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Neuroprotective Effects of Celastrol on Transient Global Cerebral Ischemia Rats via Regulating HMGB1/NF-κB Signaling Pathway
Frontiers in Neuroscience ( IF 4.3 ) Pub Date : 2020-08-11 , DOI: 10.3389/fnins.2020.00847
Bo Zhang 1, 2 , Qi Zhong 1, 3 , Xuhui Chen 2, 4 , Xi Wu 1, 2 , Rong Sha 5 , Guizhi Song 6 , Chuanhan Zhang 2 , Xiangdong Chen 1
Affiliation  

Cerebral ischemia is a major cause of brain dysfunction, neuroinflammation and oxidative stress have been implicated in the pathophysiological process of cerebral ischemia/reperfusion injury. Celastrol is a potent inhibitor of inflammation and oxidative stress that has little toxicity. The present study was designed to evaluate whether celastrol has neuroprotective effects through anti-inflammatory and antioxidant actions, and to elucidate the possible involved mechanisms in transient global cerebral ischemia reperfusion (tGCI/R) rats. Celastrol (1, 2, or 4 mg/kg) was administrated intraperitoneally immediately after reperfusion and the effect of celastrol on reverting spatial learning and memory impairment was determined by Morris water maze (MWM) task. Inflammatory response and oxidative stress, hippocampal neuronal damage and glial activation, and HMGB1/NF-κB signaling pathway proteins were also examined. Our results indicated that celastrol dose-dependently reduced hippocampal and serum concentration of pro-inflammatory markers (TNF-α, IL-1β, and IL-6) and oxidative stress marker (MDA), whereas the anti-inflammatory marker IL-10 and antioxidant markers (GSH, SOD, and CAT) were increased significantly in celastrol treated tGCI/R rats. Celastrol alleviated apoptotic neuronal death, inhibited reactive glial activation and proliferation and improved ischemia-induced neurological deficits. Simultaneously, we found that mechanisms responsible for the neuroprotective effect of celastrol could be attributed to its anti-inflammatory and antioxidant actions via inhibiting HMGB1/NF-κB signaling pathway. These findings provide a proof of concept for the further validation that celastrol may be a superior candidate for the treatment of severe cerebral ischemic patients in clinical practice in the future.

中文翻译:

Celastrol 通过调节 HMGB1/NF-κB 信号通路对一过性脑缺血大鼠的神经保护作用

脑缺血是脑功能障碍的主要原因,神经炎症和氧化应激与脑缺血/再灌注损伤的病理生理过程有关。Celastrol 是一种有效的炎症和氧化应激抑制剂,毒性很小。本研究旨在评估 celastrol 是否通过抗炎和抗氧化作用具有神经保护作用,并阐明短暂性全脑缺血再灌注 (tGCI/R) 大鼠可能涉及的机制。Celastrol(1、2 或 4 mg/kg)在再灌注后立即腹膜内给药,通过 Morris 水迷宫 (MWM) 任务确定 Celastrol 对恢复空间学习和记忆障碍的影响。炎症反应和氧化应激,海马神经元损伤和神经胶质激活,还检查了 HMGB1/NF-κB 信号通路蛋白。我们的结果表明,celastrol 剂量依赖性地降低了促炎标志物(TNF-α、IL-1β 和 IL-6)和氧化应激标志物(MDA)的海马和血清浓度,而抗炎标志物 IL-10 和在 celastrol 治疗的 tGCI/R 大鼠中,抗氧化标志物(GSH、SOD 和 CAT)显着增加。Celastrol 减轻了细胞凋亡的神经元死亡,抑制了反应性胶质细胞的激活和增殖,并改善了缺血引起的神经功能缺损。同时,我们发现 celastrol 神经保护作用的机制可归因于其通过抑制 HMGB1/NF-κB 信号通路的抗炎和抗氧化作用。
更新日期:2020-08-11
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