Abstract

Hepatic encephalopathy (HE) is a serious brain disorder which associated with neurological and psychiatric manifestations. Oxidative stress and neuroinflammation and apoptosis play main roles in the development of brain damage in HE. Levetiracetam is an antiseizure drug with established antioxidant and anti-inflammatory activities. In the present study we investigated the therapeutic effects of levetiracetam against brain injury in HE and its underlying mechanisms of action. Male C57BL/6 mice were subjected to the induction of HE by the injection of thioacetamide (200 mg/kg) for 2 days. Mice were treated with levetiracetam at two doses (50 or 100 mg/kg/day) for 3 days in the treatment groups. Animals were subjected to a behavioral test and the brain tissues were dissected for histopathological, biochemical, gene expression and immunofluorescence analysis. The results showed that levetiracetam alleviated body weight loss and improved locomotor activity of mice with HE. Levetiracetam treatment decreased the histopathological changes, lipid peroxidation and protein carbonylation while restored the antioxidants (GSH, SOD and CAT) in the brain. Levetiracetam decreased the expression and activity of NF-κB, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) in the brain tissue. Administration of levetiracetam inhibited iNOS/NO pathway and myeloperoxidase (MPO) activity in the brain. Moreover, caspase-3 was decreased and the ratio of Bcl2/Bax was increased in the brain of mice treated with levetiracetam. These findings suggest that levetiracetam may be a promising therapeutic agent for brain injury in HE through inhibiting the oxidative, inflammatory and apoptotic pathways.

中文翻译：

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左乙拉西坦通过抑制氧化应激和下调 NF-κB、NLRP3、iNOS/NO、促炎性细胞因子和细胞凋亡对硫代乙酰胺诱导的肝性脑病的治疗作用

摘要

肝性脑病（HE）是一种与神经和精神表现相关的严重脑部疾病。氧化应激、神经炎症和细胞凋亡在 HE 脑损伤的发展中起主要作用。左乙拉西坦是一种抗癫痫药物，具有明确的抗氧化和抗炎活性。在本研究中，我们研究了左乙拉西坦对 HE 脑损伤的治疗作用及其潜在作用机制。雄性C57BL/6小鼠通过注射硫代乙酰胺(200mg/kg)诱导HE 2天。治疗组的小鼠接受两种剂量（50 或 100 mg/kg/天）的左乙拉西坦治疗 3 天。对动物进行行为测试，并解剖脑组织进行组织病理学、生化、基因表达和免疫荧光分析。结果表明，左乙拉西坦减轻了 HE 小鼠的体重减轻并改善了运动能力。左乙拉西坦治疗减少了组织病理学变化、脂质过氧化和蛋白质羰基化，同时恢复了大脑中的抗氧化剂（GSH、SOD 和 CAT）。左乙拉西坦降低大脑中 NF-κB、NOD 样受体热蛋白结构域蛋白 3 (NLRP3) 和促炎细胞因子（TNF-α、IL-1β、IL-6 和 IFN-γ）的表达和活性组织。左乙拉西坦的给药抑制了大脑中的 iNOS/NO 通路和髓过氧化物酶 (MPO) 活性。此外，用左乙拉西坦治疗的小鼠大脑中 caspase-3 减少，Bcl2/Bax 比率增加。这些发现表明，左乙拉西坦可能通过抑制氧化、炎症和细胞凋亡途径，成为治疗 HE 脑损伤的有前景的药物。