Atsushi Takeda, Tamano Haruna
Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
J Trace Elem Med Biol. 2020 Sep;61:126545. doi: 10.1016/j.jtemb.2020.126545. Epub 2020 May 11.
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.
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.
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 Zn dysregulation. Loss of nigral dopaminergic neurons is accelerated by age-related intracellular Zn dysregulation in the SNpc of rat PD models. The intracellular Zn dysregulation in nigral dopaminergic neurons is linked with the rapid influx of extracellular Zn via postsynaptic AMPA receptor activation, suggesting that PQ- and 6-OHDA-induced pathogenesis is linked with age-related intracellular Zn dysregulation in the SNpc. Postsynaptic TRPM2 channels may be also involved in intracellular Zn dysregulation in the SNpc.
A novel mechanism of nigral dopaminergic degeneration, in which ROS induce rapid intracellular Zn 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 Zn influx and its proposed defense strategy.
帕金森病（PD）是老年人常见的神经退行性疾病，其特征为震颤等运动症状，由黑质多巴胺能神经元的选择性丧失所致。多巴胺自氧化诱导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。
为了解黑质多巴胺能神经元的选择性丧失，本文围绕百草枯（PQ）和6-羟基多巴胺（6-OHDA）诱导的大鼠帕金森病模型，对帕金森病的发病机制进行综述。
PQ和6-OHDA产生的活性氧（ROS）逆向转运至突触前谷氨酸能神经元终末。ROS激活突触前瞬时受体电位香草酸亚型2（TRPM2）阳离子通道，导致黑质致密部（SNpc）细胞外谷氨酸蓄积，随后出现与年龄相关的细胞内锌失调。在大鼠帕金森病模型的SNpc中，与年龄相关的细胞内锌失调加速了黑质多巴胺能神经元的丧失。黑质多巴胺能神经元的细胞内锌失调与突触后α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体激活引起的细胞外锌快速内流有关，提示PQ和6-OHDA诱导的发病机制与SNpc中与年龄相关的细胞内锌失调有关。突触后TRPM2通道可能也参与了SNpc中的细胞内锌失调。
ROS诱导细胞内锌快速失调这一黑质多巴胺能神经元变性的新机制，阐明了PQ和6-OHDA诱导的大鼠帕金森病发病机制。本综述探讨了ROS介导的细胞外锌内流及其提出的防御策略对帕金森病发病机制的新见解。
