Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Neurochem Res. 2024 May;49(5):1306-1321. doi: 10.1007/s11064-024-04115-x. Epub 2024 Mar 12.
Sepsis-induced neuroinflammation is significantly associated with sepsis-related brain dysfunction. Remimazolam is a novel ultra-short-acting benzodiazepine anesthetic with multiple organ protective effects. However, it is unknown whether remimazolam can ameliorate LPS-induced brain impairment. In this study, Lipopolysaccharide (5 mg/kg, LPS) severely impaired Sprague-Dawley rats spatial learning ability, memory, and cognitive function. However, remimazolam treatment showed a protective effect on LPS-induced cognitive dysfunction. Remimazolam partly reversed LPS-induced splenomegaly, decreased serum cytokine expression, suppressed hippocampal M1 microglial activation, and mitigated oxidative stress injury and neuroinflammation. Electroacupuncture (EA) or PNU282987 treatment improved LPS-induced cognitive dysfunction and also significantly inhibited neuroinflammation and systemic inflammation. However, MLA, ML385, or subdiaphragmatic vagus nerve (SDV) treatment abolished the protective effects of remimazolam. Further mechanistic studies showed that remimazolam induces protective effects by activating subdiaphragmatic vagus nerve target α7nAChR-mediated Nrf2/HO-1 signaling pathway. These results demonstrate that remimazolam can up-regulate α7nAChR, Cyto-Nrf2, HO-1, and cognitive-related (CREB, BDNF, PSD95) protein expressions, suppress M1 microglia, ameliorate neuroinflammation or systemic inflammation, and reverse cognitive dysfunction. Therefore, this study provides insight into a new therapeutic target for the treatment of sepsis-induced cerebral dysfunction.
脓毒症引起的神经炎症与脓毒症相关的脑功能障碍显著相关。雷米唑仑是一种新型的超短效苯二氮䓬类麻醉剂，具有多种器官保护作用。然而，目前尚不清楚雷米唑仑是否能改善脂多糖（LPS）诱导的脑损伤。在这项研究中，脂多糖（5mg/kg，LPS）严重损害了 Sprague-Dawley 大鼠的空间学习能力、记忆和认知功能。然而，雷米唑仑治疗对 LPS 诱导的认知功能障碍表现出保护作用。雷米唑仑部分逆转了 LPS 诱导的脾肿大，降低了血清细胞因子表达，抑制了海马 M1 小胶质细胞的激活，并减轻了氧化应激损伤和神经炎症。电针（EA）或 PNU282987 治疗改善了 LPS 诱导的认知功能障碍，同时也显著抑制了神经炎症和全身炎症。然而，MLA、ML385 或膈下迷走神经（SDV）治疗消除了雷米唑仑的保护作用。进一步的机制研究表明，雷米唑仑通过激活膈下迷走神经靶标α7nAChR 介导的 Nrf2/HO-1 信号通路发挥保护作用。这些结果表明，雷米唑仑可以上调α7nAChR、Cyto-Nrf2、HO-1 和与认知相关的（CREB、BDNF、PSD95）蛋白表达，抑制 M1 小胶质细胞，改善神经炎症或全身炎症，并逆转认知功能障碍。因此，本研究为治疗脓毒症引起的脑功能障碍提供了一个新的治疗靶点。
