Melatonin Inhibits Manganese-Induced Motor Dysfunction and Neuronal Loss in Mice: Involvement of Oxidative Stress and Dopaminergic Neurodegeneration
Melatonin Inhibits Manganese-Induced Motor Dysfunction and Neuronal Loss in Mice: Involvement of Oxidative Stress and Dopaminergic Neurodegeneration
复制标题
褪黑素抑制锰引起的小鼠运动功能障碍和神经元损失：氧化应激和多巴胺能神经变性的参与
DOI：
10.1007/s12035-014-8789-3
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发表时间：
2015-02-01
影响因子：
5.1
通讯作者：
Xu, Zhaofa
中科院分区：
文献类型：
--
作者：
Deng, Yu;Jiao, Congcong;Xu, Zhaofa
过量的锰会导致氧化应激和多巴胺能神经变性。然而，它们在锰神经毒性过程中的关系尚不清楚。本研究旨在探讨褪黑素(MLT)对抗氧化应激和多巴胺能神经变性所致的运动功能障碍和神经元丢失的可能作用。将小鼠随机分为5组：对照组、MnCl2组、低MLT+MnCl2组、中MLT+MnCl2组、高MLT+MnCl2组。给予MnCl2(50 mg/kg)2周可引起大鼠黑质和纹状体运动功能减退、多巴胺能神经元变性和丢失、神经元超微结构损伤和细胞凋亡。这些情况的部分原因是活性氧的过量产生，丙二醛的积累，以及非酶(GSH-Px)和酶(GSH-Px、超氧化物歧化酶、苯醌氧化还原酶1、谷胱甘肽S转移酶和谷胱甘肽还原酶)抗氧化防御系统的功能障碍。锰诱导的神经元变性、星形胶质细胞和小胶质细胞活化参与氧化应激标志物的变化。染锰后多巴胺(DA)耗竭，DA转运体和受体表达下调，并可引起运动功能障碍和神经元丢失。MLT可预防锰诱导的氧化应激和多巴胺能神经退行性变，并抑制两者之间的相互作用。结果表明，MLT可显著减轻锰所致的运动功能障碍和神经元丢失。总之，锰处理导致运动功能障碍和神经元丢失，可能涉及黑质和纹状体的氧化应激和多巴胺能神经变性之间的相互作用。MLT通过其抗氧化作用和促进DA系统而减轻了锰的神经毒性。
Excessive manganese (Mn) induces oxidative stress and dopaminergic neurodegeneration. However, the relationship between them during Mn neurotoxicity has not been clarified. The purpose of this study was to investigate the probable role of melatonin (MLT) against Mn-induced motor dysfunction and neuronal loss as a result of antagonizing oxidative stress and dopaminergic neurodegeneration. Mice were randomly divided into five groups as follows: control, MnCl2, low MLT + MnCl2, median MLT + MnCl2, and high MLT + MnCl2. Administration of MnCl2 (50 mg/kg) for 2 weeks significantly induced hypokinesis, dopaminergic neurons degeneration and loss, neuronal ultrastructural damage, and apoptosis in the substantia nigra and the striatum. These conditions were caused in part by the overproduction of reactive oxygen species, malondialdehyde accumulation, and dysfunction of the nonenzymatic (GSH) and enzymatic (GSH-Px, superoxide dismutase, quinone oxidoreductase 1, glutathione S-transferase, and glutathione reductase) antioxidative defense systems. Mn-induced neuron degeneration, astrocytes, and microglia activation contribute to the changes of oxidative stress markers. Dopamine (DA) depletion and downregulation of DA transporter and receptors were also found after Mn administration, this might also trigger motor dysfunction and neurons loss. Pretreatment with MLT prevented Mn-induced oxidative stress and dopaminergic neurodegeneration and inhibited the interaction between them. As a result, pretreatment with MLT significantly alleviated Mn-induced motor dysfunction and neuronal loss. In conclusion, Mn treatment resulted in motor dysfunction and neuronal loss, possibly involving an interaction between oxidative stress and dopaminergic neurodegeneration in the substantia nigra and the striatum. Pretreatment with MLT attenuated Mn-induced neurotoxicity by means of its antioxidant properties and promotion of the DA system.