Epilepsy (EP) is one of the most universal neurological disorders. This study investigated the mechanism of forkhead box protein O4 (FOXO4) on hippocampal neuronal damage in EP mice. Initially, the EP mouse model and the in vitro HT-22 cell model were established. EP seizures and neuronal damage in mice were assessed. FOXO4, microRNA (miR)-138-5p, and rho-associated coiled-coil containing protein kinase 2 (ROCK2) levels in hippocampal tissues or HT-22 cells were examined. The cell viability and apoptosis of HT-22 cells were determined. The concentrations of oxidative stress markers and the levels of inflammatory cytokines in hippocampal tissues or HT-22 cells were detected. We found that FOXO4 was poorly expressed in EP. FOXO4 overexpression alleviated hippocampal neuronal damage in EP mice and improved HT-22 cell viability and inhibited apoptosis, and decreased oxidative stress and inflammation in hippocampal tissue and HT-22 cells. The bindings of miR-138-5p to FOXO4 and ROCK2 were analyzed, which showed that FOXO4 promoted miR-138-5p via binding to the miR-138-5p promoter region, and miR-138-5p inhibited ROCK2 expression. Joint experiments showed that miR-138-5p suppression or ROCK2 overexpression reversed the alleviation of FOXO4 overexpression on hippocampal neuronal damage. FOXO4 inhibited ROCK2 expression via promoting miR-138-5p expression, thus alleviating hippocampal neuronal damage in EP mice.

中文翻译：

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FOXO4 通过 miR-138-5p/ROCK2 轴减轻癫痫小鼠海马神经元损伤

癫痫 (EP) 是最普遍的神经系统疾病之一。本研究调查了叉头盒蛋白 O4 (FOXO4) 对 EP 小鼠海马神经元损伤的机制。初步建立了EP小鼠模型和体外HT-22细胞模型。评估了小鼠的 EP 发作和神经元损伤。检查了海马组织或 HT-22 细胞中的 FOXO4、microRNA (miR)-138-5p 和 rho 相关卷曲螺旋蛋白激酶 2 (ROCK2) 水平。测定了 HT-22 细胞的细胞活力和凋亡。检测海马组织或HT-22细胞中氧化应激标志物的浓度和炎性细胞因子的水平。我们发现 FOXO4 在 EP 中的表达很差。FOXO4 过表达减轻 EP 小鼠海马神经元损伤，提高 HT-22 细胞活力并抑制细胞凋亡，并减少海马组织和 HT-22 细胞的氧化应激和炎症。分析miR-138-5p与FOXO4和R​​OCK2的结合，发现FOXO4通过结合miR-138-5p启动子区促进miR-138-5p的表达，miR-138-5p抑制ROCK2的表达。联合实验表明，抑制 miR-138-5p 或 ROCK2 过表达可逆转 FOXO4 过表达对海马神经元损伤的缓解作用。FOXO4 通过促进 miR-138-5p 的表达来抑制 ROCK2 的表达，从而减轻 EP 小鼠的海马神经元损伤。联合实验表明，抑制 miR-138-5p 或 ROCK2 过表达可逆转 FOXO4 过表达对海马神经元损伤的缓解作用。FOXO4 通过促进 miR-138-5p 的表达来抑制 ROCK2 的表达，从而减轻 EP 小鼠的海马神经元损伤。联合实验表明，抑制 miR-138-5p 或 ROCK2 过表达可逆转 FOXO4 过表达对海马神经元损伤的缓解作用。FOXO4 通过促进 miR-138-5p 的表达来抑制 ROCK2 的表达，从而减轻 EP 小鼠的海马神经元损伤。