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.
Neurotoxicology. 2023 Mar;95:173-180. doi: 10.1016/j.neuro.2023.02.003. Epub 2023 Feb 10.
Glutamate excitotoxicity is involved in dopaminergic degeneration in the substantia nigra pars compacta (SNpc). Here we compared vulnerability to neurodegeneration after exposure to NMDA and AMPA. Apomorphine-induced movement disorder and dopaminergic degeneration in the SNpc, which are associated with Parkinson's syndrome, were induced after injection of AMPA into the SNpc of rats, but not after injection of NMDA. Co-injection of 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca- and Zn-permeable GluR2-lacking AMPA receptors rescued dopaminergic degeneration and increase in intracellular Zn by AMPA. Furthermore, we tested the effect of capturing reactive oxygen species (ROS) produced by Zn on neuroprotection in vivo. The levels of ROS, which were determined by HYDROP, a membrane-permeable HO fluorescence probe and Aminophenyl Fluorescein (APF), a fluorescence probe for hydroxyl radical and peroxynitrite, were increased after injection of AMPA, but not after co-injection of CaEDTA, an extracellular Zn chelator, suggesting that increase in Zn influx by AMPA elevates the levels of intracellular ROS. AMPA-mediated dopaminergic degeneration was completely rescued by co-injection of either HYDROP or APF. The present study indicates that neurotoxic signaling of the influx of extracellular Zn through Zn-permeable GluR2-lacking AMPA receptors is converted to ROS production and that capturing the ROS completely protects dopaminergic degeneration after exposure to AMPA, but not NMDA. It is likely that regulation of the conversion from Zn influx into ROS production plays a key role to preventing Parkinson's syndrome.
谷氨酸兴奋性毒性参与黑质致密部（SNpc）中多巴胺能神经元的变性。在这里，我们比较了暴露于 NMDA 和 AMPA 后神经退行性变的易感性。APO 诱导的运动障碍和 SNpc 中的多巴胺能神经元变性与帕金森综合征有关，在大鼠 SNpc 中注射 AMPA 后会引起，但在注射 NMDA 后不会引起。1-萘基乙酰基 spermine（NASPM），一种选择性的 Ca 和 Zn 通透性的 GluR2 缺乏的 AMPA 受体阻断剂，可挽救 AMPA 引起的多巴胺能神经元变性和细胞内 Zn 的增加。此外，我们还测试了捕获由 Zn 产生的活性氧（ROS）对体内神经保护的影响。通过 HYDROP（一种膜通透性 HO 荧光探针）和 Aminophenyl Fluorescein（APF，一种用于羟基自由基和过氧亚硝酸盐的荧光探针）测定的 ROS 水平在注射 AMPA 后增加，但在共注射 CaEDTA（一种细胞外 Zn 螯合剂）后没有增加，这表明 AMPA 引起的 Zn 内流增加了细胞内 ROS 的水平。共注射 HYDROP 或 APF 可完全挽救 AMPA 介导的多巴胺能神经元变性。本研究表明，通过 Zn 通透性的 GluR2 缺乏的 AMPA 受体进入细胞外 Zn 的神经毒性信号转导转化为 ROS 的产生，并且捕获 ROS 完全保护 AMPA 暴露后多巴胺能神经元变性，但不保护 NMDA。调节从 Zn 内流到 ROS 产生的转换可能在预防帕金森综合征中起关键作用。
