Department of Pharmacology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran; Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
Int Immunopharmacol. 2022 Oct;111:109119. doi: 10.1016/j.intimp.2022.109119. Epub 2022 Aug 4.
Brain injury is the most common and serious consequence of hepatic encephalopathy (HE), and its pathophysiology is poorly understood. Excessive inflammatory, oxidative and apoptotic responses are the major mechanisms involved in the progression of brain injury induced by HE. Carvedilol is an adrenergic receptor antagonist with pronouncedantioxidant and anti-inflammatory activity. The present study aimed to investigatethe effects and underlying mechanisms of carvedilol on HE-induced brain damage in mice. Experimental model of HE was induced by the injection of thioacetamide (200 mg/kg) for two consecutive days and then mice were treated with carvedilol (10 or 20 mg/kg/day, orally) for 3 days in treatment groups. After the behavioral test, animals were sacrificed and the brain tissues were collected for biochemical, real time PCR and immunohistochemical analysis. The results showed that carvedilol improved locomotor impairment and reduced mortality rate in mice with HE. Carvedilol treatment decreased the brain levels of oxidative stress markers and induced Nrf2/HO-1 pathway. Carvedilol inhibited the activity of nuclear factor kappa B (NF-κB) and the expression of pro-inflammatory cytokines TNF-α, IL1β and IL-6 in the brain tissues. Treatment of mice with carvedilol caused a significant reduction in the brain levels of iNOS/NO, myeloperoxidase (MPO), cyclooxygenase (COX)-2 and chemokine MCP-1 as proinflammatory mediators in HE. Moreover, the ratio of Bcl2/Bax was increased and apoptotic cell death was decreased in the brain of mice treated with carvedilol. In conclusion, carvedilol exerted protective effect against HE-induced brain injury through increasing antioxidant defense mechanisms and inhibitionof inflammatory and apoptotic pathways.
脑损伤是肝性脑病（HE）最常见和最严重的后果，其病理生理学尚未完全了解。过度的炎症、氧化和细胞凋亡反应是 HE 诱导的脑损伤进展的主要机制。卡维地洛是一种肾上腺素能受体拮抗剂，具有明显的抗氧化和抗炎活性。本研究旨在探讨卡维地洛对小鼠 HE 诱导的脑损伤的作用及其机制。采用连续 2 天注射硫代乙酰胺（200mg/kg）诱导 HE 实验模型，然后在治疗组中用卡维地洛（10 或 20mg/kg/天，口服）治疗 3 天。行为测试后，处死动物并采集脑组织进行生化、实时 PCR 和免疫组织化学分析。结果表明，卡维地洛改善了 HE 小鼠的运动障碍并降低了死亡率。卡维地洛治疗降低了脑组织氧化应激标志物的水平，并诱导了 Nrf2/HO-1 通路。卡维地洛抑制了核因子 kappa B（NF-κB）的活性和脑组织中促炎细胞因子 TNF-α、IL1β 和 IL-6 的表达。用卡维地洛治疗小鼠可显著降低脑内诱导型一氧化氮合酶（iNOS）/NO、髓过氧化物酶（MPO）、环氧化酶（COX）-2 和趋化因子 MCP-1 的水平，这些都是 HE 中的促炎介质。此外，卡维地洛治疗可增加 Bcl2/Bax 的比值并减少脑内的凋亡细胞死亡。总之，卡维地洛通过增加抗氧化防御机制和抑制炎症和凋亡途径对 HE 诱导的脑损伤发挥保护作用。
