Division of Cell Biology and Physiology, Laboratory of Clinical & Experimental Neuroscience, Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
J Pineal Res. 2009 Nov;47(4):293-300. doi: 10.1111/j.1600-079X.2009.00713.x. Epub 2009 Oct 1.
We tested the hypothesis that melatonin regulates formation of 6-hydroxydopamine (6-OHDA) in the brain and thereby protects animals from dopaminergic neurotoxicity and the development of parkinsonism in animals. Employing a ferrous-ascorbate-dopamine (FAD) hydroxyl radical ((*)OH) generating system, in the present study we demonstrate a dose-dependent attenuation of 6-OHDA generation by melatonin in vitro. Intra-median forebrain bundle infusion of FAD caused significant depletion of striatal dopamine (DA), which was blocked by melatonin. Per-oral administration of l-3,4-dihydroxyphenylalanine (L-DOPA) for 7 days caused a dose-dependent increase in the formation of 6-OHDA in the mouse striatum, which was increased synergistically by the systemic administration of the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the 7th day of L-DOPA treatment. Melatonin treatment significantly attenuated both the L-DOPA and MPTP-induced increases in the levels of striatal 6-OHDA, and protected against striatal DA depletion caused by the neurotoxin. These observations suggest a novel mode of melatonin-induced dopaminergic neuroprotection in two models of Parkinson's disease, and suggest the possible therapeutic use of this well-known antioxidant indoleamine neurohormone in parkinsonism.
我们检验了这样一个假设，即褪黑素调节大脑中 6-羟多巴胺（6-OHDA）的形成，从而保护动物免受多巴胺能神经毒性和帕金森病动物模型的发展。本研究采用亚铁-抗坏血酸-多巴胺（FAD）羟自由基（(*)OH）生成系统，证明褪黑素在体外具有剂量依赖性抑制 6-OHDA 生成的作用。中脑束内输注 FAD 导致纹状体多巴胺（DA）明显耗竭，而褪黑素则能阻断这一过程。连续 7 天给予左旋多巴（L-DOPA）会导致小鼠纹状体中 6-OHDA 的形成呈剂量依赖性增加，而在第 7 天给予帕金森病神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）后，这种增加会呈协同性增加。褪黑素治疗显著减轻了 L-DOPA 和 MPTP 诱导的纹状体 6-OHDA 水平升高，并防止了神经毒素引起的纹状体 DA 耗竭。这些观察结果表明褪黑素在两种帕金森病模型中具有一种新型的多巴胺能神经保护作用模式，并提示这种广为人知的抗氧化吲哚胺神经激素在帕金森病中的可能治疗用途。
