School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Neurotoxicology. 2022 May;90:136-144. doi: 10.1016/j.neuro.2022.03.010. Epub 2022 Mar 24.
Parkinson's disease is characterized by a selective death of nigrostriatal dopaminergic neurons, while the difference in the vulnerability to the death between the substantia nigra pars compacta (SNpc) and the striatum is poorly understood. Here we tested the difference focused on paraquat (PQ)-induced intracellular Zn toxicity via extracellular glutamate accumulation. When PQ was locally injected into the SNpc and the striatum, dopaminergic degeneration was observed in the SNpc, but not in the striatum. Intracellular hydrogen peroxide (HO) produced by PQ was increased in both the SNpc and the striatum. In contrast, extracellular glutamate accumulation was observed only in the SNpc and rescued in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) cation channels. PQ increased intracellular Zn level in the SNpc, but not in the striatum. The increase was rescued by 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca- and Zn-permeable GluR2-lacking AMPA receptors. PQ-induced dopaminergic degeneration in the SNpc was rescued by ACA, NASPM, and GBR, a dopamine reuptake inhibitor. The present study indicates intracellular HO produced by PQ, which is taken up through dopamine transporters, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn dysregulation via Ca- and Zn-permeable GluR2-lacking AMPA receptor activation, resulting in dopaminergic degeneration in the SNpc. However, HO signaling is not the case in the striatum. Paraquat-induced Zn dysregulation plays a key role for neurodegeneration in the SNpc, but not in the striatum.
帕金森病的特征是黑质致密部（SNpc）多巴胺能神经元选择性死亡，而 SNpc 和纹状体对死亡的易感性差异尚不清楚。在这里，我们通过细胞外谷氨酸积累测试了针对百草枯（PQ）诱导的细胞内 Zn 毒性的差异。当 PQ 局部注射到 SNpc 和纹状体时，观察到多巴胺能神经元在 SNpc 中退化，但不在纹状体中。PQ 在 SNpc 和纹状体中均产生细胞内过氧化氢（HO）。相比之下，仅在 SNpc 中观察到细胞外谷氨酸积累，并且在存在 N-（对氨基肉桂酰基）-anthranilic 酸（ACA）时得到挽救，ACA 是瞬时受体电位 melastatin 2（TRPM2）阳离子通道的阻断剂。PQ 增加了 SNpc 中的细胞内 Zn 水平，但不在纹状体中。该增加被 1-萘基乙酰基 spermine（NASPM）挽救，NASPM 是 Ca 和 Zn 可渗透的缺乏 GluR2 的 AMPA 受体的选择性阻断剂。ACA、NASPM 和多巴胺再摄取抑制剂 GBR 挽救了 PQ 在 SNpc 中诱导的多巴胺能神经元变性。本研究表明，PQ 产生的细胞内 HO 通过多巴胺转运体摄取，被逆行转运到突触前谷氨酸能末梢，激活 TRPM2 通道，在细胞外间隙积累谷氨酸，并通过 Ca 和 Zn 可渗透的缺乏 GluR2 的 AMPA 受体激活诱导细胞内 Zn 失调，导致 SNpc 中的多巴胺能神经元变性。然而，HO 信号在纹状体中并非如此。PQ 诱导的 Zn 失调在 SNpc 中的神经退行性变中起关键作用，但不在纹状体中。
