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.
Chen
Liu-Ji
LJ
National Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai, China.
Gao
Yan-Qin
YQ
Li
Xue-Jun
XJ
Shen
Di-Han
DH
Sun
Feng-Yan
FY
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