Melatonin protects against MPTP/MPP+-induced mitochondrial DNA oxidative damage in vivo and in vitro
Melatonin protects against MPTP/MPP+-induced mitochondrial DNA oxidative damage in vivo and in vitro
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DOI：
10.1111/j.1600-079x.2005.00209.x
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发表时间：
2005-08-01
影响因子：
10.3
通讯作者：
Sun, FY
中科院分区：
文献类型：
--
作者：
Chen, LJ;Gao, YQ;Sun, FY
采用离体和体内实验方法，研究褪黑素对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）和1-甲基-4-苯基吡啶离子（MPP+）诱导的线粒体DNA（mtDNA）损伤的影响。MPTP（24 mg/kg，s.c.）诱导小鼠脑黑质致密区神经元细胞质中8-羟基鸟嘌呤（8-oxoG）免疫反应性的快速增加，8-oxoG是DNA氧化损伤的常见生物标志物。褪黑素预注射（7.5、15或30 mg/kg，i.第页）剂量依赖性地防止MPTP诱导的DNA氧化损伤。在SH-SY 5 Y细胞中，MPP+（1 mm）在处理后1小时增加线粒体中8-oxoG的免疫反应性，在处理后3小时增加细胞核中8-oxoG的免疫反应性。褪黑激素（200 μ M）预孵育显着减弱MPP+诱导的mtDNA氧化损伤。MPP+处理后1 ~ 24 h，线粒体氧自由基（mtOFR）增加，18 ~ 36 h，线粒体膜电位（Psim）逐渐降低。孵育后72小时，MPP+导致对照组49%的细胞死亡。然而，褪黑激素阻止MPP+诱导的mtOFR产生和Wm崩溃，以及后来的细胞死亡。目前的研究结果表明，褪黑激素对MPTP/ MPP+诱导的细胞死亡的细胞保护作用可能与通过抑制mtOFR的产生和防止Wm崩溃的mtDNA氧化损伤的衰减。
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 mu 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 (Psi 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 Wm 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 Wm collapse.