of psi m collapse.