BACKGROUND Parkinson's disease (PD) is the common neurodegenerative disorder in the elderly characterized by motor symptoms such as tremors, which is caused by selective loss of nigral dopaminergic neurons. Oxidative stress induced by the auto-oxidation of dopamine has been implicated as a key cause of the selective loss of dopaminergic neurons. METHODS To understand the selective loss of nigral dopaminergic neurons, the PD pathogenesis is reviewed focused on paraquat (PQ) and 6-hydroxydopamine (6-OHDA)-induced PD in rats. RESULTS Reactive oxygen species (ROS), which are produced by PQ and 6-OHDA, are retrogradely transported to presynaptic glutamatergic neuron terminals. ROS activate presynaptic transient receptor potential melastatin 2 (TRPM2) cation channels and induce extracellular glutamate accumulation in the substantia nigra pars compacta (SNpc), followed by age-related intracellular Zn2+ dysregulation. Loss of nigral dopaminergic neurons is accelerated by age-related intracellular Zn2+ dysregulation in the SNpc of rat PD models. The intracellular Zn2+ dysregulation in nigral dopaminergic neurons is linked with the rapid influx of extracellular Zn2+ via postsynaptic AMPA receptor activation, suggesting that PQ- and 6-OHDA-induced pathogenesis is linked with age-related intracellular Zn2+ dysregulation in the SNpc. Postsynaptic TRPM2 channels may be also involved in intracellular Zn2+ dysregulation in the SNpc. CONCLUSION A novel mechanism of nigral dopaminergic degeneration, in which ROS induce rapid intracellular Zn2+ dysregulation, figures out the PD pathogenesis induced by PQ and 6-OHDA in rats. This review deals with new insight into PD pathogenesis from ROS-mediated extracellular Zn2+ influx and its proposed defense strategy.

中文翻译：

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从活性氧介导的细胞外 Zn2+ 流入对帕金森病发病机制的新见解。


背景技术帕金森病(PD)是老年人常见的神经退行性疾病，其特征是震颤等运动症状，其由黑质多巴胺能神经元选择性丧失引起。多巴胺自动氧化引起的氧化应激被认为是多巴胺能神经元选择性丧失的关键原因。方法 为了了解黑质多巴胺能神经元的选择性丧失，重点回顾了百草枯 (PQ) 和 6-羟基多巴胺 (6-OHDA) 诱导的大鼠 PD 发病机制。结果 PQ 和 6-OHDA 产生的活性氧 (ROS) 逆行转运至突触前谷氨酸能神经元末梢。 ROS 激活突触前瞬时受体电位褪黑素 2 (TRPM2) 阳离子通道，诱导黑质致密部 (SNpc) 细胞外谷氨酸积累，随后导致与年龄相关的细胞内 Zn2+ 失调。在大鼠 PD 模型的 SNpc 中，与年龄相关的细胞内 Zn2+ 失调会加速黑质多巴胺能神经元的丧失。黑质多巴胺能神经元中的细胞内 Zn2+ 失调与通过突触后 AMPA 受体激活的细胞外 Zn2+ 快速流入有关，表明 PQ-和 6-OHDA 诱导的发病机制与 SNpc 中年龄相关的细胞内 Zn2+ 失调有关。突触后 TRPM2 通道也可能参与 SNpc 细胞内 Zn2+ 失调。结论 ROS 诱导细胞内 Zn2+ 快速失调的黑质多巴胺能变性的新机制，阐明了 PQ 和 6-OHDA 诱导的大鼠 PD 发病机制。这篇综述涉及 ROS 介导的细胞外 Zn2+ 流入的 PD 发病机制及其提出的防御策略。