Imipramine protects mouse hippocampus against tunicamycin-induced cell death
Imipramine protects mouse hippocampus against tunicamycin-induced cell death
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DOI：
10.1016/j.ejphar.2012.09.037
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发表时间：
2012-12-05
影响因子：
5
通讯作者：
Hara, Hideaki
中科院分区：
文献类型：
--
作者：
Ono, Yoko;Shimazawa, Masamitsu;Hara, Hideaki
内质网（ER）应激与多种疾病有关。最近，一些报告表明，σ-1受体可能在ER应激中发挥作用，并且许多抗抑郁药对σ-1受体具有高亲和力。在本研究中，我们集中在丙咪嗪，一种广泛使用的抗抑郁药，并调查它是否可以保护对衣霉素，内质网应激诱导剂诱导的神经细胞死亡。在培养的小鼠海马HT 22细胞中，丙咪嗪抑制衣霉素诱导的细胞死亡和caspase-3激活，但它并没有改变78 kDa葡萄糖调节蛋白（GRP 78）和C/EBP同源蛋白（CHOP）的表达升高。有趣的是，在这样的细胞中，丙咪嗪的应用使σ-1受体的表达正常化，其通过单独用衣霉素处理而降低。此外，NE-100，一种选择性σ-1受体拮抗剂，消除了丙咪嗪对这种衣霉素诱导的细胞死亡的保护作用。丙咪嗪可抑制衣霉素引起的线粒体膜电位降低，NE-100可阻断丙咪嗪的这种调节作用。此外，在麻醉的小鼠中，侧脑室内给予衣霉素减少了海马中的神经元细胞的数量，特别是在CA 1和齿状回（DG）区域，并且7天的丙咪嗪处理（10 mg/kg/天; i. p.）显著抑制了CA 1和DG的这些减少。这些结果表明，丙咪嗪保护对ER应激诱导的海马神经元细胞死亡在体外和体内。这种保护可能部分是由于sigma-1受体。(C)2012爱思唯尔有限公司版权所有。
Endoplasmic reticulum (ER) stress is implicated in various diseases. Recently, some reports have suggested that the sigma-1 receptor may play a role in ER stress, and many antidepressants have a high affinity for the sigma-1 receptor. In the present study, we focused on imipramine, a widely used antidepressant, and investigated whether it might protect against the neuronal cell death induced by tunicamycin, an ER stress inducer. In mouse cultured hippocampal HT22 cells, imipramine inhibited cell death and caspase-3 activation induced by tunicamycin, although it did not alter the elevated expressions of 78 kDa glucose-regulated protein (GRP78) and C/EBP-homologous protein (CHOP). Interestingly, in such cells application of imipramine normalized the expression of the sigma-1 receptor, which was decreased by treatment with tunicamycin alone. Additionally, NE-100, a selective sigma-1 receptor antagonist, abolished the protective effect of imipramine against such tunicamycin-induced cell death. Imipramine inhibited the reduction of mitochondrial membrane potential induced by tunicamycin, and NE-100 blocked this modulating effect of imipramine. Furthermore, in anesthetized mice intracerebroventricular administration of tunicamycin decreased the number of neuronal cells in the hippocampus, particularly in the CA1 and dentate gyms (DG) areas, and 7 days' imipramine treatment (10 mg/kg/day; i.p.) significantly suppressed these reductions in CA1 and DG. These findings suggest that imipramine protects against ER stress-induced hippocampal neuronal cell death both in vitro and in vivo. Such protection may be partly due to the sigma-1 receptor. (C) 2012 Elsevier B.V. All rights reserved.