Department of Anesthesiology and Pain Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Anesthesiology and Pain Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
Biomed Pharmacother. 2022 Jun;150:113006. doi: 10.1016/j.biopha.2022.113006. Epub 2022 Apr 26.
Surgical trauma can induce an inflammatory response in the central nervous system. Neuroinflammation is a crucial pathological mechanism of perioperative neurocognitive disorders (PND). Dexmedetomidine (Dex) is an alpha (α)-2 adrenoceptor agonist that is widely used in the perioperative period. Previous studies have shown that Dex has neuroprotection in various nerve injury models, but its role in PND remains unclear. Our study aimed to observe the neuroprotective effect of Dex pretreatment on postoperative cognitive change and explore the effects of hippocampal neuroinflammation, microglial polarization and HMGB1/RAGE/NF-κB signaling pathway involved in Dex on PND in rats. Rats were pretreated with Dex alone or in combination with yohimbine (α-2 adrenoceptor antagonist) before surgery. Behavioral tests results showed that Dex ameliorated surgery-induced cognitive impairment in rats. Nissl, immunohistochemistry and TUNEL-NeuN staining results indicated that Dex reduced hippocampus damage and neuronal apoptosis caused by surgery. Dex preconditioning reduced the expression of the proinflammatory cytokines IL-1β, TNF-α and IL-6 in hippocampus. Immunohistochemical and immunofluorescence results showed that Dex preconditioning inhibited the activation of glial cells induced by surgery. Western blot analysis showed that Dex preconditioning downregulated the expression of M1 phenotype markers (CD86 and iNOS), HMGB1, RAGE and nuclear NF-κB and upregulated the expression of M2 phenotype markers (Arginase 1 and CD206) and cytoplasmic NF-κB. Yohimbine could inhibit the neuroprotective effect of Dex. These results indicated that Dex pretreatment could improve postoperative short-term cognitive impairment, and the neuroprotective mechanism may involve the suppression of hippocampal neuroinflammation, regulation of M1/M2 polarization, and inhibition of HMGB1/RAGE/NF-κB signal transduction.
手术创伤可诱发中枢神经系统的炎症反应。神经炎症是围手术期神经认知障碍（PND）的关键病理机制。右美托咪定（Dex）是一种广泛应用于围手术期的α2-肾上腺素受体激动剂。先前的研究表明，Dex 在各种神经损伤模型中具有神经保护作用，但它在 PND 中的作用尚不清楚。本研究旨在观察 Dex 预处理对术后认知改变的神经保护作用，并探讨 Dex 对大鼠 PND 中海马神经炎症、小胶质细胞极化以及 HMGB1/RAGE/NF-κB 信号通路的影响。大鼠术前单独或联合育亨宾（α2-肾上腺素受体拮抗剂）预处理 Dex。行为学测试结果表明，Dex 改善了手术引起的大鼠认知障碍。尼氏染色、免疫组化和 TUNEL-NeuN 染色结果表明，Dex 减少了手术引起的海马损伤和神经元凋亡。Dex 预处理降低了海马中促炎细胞因子 IL-1β、TNF-α 和 IL-6 的表达。免疫组化和免疫荧光结果表明，Dex 预处理抑制了手术引起的小胶质细胞激活。Western blot 分析表明，Dex 预处理下调了 M1 表型标志物（CD86 和 iNOS）、HMGB1、RAGE 和核 NF-κB 的表达，上调了 M2 表型标志物（精氨酸酶 1 和 CD206）和细胞质 NF-κB 的表达。育亨宾可抑制 Dex 的神经保护作用。这些结果表明，Dex 预处理可改善术后短期认知障碍，其神经保护机制可能涉及抑制海马神经炎症、调节 M1/M2 极化以及抑制 HMGB1/RAGE/NF-κB 信号转导。
