Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation.
Histone deacetylase inhibitor SAHA attenuates post-seizure hippocampal microglia TLR4/MYD88 signaling and inhibits TLR4 gene expression via histone acetylation.
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DOI：
10.1186/s12868-016-0264-9
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发表时间：
2016-05-18
期刊：
影响因子：
2.4
通讯作者：
Mao DA
中科院分区：
文献类型：
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作者：
Hu QP;Mao DA
癫痫是一种常见的神经系统疾病，其特征是反复发作。癫痫诱导的TLR4/MYD88信号在激活小胶质细胞和触发神经元凋亡中起关键作用。SAHA是一种组蛋白去乙酰化酶抑制剂，通过增加染色质组蛋白乙酰化来调节基因表达。在本研究中，我们研究了SAHA在大鼠癫痫模型中TLR4/MYD88信号传导中的作用。用SAHA治疗kainic acid （KA）诱导的癫痫大鼠。在癫痫发作后第2、6小时和第1、2、3天检测海马组织中TLR4、MYD88、NF-κB P65、IL-1β的表达。SAHA预处理增加了癫痫发作潜伏期，降低了癫痫发作评分。KA处理后，活化小胶质细胞和凋亡神经元中TLR4、MYD88、NF-κB和IL-1β的表达水平均显著升高。SAHA的作用减弱。染色质免疫沉淀检测显示，KA治疗组H3组蛋白乙酰化水平显著降低，H3K9水平显著升高。经50 mg/kg的SAHA预处理后，H3和H3K9乙酰化水平恢复到对照水平。TLR4的表达与H3K9的乙酰化水平呈正相关。组蛋白去乙酰化酶抑制剂SAHA可通过组蛋白乙酰化调控，抑制癫痫诱导的TLR4/MYD88信号，抑制TLR4基因表达。这表明SAHA可以预防癫痫引起的脑损伤。
Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. Seizure-induced TLR4/MYD88 signaling plays a critical role in activating microglia and triggering neuron apoptosis. SAHA is a histone deacetylase inhibitor that regulates gene expression by increasing chromatin histone acetylation. In this study, we investigated the role of SAHA in TLR4/MYD88 signaling in a rat seizure model. Sprague–Dawley rats with kainic acid (KA)-induced seizures were treated with SAHA. The expression of TLR4, MYD88, NF-κB P65 and IL-1β in hippocampus was detected at hour 2 and 6 and day 1, 2, and 3 post seizure. SAHA pretreatment increased seizure latency and decreased seizure scores. The expression levels of TLR4, MYD88, NF-κB and IL-1β increased significantly in both activated microglia and apoptotic neurons after KA treatment. The effects were attenuated by SAHA. Chromatin immunoprecipitation assays indicated that the H3 histone acetylation levels significantly decreased while H3K9 levels significantly increased in the KA treatment group. The H3 and H3K9 acetylation levels returned to control levels after SAHA (50 mg/kg) pretreatment. There was a positive correlation between the expression of TLR4 and the acetylation levels of H3K9. Histone deacetylase inhibitor SAHA can suppress seizure-induced TLR4/MYD88 signaling and inhibit TLR4 gene expression through histone acetylation regulation. This suggests that SAHA may protect against seizure-induced brain damage.