右美托咪定通过 α2 肾上腺素受体发挥抗炎作用，预防脂多糖诱导的小鼠认知功能下降。

Dexmedetomidine Exerts an Anti-inflammatory Effect via α2 Adrenoceptors to Prevent Lipopolysaccharide-induced Cognitive Decline in Mice.

机构信息

From the Department of Anesthesiology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China (R.L., P.Z.) the Center for Brain Science, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China (R.L.) the Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care (R.L., I.K.L., J.Z.P., M.M.) the Brain and Spinal Injury Center (J.Z.P.), University of California, San Francisco, California.

出版信息

Anesthesiology. 2020 Aug;133(2):393-407. doi: 10.1097/ALN.0000000000003390.

DOI:10.1097/ALN.0000000000003390

PMID:32482998

Abstract

BACKGROUND

Clinical studies have shown that dexmedetomidine ameliorates cognitive decline in both the postoperative and critical care settings. This study determined the mechanism(s) for the benefit provided by dexmedetomidine in a medical illness in mice induced by lipopolysaccharide.

METHODS

Cognitive decline, peripheral and hippocampal inflammation, blood-brain barrier permeability, and inflammation resolution were assessed in male mice. Dexmedetomidine was administered in the presence of lipopolysaccharide and in combination with blockers. Cultured macrophages (RAW 264.7; BV-2) were exposed to lipopolysaccharide ± dexmedetomidine ± yohimbine; tumor necrosis factor α release into the medium and monocyte NFκB activity was determined.

RESULTS

In vivo, lipopolysaccharide-induced cognitive decline and inflammation (mean ± SD) were reversed by dexmedetomidine (freezing time, 55.68 ± 12.31 vs. 35.40 ± 17.66%, P = 0.0286, n = 14; plasma interleukin [IL]-1β: 30.53 ± 9.53 vs. 75.68 ± 11.04 pg/ml, P < 0.0001; hippocampal IL-1β: 3.66 ± 1.88 vs. 28.73 ± 5.20 pg/mg, P < 0.0001; n = 8), which was prevented by α2 adrenoceptor antagonists. Similar results were found in 12-month-old mice. Lipopolysaccharide also increased blood-brain barrier leakage, inflammation-resolution orchestrator, and proresolving and proinflammatory mediators; each lipopolysaccharide effect was attenuated by dexmedetomidine, and yohimbine prevented dexmedetomidine's attenuating effect. In vitro, lipopolysaccharide-induced tumor necrosis factor α release (RAW 264.7: 6,308.00 ± 213.60 vs. 7,767.00 ± 358.10 pg/ml, P < 0.0001; BV-2: 1,075.00 ± 40.41 vs. 1,280.00 ± 100.30 pg/ml, P = 0.0003) and NFκB-p65 activity (nuclear translocation [RAW 264.7: 1.23 ± 0.31 vs. 2.36 ± 0.23, P = 0.0031; BV-2: 1.08 ± 0.26 vs. 1.78 ± 0.14, P = 0.0116]; phosphorylation [RAW 264.7: 1.22 ± 0.40 vs. 1.94 ± 0.23, P = 0.0493; BV-2: 1.04 ± 0.36 vs. 2.04 ± 0.17, P = 0.0025]) were reversed by dexmedetomidine, which was prevented by yohimbine.

CONCLUSIONS

Preclinical studies suggest that the cognitive benefit provided by dexmedetomidine in mice administered lipopolysaccharide is mediated through α2 adrenoceptor-mediated anti-inflammatory pathways.

摘要

背景

临床研究表明，右美托咪定可改善术后和重症监护环境中的认知功能下降。本研究旨在确定脂多糖诱导的小鼠疾病中右美托咪定的获益机制。

方法

评估雄性小鼠的认知功能下降、外周和海马炎症、血脑屏障通透性和炎症消退情况。在给予脂多糖的同时给予右美托咪定，并与阻滞剂联合使用。将培养的巨噬细胞（RAW 264.7；BV-2）暴露于脂多糖±右美托咪定±育亨宾；测定肿瘤坏死因子 α 释放到培养基中和单核细胞 NFκB 活性。

结果

体内，右美托咪定逆转了脂多糖诱导的认知功能下降和炎症（平均 ± SD）（冻结时间：55.68 ± 12.31 对 35.40 ± 17.66%，P = 0.0286，n = 14；血浆白细胞介素[IL]-1β：30.53 ± 9.53 对 75.68 ± 11.04 pg/ml，P < 0.0001；海马 IL-1β：3.66 ± 1.88 对 28.73 ± 5.20 pg/mg，P < 0.0001，n = 8），这种作用被 α2 肾上腺素能受体拮抗剂所阻断。在 12 个月大的小鼠中也发现了类似的结果。脂多糖还增加了血脑屏障渗漏、炎症消退协调器、促消退和促炎介质；脂多糖的每种作用都被右美托咪定减弱，育亨宾则阻止了右美托咪定的减弱作用。体外，脂多糖诱导的肿瘤坏死因子 α 释放（RAW 264.7：6308.00 ± 213.60 对 7767.00 ± 358.10 pg/ml，P < 0.0001；BV-2：1075.00 ± 40.41 对 1280.00 ± 100.30 pg/ml，P = 0.0003）和 NFκB-p65 活性（核转位[RAW 264.7：1.23 ± 0.31 对 2.36 ± 0.23，P = 0.0031；BV-2：1.08 ± 0.26 对 1.78 ± 0.14，P = 0.0116]；磷酸化[RAW 264.7：1.22 ± 0.40 对 1.94 ± 0.23，P = 0.0493；BV-2：1.04 ± 0.36 对 2.04 ± 0.17，P = 0.0025]）均被右美托咪定逆转，育亨宾则阻止了这种作用。