Epigenetic Histone Deacetylation Inhibition Prevents the Development and Persistence of Temporal Lobe Epilepsy
Epigenetic Histone Deacetylation Inhibition Prevents the Development and Persistence of Temporal Lobe Epilepsy
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DOI：
10.1124/jpet.117.244939
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发表时间：
2018-01-01
影响因子：
3.5
通讯作者：
Reddy, Doodipala Samba
中科院分区：
文献类型：
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作者：
Reddy, Sandesh D.;Clossen, Bryan L.;Reddy, Doodipala Samba
癫痫是一种以反复无端发作为特征的慢性脑部疾病。目前，还不存在治愈癫痫或对高危人群进行疾病改造的药物疗法。尽管出现了几种新的机制，但关于表观遗传信号在癫痫发生中的研究很少，癫痫发生是正常大脑因诱发因素而逐渐癫痫的过程。在这里，我们报告了一个新的作用，组蛋白去乙酰化作为一个关键的表观遗传机制，在癫痫的发生。在颞叶癫痫(TLE)的海马区点燃模型中，使用组蛋白脱乙酰酶(HDAC)抑制剂丁酸钠进行了实验，TLE是一种经典的癫痫治疗药物批准模型。丁酸盐的日常治疗显着抑制HDAC活性，延缓边缘癫痫的发展，但不影响后放电信号。抑制HDAC明显损害癫痫形成后数周癫痫表达的持续性。此外，亚慢性HDAC抑制2周可显著延缓癫痫的发生。出乎意料的是，对HDAC的抑制也表明癫痫动物的致痫状态被消除了。最后，丁酸盐处理的动物在苔藓纤维发芽方面表现出强大的减少，苔藓纤维发芽是癫痫发生的一种形态指标。总之，这些结果强调了HDAC抑制阻止TLE的发展，表明HDAC在癫痫发生中的关键信号作用。因此，这些发现设想了一种独特的新疗法，通过靶向表观遗传的HDAC途径来预防或治疗癫痫。
Epilepsy is a chronic brain disease characterized by repeated unprovoked seizures. Currently, no drug therapy exists for curing epilepsy or disease modification in people at risk. Despite several emerging mechanisms, there have been few studies of epigenetic signaling in epileptogenesis, the process whereby a normal brain becomes progressively epileptic because of precipitating factors. Here, we report a novel role of histone deacetylation as a critical epigenetic mechanism in epileptogenesis. Experiments were conducted using the histone deacetylase (HDAC) inhibitor sodium butyrate in the hippocampus kindling model of temporal lobe epilepsy (TLE), a classic model heavily used to approve drugs for treatment of epilepsy. Daily treatment with butyrate significantly inhibited HDAC activity and retarded the development of limbic epileptogenesis without affecting after-discharge signal. HDAC inhibition markedly impaired the persistence of seizure expression many weeks after epilepsy development. Moreover, subchronic HDAC inhibition for 2 weeks resulted in a striking retardation of epileptogenesis. HDAC inhibition, unexpectedly, also showed erasure of the epileptogenic state in epileptic animals. Finally, butyrate-treated animals exhibited a powerful reduction in mossy fiber sprouting, a morphologic index of epileptogenesis. Together these results underscore that HDAC inhibition prevents the development of TLE, indicating HDAC's critical signaling role in epileptogenesis. These findings, therefore, envisage a unique novel therapy for preventing or curing epilepsy by targeting the epigenetic HDAC pathway.