雷米佐胺通过 HMGB1-TLR4-NF-κB 通路改善深低温停循环后术后认知功能障碍。

Remimazolam ameliorates postoperative cognitive dysfunction after deep hypothermic circulatory arrest through HMGB1-TLR4-NF-κB pathway.

机构信息

Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

出版信息

Brain Res Bull. 2024 Oct 15;217:111086. doi: 10.1016/j.brainresbull.2024.111086. Epub 2024 Sep 23.

DOI:10.1016/j.brainresbull.2024.111086

PMID:39322086

Abstract

BACKGROUND

Postoperative cognitive dysfunction (POCD) is a complication of deep hypothermic circulatory arrest (DHCA). Various amounts of neurologic dysfunctions have been shown after DHCA, which has often been attributed to systemic inflammatory response syndrome and cerebral ischemia/reperfusion injury. Remimazolam is one of the commonly used anesthetic drugs with protective actions against inflammatory diseases, such as sepsis and cerebral ischemia/reperfusion injury. Here, we determined the protective effect and potential mechanism of action of remimazolam against neuronal damage after DHCA.

METHODS

A rat model of DHCA was established, and a gradient dosage of remimazolam was administered during cardiopulmonary bypass (CPB). The cognitive function of rats was evaluated by Morris water maze. Hematoxylin and eosin and TUNEL staining were performed to assess hippocampus tissue injury and neuronal apoptosis. Inflammatory cytokines concentration were analyzed by enzyme-linked immunosorbent assay. The protein expression was analyzed using automated electrophoresis western analysis and immunohistochemical analysis.

RESULTS

The appropriate dosage of remimazolam reduced histologic injury, neuronal apoptosis, microglia activation, and secondary inflammatory cascades, as well as the downregulation of the expression of the HMGB1-TLR4-NF-κB pathway after DHCA, improved the memory and learning abilities in DHCA rats. Further, administration of a TLR4 antagonist TAK-242 had a similar effect to remimazolam, while the TLR4 agonist LPS attenuated the effect of remimazolam.

CONCLUSIONS

Remimazolam could ameliorate POCD after DHCA through the HMGB1-TLR4-NF-κB signaling pathway.

摘要

背景

术后认知功能障碍（POCD）是深低温停循环（DHCA）的并发症。DHCA 后会出现各种程度的神经功能障碍，这通常归因于全身炎症反应综合征和脑缺血/再灌注损伤。瑞马唑仑是一种常用的麻醉药物，具有抗炎作用，如脓毒症和脑缺血/再灌注损伤。在这里，我们确定了瑞马唑仑对 DHCA 后神经元损伤的保护作用及其潜在的作用机制。

方法

建立大鼠 DHCA 模型，并在体外循环（CPB）期间给予瑞马唑仑梯度剂量。通过 Morris 水迷宫评估大鼠的认知功能。苏木精和伊红和 TUNEL 染色评估海马组织损伤和神经元凋亡。通过酶联免疫吸附试验分析炎性细胞因子浓度。使用自动电泳 Western 分析和免疫组织化学分析分析蛋白表达。

结果

适当剂量的瑞马唑仑减轻了 DHCA 后的组织损伤、神经元凋亡、小胶质细胞激活和二次炎症级联反应，以及 HMGB1-TLR4-NF-κB 通路表达的下调，改善了 DHCA 大鼠的记忆和学习能力。此外，TLR4 拮抗剂 TAK-242 的给药具有与瑞马唑仑相似的作用，而 TLR4 激动剂 LPS 则减弱了瑞马唑仑的作用。