SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease
SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease
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DOI：
10.1016/j.neuropharm.2011.08.041
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发表时间：
2011-12-01
影响因子：
4.7
通讯作者：
Matsuda, Toshio
中科院分区：
文献类型：
--
作者：
Ago, Yukio;Kawasaki, Toshiyuki;Matsuda, Toshio
我们最近发现 Na+/Ca2+ 交换器 (NCX) 参与培养的星形胶质细胞和神经元中一氧化氮 (NO) 诱导的细胞毒性。然而，没有体内证据表明 NO( 在与 NO 相关的神经退行性疾病中发挥作用。NO 与帕金森病等神经退行性疾病的发病机制有关。本研究在帕金森病模型中检查了特定 NCX 抑制剂 SEA0400 对 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的多巴胺能神经毒性的影响。 C57BL/6J 小鼠。MPTP 治疗（10 mg/kg，每 2 小时间隔 4 次）降低了中脑中的多巴胺水平并损害了运动协调性，而这些影响被 S-甲硫基瓜氨酸所抵消，S-甲硫基瓜氨酸是一种选择性神经元 NO 合酶抑制剂，可防止多巴胺能神经毒性（由中脑和纹状体中的多巴胺水平以及中脑和纹状体中的酪氨酸羟化酶免疫反应性决定）。 MPTP 处理的小鼠中的黑质和纹状体、纹状体多巴胺释放和运动缺陷）没有自由基清除活性，SEA0400 不影响 MPTP 代谢和 MPTP 诱导的 NO 产生和小胶质细胞活化，同时减弱 MPTP 诱导的细胞外信号调节激酶 (ERK) 磷酸化和脂质过氧化产物硫代巴比妥酸反应物质的增加。 SEA0400 可能通过阻断 NCX 介导的 Ca2+ 流入下游的 ERK 磷酸化和脂质过氧化来防止 MPTP 诱导的神经毒性。 (C) 2011 Elsevier Ltd. 保留所有权利。
We have recently shown that the Na+/Ca2+ exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NO( in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca2+ influx. (C) 2011 Elsevier Ltd. All rights reserved.