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. 2021 Mar;83:69-76. doi: 10.1016/j.neuro.2020.12.014. Epub 2021 Jan 2.
On the basis of the evidence that extracellular Zn influx induced with AMPA causes Parkinson's syndrome in rats that apomorphine-induced movement disorder emerges, here we used a low dose of AMPA, which does not increase intracellular Zn level in the substantia nigra pars compacta (SNpc) of young adult rats, and tested whether intracellular Zn dysregulation induced with AMPA is accelerated in the SNpc of aged rats, resulting in age-related vulnerability to Parkinson's syndrome. When AMPA (1 mM) was injected at the rate of 0.05 μl/min for 20 min into the SNpc, intracellular Zn level was increased in the SNpc of aged rats followed by increase in turning behavior in response to apomorphine and nigral dopaminergic degeneration. In contrast, young adult rats do not show movement disorder and nigral dopaminergic degeneration, in addition to no increase in intracellular Zn. In aged rats, movement disorder and nigral dopaminergic degeneration were rescued by co-injection of either extracellular (CaEDTA) or intracellular (ZnAF-2DA) Zn chelators. 1-Naphthyl acetyl spermine (NASPM), a selective blocker of Ca- and Zn-permeable GluR2-lacking AMPA receptors blocked increase in intracellular Zn in the SNpc of aged rats followed by rescuing nigral dopaminergic degeneration. The present study indicates that intracellular Zn dysregulation is accelerated by Ca- and Zn-permeable GluR2-lacking AMPA receptor activation in the SNpc of aged rats, resulting in age-related vulnerability to Parkinson's syndrome.
基于 AMPA 诱导的细胞外锌内流导致吗啡诱导运动障碍的大鼠出现帕金森综合征的证据，我们在此使用低剂量的 AMPA，其不会增加年轻成年大鼠黑质致密部（SNpc）的细胞内锌水平，并测试 AMPA 诱导的细胞内锌失调是否在老年大鼠的 SNpc 中加速，导致与年龄相关的帕金森综合征易感性。当 AMPA（1 mM）以 0.05 μl/min 的速度注射 20 分钟到 SNpc 时，老年大鼠的 SNpc 中细胞内锌水平增加，随后对阿扑吗啡的转动行为增加和黑质多巴胺能变性。相比之下，年轻成年大鼠除了细胞内锌没有增加外，不会出现运动障碍和黑质多巴胺能变性。在老年大鼠中，通过共注射细胞外（CaEDTA）或细胞内（ZnAF-2DA）锌螯合剂，运动障碍和黑质多巴胺能变性得到挽救。1-萘基乙酰基 spermine（NASPM），一种选择性阻断 Ca 和 Zn 通透性 GluR2 缺失的 AMPA 受体的抑制剂，可阻止老年大鼠 SNpc 中细胞内锌的增加，并挽救黑质多巴胺能变性。本研究表明，Ca 和 Zn 通透性 GluR2 缺失的 AMPA 受体激活导致老年大鼠 SNpc 中细胞内锌失调加速，导致与年龄相关的帕金森综合征易感性。
