HRD1 Levels Increased by Zonisamide Prevented Cell Death and Caspase-3 Activation Caused by Endoplasmic Reticulum Stress in SH-SY5Y Cells
HRD1 Levels Increased by Zonisamide Prevented Cell Death and Caspase-3 Activation Caused by Endoplasmic Reticulum Stress in SH-SY5Y Cells
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DOI：
10.1007/s12031-011-9638-8
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发表时间：
2012-03-01
影响因子：
3.1
通讯作者：
Matsubara, Kazuo
中科院分区：
文献类型：
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作者：
Omura, Tomohiro;Asari, Masaru;Matsubara, Kazuo
唑尼沙胺通常以高剂量（200-400 毫克/天）用于治疗部分性癫痫发作，最近以低剂量（25 毫克/天）用于改善帕金森综合征。然而，唑尼沙胺抗帕金森病作用的分子机制尚未阐明。在这里，我们发现低微摩尔浓度的唑尼沙胺可防止人多巴胺能 SH-SY5Y 神经母细胞瘤细胞中 caspase-3 的裂解和细胞死亡，这些细胞受到衣霉素或 6-羟基多巴胺诱导的内质网应激。 Hypodense zonisamide 增加了 SEL1L 的表达水平，已知 SEL1L 可以稳定泛素连接酶 HRD1。事实上，观察到 HRD1 蛋白的上调。因此，这项研究的结果强烈表明，低浓度的唑尼沙胺通过增加帕金森病患者的 HRD1 蛋白水平来抑制神经元细胞死亡。因此，除了治疗帕金森病外，还应考虑唑尼沙胺治疗多种病理生理机制涉及内质网应激的神经退行性疾病的治疗潜力。
Zonisamide, which is commonly prescribed at high doses (200-400 mg/day) for the treatment of partial seizures, has recently been used at a low dose (25 mg/day) for improving parkinsonian syndrome. However, the molecular mechanisms that underlie the antiparkinsonian effects of zonisamide have not been clarified. Here we show that low micromolar concentrations of zonisamide prevented cleavage of caspase-3 and cell death in human dopaminergic SH-SY5Y neuroblastoma cells that were subjected to endoplasmic reticulum stress induced by tunicamycin or 6-hydroxydopamine. Hypodense zonisamide increased the expression levels of SEL1L, which is known to stabilize the ubiquitin ligase HRD1. Indeed, upregulation of HRD1 protein was observed. Thus, the results of this study strongly suggest that low concentrations of zonisamide inhibit neuronal cell death by increasing HRD1 protein levels in patients with Parkinson's disease. Consequently, in addition to the treatment of Parkinson's disease, the therapeutic potential of zonisamide should be considered for the treatment of several neurodegenerative disorders with pathophysiological mechanisms involving endoplasmic reticulum stress.