Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate
Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate
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DOI：
10.1016/j.neuroscience.2006.11.010
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发表时间：
2007-02-23
期刊：
影响因子：
3.3
通讯作者：
Wang, J. -F.
中科院分区：
文献类型：
--
作者：
Cui, J.;Shao, L.;Wang, J. -F.
情绪稳定药物锂和丙戊酸盐是双相情感障碍最常用的治疗方法。我们实验室先前的研究表明，锂和丙戊酸盐的长期治疗可抑制原代培养的大鼠大脑皮层细胞的氧化损伤。谷胱甘肽作为大脑中的主要抗氧化剂，在防御氧化损伤方面发挥着关键作用。本研究的目的是确定谷胱甘肽在锂和丙戊酸对抗氧化损伤的神经保护作用中的作用。我们发现，长期使用锂和丙戊酸盐治疗可抑制原代培养的大鼠大脑皮质细胞中活性氧代谢物H2O2诱导的细胞死亡，而丁硫氨酸亚砜亚胺（谷胱甘肽限速合成酶谷氨酸半胱氨酸连接酶的抑制剂）则降低了锂和丙戊酸盐对H2O2诱导的细胞死亡的神经保护作用。此外，我们发现，锂和丙戊酸的长期治疗会增加原代培养的大鼠大脑皮层细胞中的谷胱甘肽水平，并且锂和丙戊酸对人神经母细胞 SH-SY5Y 细胞中谷胱甘肽水平的影响呈剂量依赖性。锂和丙戊酸的长期治疗还增加了大鼠大脑皮层细胞和 SH-SY5Y 细胞中谷氨酸-半胱氨酸连接酶的表达。此外，使用其他情绪稳定药物拉莫三嗪和卡马西平（而非抗抑郁药地昔帕明和氟西汀）进行长期治疗，可以增加SH-SY5Y细胞中谷胱甘肽水平和谷氨酸半胱氨酸连接酶的表达。这些结果表明谷胱甘肽在锂和丙戊酸的神经保护作用中发挥着重要作用，并且谷胱甘肽可能是情绪稳定药物的常见靶点。 (c) 2006 年国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Mood stabilizing drugs lithium and valproate are the most commonly used treatments for bipolar disorder. Previous studies in our laboratory indicate that chronic treatment with lithium and valproate inhibits oxidative damage in primary cultured rat cerebral cortical cells. Glutathione, as the major antioxidant in the brain, plays a key role in defending against oxidative damage. The purpose of this study was to determine the role of glutathione in the neuroprotective effects of lithium and valproate against oxidative damage. We found that chronic treatment with lithium and valproate inhibited reactive oxygen metabolite H2O2-induced cell death in primary cultured rat cerebral cortical cells, while buthionine sulfoximine, an inhibitor of glutathione rate-limiting synthesis enzyme glutamate-cysteine ligase, reduced the neuroprotective effect of lithium and valproate against H2O2-induced cell death. Further, we found that chronic treatment with lithium and valproate increased glutathione levels in primary cultured rat cerebral cortical cells and that the effects of lithium and valproate on glutathione levels were dose-dependent in human neuroblastorna SH-SY5Y cells. Chronic treatment with lithium and valproate also increased the expression of glutamate-cysteine ligase in both rat cerebral cortical cells and SH-SY5Y cells. In addition, chronic treatment with other mood stabilizing drugs lamotrigine and carbamazepine, but not antidepressants desipramine and fluoxetine, increased both glutathione levels and the expression of glutamate-cysteine ligase in SH-SY5Y cells. These results suggest that glutathione plays an important role in the neuroprotective effects of lithium and valproate, and that glutathione may be a common target for mood stabilizing drugs. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.