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. 2018 Dec;69:23-28. doi: 10.1016/j.neuro.2018.08.008. Epub 2018 Aug 31.
On the basis of the findings that the rapid influx of extracellular Zn into nigral dopaminergic neurons causes dopaminergic neurodegeneration, here we report that AMPA causes movement disorder in rats. AMPA markedly increased turning behavior in response to apomorphine 1 and 2 weeks after AMPA injection into the substantia nigra pars compacta (SNpc), while AMPA-induced movement disorder was suppressed by co-injection of intracellular Zn chelators, i.e., ZnAF-2DA and TPEN, suggesting that AMPA-induced movement disorder is due to intracellular Zn dysregulation. Furthermore, AMPA markedly induced loss of nigrostriatal dopaminergic neurons 2 weeks after AMPA injection into the SNpc, while AMPA-induced neurodegeneration was also suppressed in the SNpc and the striatum by co-injection of ZnAF-2DA and TPEN. AMPA rapidly increased nigral intracellular Zn after AMPA injection into the SNpc and this increase was blocked by co-injection of TPEN. These results indicate that AMPA receptor activation rapidly increases influx of extracellular Zn into nigral dopaminergic neurons and causes nigrostriatal dopaminergic neurodegeneration, resulting in movement disorder in rats. The evidence that AMPA-induced intracellular Zn dysregulation causes movement disorder via nigrostriatal dopaminergic neurodegeneration suggests that AMPA receptors, probably Ca- and Zn-permeable GluR2-lacking AMPA receptors are potential targets for overcoming Parkinson's syndrome.
基于细胞外锌大量涌入黑质多巴胺能神经元会导致多巴胺能神经退行性变的发现，我们在此报告 AMPA 会导致大鼠运动障碍。AMPA 注射到黑质致密部（SNpc）后 1 周和 2 周，明显增加了对阿扑吗啡的旋转行为，而 AMPA 诱导的运动障碍可被细胞内锌螯合剂 ZnAF-2DA 和 TPEN 共同注射所抑制，表明 AMPA 诱导的运动障碍是由于细胞内锌失调所致。此外，AMPA 注射到 SNpc 后 2 周明显诱导黑质纹状体多巴胺能神经元丧失，而 ZnAF-2DA 和 TPEN 共同注射也可抑制 SNpc 和纹状体中的 AMPA 诱导的神经退行性变。AMPA 注射到 SNpc 后，迅速增加了黑质细胞内锌，而 TPEN 共同注射则阻断了这种增加。这些结果表明，AMPA 受体激活会迅速增加细胞外锌流入黑质多巴胺能神经元，并导致黑质纹状体多巴胺能神经退行性变，从而导致大鼠运动障碍。AMPA 诱导的细胞内锌失调通过黑质纹状体多巴胺能神经退行性变导致运动障碍的证据表明，AMPA 受体，可能是 Ca2+和 Zn2+通透性缺乏 GluR2 的 AMPA 受体，是克服帕金森综合征的潜在靶点。
