Centre of Excellence for Epilepsy, AIIMS, New Delhi, India.
Department of Neurosurgery, AIIMS, New Delhi, India.
Cell Mol Neurobiol. 2022 May;42(4):1049-1064. doi: 10.1007/s10571-020-00994-0. Epub 2020 Nov 28.
Histone deacetylases (HDACs) have been described to have both neurotoxic and neuroprotective roles, and partly, depend on its sub-cellular distribution. HDAC inhibitors have a long history of use in the treatment of various neurological disorders including epilepsy. Key role of HDACs in GABAergic neurotransmission, synaptogenesis, synaptic plasticity and memory formation was demonstrated whereas very less is known about their role in drug-resistant epilepsy pathologies. The present study was aimed to investigate the changes in the expression of HDACs, activity and its sub-cellular distribution in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. For this study, surgically resected hippocampal tissue specimens of 28 MTLE-HS patients and 20 hippocampus from post-mortem cases were obtained. Real-time PCR was done to analyse the mRNA expression. HDAC activity and the protein levels of HDACs in cytoplasm as well as nucleus were measured spectrophotometrically. Further, sub-cellular localization of HDACs was characterized by immunofluorescence. Significant upregulation of HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC10 and HDAC11 mRNA were observed in MTLE-HS. Alterations in the mRNA expression of glutamate and gamma-aminobutyric acid (GABA) receptor subunits have been also demonstrated. We observed significant increase of HDAC activity and nuclear level of HDAC1, HDAC2, HDAC5 and HDAC11 in the hippocampal samples obtained from patients with MTLE-HS. Moreover, we found altered cytoplasmic level of HDAC4, HDAC6 and HDAC10 in the hippocampal sample obtained from patients with MTLE-HS. Alterations in the level of HDACs could potentially be part of a dynamic transcription regulation associated with MTLE-HS. Changes in cytoplasmic level of HDAC4, 6 and 10 suggest that cytoplasmic substrates may play a crucial role in the pathophysiology of MTLE-HS. Knowledge regarding expression pattern and sub-cellular distribution of HDACs may help to devise specific HDACi therapy for epilepsy.
组蛋白去乙酰化酶 (HDACs) 具有神经毒性和神经保护作用，部分取决于其亚细胞分布。HDAC 抑制剂在治疗各种神经疾病（包括癫痫）方面有着悠久的历史。已经证明 HDAC 在 GABA 能神经传递、突触发生、突触可塑性和记忆形成中起关键作用，而关于它们在耐药性癫痫病理中的作用知之甚少。本研究旨在研究内侧颞叶癫痫伴海马硬化 (MTLE-HS) 患者中 HDAC 的表达、活性及其亚细胞分布的变化。为此，本研究获得了 28 例 MTLE-HS 患者和 20 例尸检海马组织标本。通过实时 PCR 分析 mRNA 表达。通过分光光度法测量 HDAC 活性和细胞质以及细胞核中 HDAC 的蛋白水平。进一步通过免疫荧光法对 HDAC 的亚细胞定位进行了表征。在 MTLE-HS 中观察到 HDAC1、HDAC2、HDAC4、HDAC5、HDAC6、HDAC10 和 HDAC11 的 mRNA 显著上调。谷氨酸和γ-氨基丁酸 (GABA) 受体亚基的 mRNA 表达改变也得到了证实。我们观察到在来自 MTLE-HS 患者的海马样本中 HDAC 活性和 HDAC1、HDAC2、HDAC5 和 HDAC11 的核水平显著增加。此外，我们发现来自 MTLE-HS 患者的海马样本中 HDAC4、HDAC6 和 HDAC10 的细胞质水平发生改变。HDAC 水平的变化可能是与 MTLE-HS 相关的动态转录调节的一部分。HDAC4、6 和 10 的细胞质水平变化表明细胞质底物可能在 MTLE-HS 的病理生理学中起关键作用。了解 HDAC 的表达模式和亚细胞分布可能有助于为癫痫制定特定的 HDACi 治疗方案。
