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Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro
Liu-Ji Chen1, Yan-Qin Gao, Xue-Jun Li
1National Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai, China.
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 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.
Insights
Melatonin protects against neurotoxin-induced mitochondrial DNA damage and cell death by reducing oxidative stress and preserving mitochondrial function. This study highlights melatonin
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pharmacology
Background:
- 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridine ion (MPP(+)) are neurotoxins that induce oxidative stress and mitochondrial dysfunction.
- Mitochondrial DNA (mtDNA) is particularly vulnerable to oxidative damage, which contributes to neurodegeneration.
Purpose of the Study:
- To investigate the protective effects of melatonin against MPTP/MPP(+)-induced mtDNA damage and cell death.
- To elucidate the mechanisms underlying melatonin's cytoprotective actions.
Main Methods:
- In vivo studies using MPTP in mice to assess DNA oxidative damage (8-hydroxyguanine) in the Substantia Nigra.
- In vitro studies using SH-SY5Y cells treated with MPP(+) to evaluate mtDNA oxidative damage, mitochondrial oxygen free radicals (mtOFR), mitochondrial membrane potential (Psim), and cell viability.
- Melatonin administration (preinjection or preincubation) was used to assess its protective effects.
Main Results:
- MPTP induced significant DNA oxidative damage in mouse brain neurons.
- Melatonin dose-dependently prevented MPTP-induced DNA oxidative damage in vivo.
- MPP(+) increased mtDNA oxidative damage, mtOFR accumulation, and Psim collapse in vitro, leading to cell death.
- Melatonin preincubation attenuated MPP(+)-induced mtDNA damage, inhibited mtOFR generation, preserved Psim, and reduced cell death.
Conclusions:
- Melatonin exhibits significant cytoprotective effects against MPTP/MPP(+)-induced neurotoxicity.
- Melatonin's protective mechanism involves the attenuation of mtDNA oxidative damage.
- Inhibition of mtOFR generation and preservation of mitochondrial membrane potential are key pathways for melatonin's neuroprotection.
