We tested the hypothesis that melatonin acts as a powerful hydroxyl radical (*OH) scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We investigated the effect of melatonin on in vitro *OH production employing a Fenton-like reaction in test tubes, and ex vivo *OH generation in isolated mitochondria induced by 1-methyl-4-phenyl pyridinium (MPP+), as well as on in vivo *OH formation in the mouse striatum following systemic administration of MPTP. We also measured reduced glutathione (GSH) levels, and superoxide dismutase (SOD) activity in the nucleus caudatus putamen (NCP) and substantia nigra (SN), 7 days following MPTP and/or melatonin administration. Melatonin caused a significant and dose-dependent inhibition of the production of *OH in the in vitro, ex vivo and in vivo experimental conditions. Melatonin caused no changes in monoamine oxidase-B activity, in vitro in mitochondrial P2 fractions or in vivo following systemic administration. MPTP treatment in mice caused a significant depletion of GSH, and increased the specific activity of SOD both in SN and NCP on the seventh day. MPTP-induced GSH depletion was dose-dependently blocked in SN and NCP by melatonin. Higher doses of melatonin exhibited a synergistic effect on MPTP-induced increase in the SOD activity in the SN. These results suggest that while GSH inhibition is a direct consequence of *OH generation following neurotoxin administration, the increase in SOD activity is a compensatory mechanism for removing superoxide radicals generated as the result of MPTP. Our results not only point to the potency of melatonin in blocking the primary insults caused by MPTP, but also provide evidence for triggering secondary neuroprotective mechanisms, suggesting its use as a therapeutic agent in neurodegenerative disorders, such as Parkinson's disease.

中文翻译：

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褪黑素可防止小鼠黑质纹状体中由1-甲基-4-苯基-1,2,3,6-四氢吡啶引起的氧化应激。

我们测试了褪黑素在体内在大脑中充当强大的羟基自由基（* OH）清除剂并干扰由帕金森氏神经毒素1-甲基-4-苯基-1,2,3,6-引起的氧化应激的假设。四氢吡啶（MPTP）。我们研究了褪黑素对在试管中采用Fenton样反应的体外* OH产生的影响以及离体* 1-甲基-4-苯基吡啶鎓（MPP +）诱导的分离线粒体中* OH生成的影响，以及全身给药MPTP后，小鼠纹状体内体内* OH的形成。我们还测量了MPTP和/或褪黑激素给药后7天，在核壳核（NCP）和黑质（SN）中降低的谷胱甘肽（GSH）水平和超氧化物歧化酶（SOD）活性。在体外，离体和体内实验条件下，褪黑激素对* OH的产生产生了显着且剂量依赖性的抑制作用。褪黑激素在体外，线粒体P2组分中或全身给药后在体内均不会引起单胺氧化酶B活性的改变。在小鼠中进行MPTP处理后，第七天的SN和NCP中的GSH明显减少，并增加了SOD的比活性。褪黑激素在SN和NCP中以剂量依赖性方式阻断MPTP诱导的GSH消耗。较高剂量的褪黑激素对MPTP诱导的SN中SOD活性增加具有协同作用。这些结果表明，虽然GSH抑制是神经毒素给药后* OH产生的直接结果，SOD活性的增加是一种去除MPTP产生的超氧自由基的补偿机制。我们的研究结果不仅指出褪黑素在阻断由MPTP引起的原发性损伤中的功效，而且还为触发继发性神经保护机制提供了证据，表明其可作为神经退行性疾病（如帕金森氏病）的治疗剂。