Cytoprotection by lithium and valproate varies between cell types and cellular stresses
Cytoprotection by lithium and valproate varies between cell types and cellular stresses
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DOI：
10.1016/j.ejphar.2006.03.076
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发表时间：
2006-06-06
影响因子：
5
通讯作者：
Li, Peter P.
中科院分区：
文献类型：
--
作者：
Lai, Justin S.;Zhao, Chunnian;Li, Peter P.
尽管有大量证据表明锂和丙戊酸这两种常用的情绪稳定剂表现出针对一系列损伤的神经保护特性，但这种作用的药理学相关性尚不清楚，因为大多数研究都检查了这些药物在超治疗剂量下对损伤的急性作用，而这些损伤与双相情感障碍的疾病相关性有限。在本研究中，我们研究了临床相关剂量的锂和丙戊酸盐是否能够以时间依赖性方式保护人神经母细胞瘤（SH-SY5Y）和神经胶质瘤（SVG和U87）细胞免受氧化应激和内质网应激。用 1 mM 锂或 0.6 mM 丙戊酸盐预处理 SH-SY5Y 细胞 7 天（但不是第 1 天）显着降低鱼藤酮和 H2O2 诱导的细胞毒性、细胞色素 c 释放和 caspase-3 活化，并增加 Bcl-2 水平。相反，用锂或丙戊酸盐对 SH-SY5Y 细胞进行急性或慢性处理均不会引发针对毒胡萝卜素诱发的细胞死亡和 caspase-3 激活的细胞保护反应。此外，糖原合成酶激酶 3 (GSK-3)、kenpaullone 和 SB216763 抑制剂可消除鱼藤酮诱导的细胞毒性，但不能消除 H2O2 诱导的细胞毒性。因此，锂和丙戊酸盐对 H2O2 诱导的细胞死亡的细胞保护作用可能与 GSK-3 抑制无关。另一方面，长期锂或丙戊酸治疗并不能改善鱼藤酮、H2O2 和毒胡萝卜素在 SVG 星形胶质细胞和 U87 MG 神经胶质瘤细胞系中诱导的细胞毒性。我们的研究结果表明，锂和丙戊酸盐可能会降低人类神经细胞（而非神经胶质细胞）对氧化应激引起的细胞损伤的脆弱性，氧化应激可能是由与双相情感障碍有关的假定线粒体紊乱引起的。 (c) 2006 Elsevier B.V. 保留所有权利。
Despite much evidence that lithium and valproate, two commonly used mood stabilizers, exhibit neuroprotective properties against an array of insults, the pharmacological relevance of such effects is not clear because most of these studies examined the acute effect of these drugs in supratherapeutic doses against insults which were of limited disease relevance to bipolar disorder. In the present study, we investigated whether lithium and valproate, at clinically relevant doses, protects human neuroblastoma (SH-SY5Y) and glioma (SVG and U87) cells against oxidative stress and endoplasmic reticulum stress in a time-dependent manner. Pretreatment of SH-SY5Y cells for 7 days, but not I day, with 1 mM of lithium or 0.6 mM of valproate significantly reduced rotenone and H2O2-induced cytotoxicity, cytochrome c release and caspase-3 activation, and increased Bcl-2 levels. Conversely, neither acute nor chronic treatment of SH-SY5Y cells with lithium or valproate elicited cytoprotective responses against thapsigargin-evoked cell death and caspase-3 activation. Moreover, inhibitors of glycogen synthase kinase-3 (GSK-3), kenpaullone and SB216763, abrogated rotenone-induced, but not H2O2-induced, cytotoxicity. Thus the cytoprotective effects of lithium and valproate against H2O2-induced cell death is likely independent of GSK-3 inhibition. On the other hand, chronic lithium or valproate treatment did not ameliorate cytotoxicity induced by rotenone, H2O2, and thapsigargin in SVG astroglial and U87 MG glioma cell lines. Our results suggest that lithium and valproate may decrease vulnerability of human neural, but not glial, cells to cellular injury evoked by oxidative stress possibly arising from putative mitochondrial disturbances implicated in bipolar disorder. (c) 2006 Elsevier B.V. All rights reserved.