Department of Anatomy, Guangzhou Medical College, 195 Dongfeng Xi Road, Guangzhou 510182, China.
Life Sci. 2012 Mar 10;90(11-12):463-8. doi: 10.1016/j.lfs.2012.01.001. Epub 2012 Jan 18.
A growing number of studies demonstrate that valproic acid (VPA), an anti-convulsant and mood-stabilizing drug, is neuroprotective against various insults. This study investigated whether treatment of ischemic stroke with VPA ameliorated hippocampal cell death and cognitive deficits. Possible mechanisms of action were also investigated.
Global cerebral ischemia was induced to mimic ischemia/reperfusion (I/R) damage. The pyramidal cells within the CA1 field were stained with cresyl violet. Cognitive ability was measured 7 days after I/R using a Morris water maze. The anti-inflammatory effects of VPA on microglia were also investigated by immunohistochemistry. Pro-inflammatory cytokine production was determined using enzyme-linked immunosorbent assays (ELISA). Western blot analysis was performed to determine the levels of acetylated H3, H4 and heat shock protein 70 (HSP70) in extracts from the ischemic hippocampus.
VPA significantly increased the density of neurons that survived in the CA1 region of the hippocampus on the 7th day after transient global ischemia. VPA ameliorated severe deficiencies in spatial cognitive performance induced by transient global ischemia. Post-insult treatment with VPA also dramatically suppressed the activation of microglia but not astrocytes, reduced the number of microglia, and inhibited other inflammatory markers in the ischemic brain. VPA treatment resulted in a significant increase in levels of acetylated histones H3 and H4 as well as HSP70 in the hippocampus.
Our results indicated that VPA protected against hippocampal cell loss and cognitive deficits. Treatment with VPA following cerebral ischemia probably involves multiple mechanisms of action, including inhibition of ischemia-induced cerebral inflammation, inhibition of histone deacetylase (HDAC) and induction of HSP.
越来越多的研究表明，丙戊酸（VPA），一种抗惊厥和稳定情绪的药物，对各种损伤具有神经保护作用。本研究探讨了用 VPA 治疗缺血性中风是否改善海马细胞死亡和认知缺陷。还研究了可能的作用机制。
诱导全脑缺血模拟缺血/再灌注（I/R）损伤。用甲苯胺蓝染色 CA1 区内的锥体神经元。用 Morris 水迷宫在 I/R 后 7 天测量认知能力。还通过免疫组织化学研究 VPA 对小胶质细胞的抗炎作用。通过酶联免疫吸附试验（ELISA）测定促炎细胞因子的产生。通过 Western blot 分析测定缺血海马提取物中乙酰化 H3、H4 和热休克蛋白 70（HSP70）的水平。
VPA 可显著增加短暂全脑缺血后第 7 天海马 CA1 区存活神经元的密度。VPA 改善了短暂全脑缺血引起的严重空间认知功能缺陷。损伤后给予 VPA 治疗也可显著抑制小胶质细胞的激活，但不抑制星形胶质细胞的激活，减少缺血大脑中小胶质细胞的数量，并抑制其他炎症标志物。VPA 治疗可显著增加海马组织中乙酰化组蛋白 H3 和 H4 以及 HSP70 的水平。
我们的结果表明，VPA 可防止海马细胞丢失和认知缺陷。脑缺血后用 VPA 治疗可能涉及多种作用机制，包括抑制缺血性脑炎症、抑制组蛋白去乙酰化酶（HDAC）和诱导 HSP。
