Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro.
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 mm) increased the immunoreactivity of 8-oxoG in the mitochondria at 1 hr and in the nucleus at 3 hr after treatment. Melatonin (200 microm) 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 (Psim) 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 Psim 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 Psim collapse.
National Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai, China.
Liu-Ji
LJ
Chen
Yan-Qin
YQ
Gao
Xue-Jun
XJ
Li
Di-Han
DH
Shen
Feng-Yan
FY
Sun
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage*; D006540:Herbicides / Q000633:toxicity*; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D051379:Mice
D000276:Adjuvants, Immunologic; D004272:DNA, Mitochondrial; D015259:Dopamine Agents; D006540:Herbicides; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008550:Melatonin; D015655:1-Methyl-4-phenylpyridinium