右美托咪定和可乐定通过α-2肾上腺素能受体减轻七氟醚诱导的幼鼠tau蛋白磷酸化和认知障碍。

Dexmedetomidine and Clonidine Attenuate Sevoflurane-Induced Tau Phosphorylation and Cognitive Impairment in Young Mice via α-2 Adrenergic Receptor.

作者信息

Sun Mingyang, Dong Yuanlin, Li Mengzhu, Zhang Yiying, Liang Feng, Zhang Jiaqiang, Soriano Sulpicio G, Xie Zhongcong

机构信息

From the Department of Anesthesiology and Perioperative Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.

出版信息

Anesth Analg. 2021 Mar 1;132(3):878-889. doi: 10.1213/ANE.0000000000005268.

DOI:10.1213/ANE.0000000000005268

PMID:33181559

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7887006/

Abstract

BACKGROUND

Anesthetic sevoflurane induces tau phosphorylation and cognitive impairment in young mice. The underlying mechanism and the targeted interventions remain largely unexplored. We hypothesized that dexmedetomidine and clonidine attenuated sevoflurane-induced tau phosphorylation and cognitive impairment by acting on α-2 adrenergic receptor.

METHODS

Six-day-old mice received anesthesia with 3% sevoflurane 2 hours daily on postnatal days 6, 9, and 12. Alpha-2 adrenergic receptor agonist dexmedetomidine and clonidine were used to treat the mice with and without the α-2 adrenergic receptor antagonist yohimbine. Mouse hippocampi were harvested and subjected to western blot analysis. The New Object Recognition Test and Morris Water Maze were used to measure cognitive function. We analyzed the primary outcomes by using 2- and 1-way analysis of variance (ANOVA) and Mann-Whitney U test to determine the effects of sevoflurane on the amounts of phosphorylated tau, postsynaptic density-95, and cognitive function in young mice after the treatments with dexmedetomidine, clonidine, and yohimbine.

RESULTS

Both dexmedetomidine and clonidine attenuated the sevoflurane-induced increase in phosphorylated tau amount (94 ± 16.3% [dexmedetomidine plus sevoflurane] versus 240 ± 67.8% [vehicle plus sevoflurane], P < .001; 125 ± 13.5% [clonidine plus sevoflurane] versus 355 ± 57.6% [vehicle plus sevoflurane], P < .001; mean ± standard deviation), sevoflurane-induced reduction in postsynaptic density-95 (82 ± 6.6% [dexmedetomidine plus sevoflurane] versus 31 ± 12.4% [vehicle plus sevoflurane], P < .001; 95 ± 6.4% [clonidine plus sevoflurane] versus 62 ± 18.4% [vehicle plus sevoflurane], P < .001), and cognitive impairment in the young mice. Interestingly, yohimbine reversed the effects of dexmedetomidine and clonidine on attenuating the sevoflurane-induced changes in phosphorylated tau, postsynaptic density-95, and cognitive function.

CONCLUSIONS

Dexmedetomidine and clonidine could inhibit the sevoflurane-induced tau phosphorylation and cognitive impairment via activation of α-2 adrenergic receptor. More studies are needed to confirm the results and to determine the clinical relevance of these findings.

摘要

背景

麻醉剂七氟醚可诱导幼鼠tau蛋白磷酸化及认知功能障碍。其潜在机制及针对性干预措施在很大程度上仍未得到探索。我们推测右美托咪定和可乐定通过作用于α-2肾上腺素能受体减轻七氟醚诱导的tau蛋白磷酸化及认知功能障碍。

方法

6日龄小鼠在出生后第6、9和12天每天接受2小时3%七氟醚麻醉。使用α-2肾上腺素能受体激动剂右美托咪定和可乐定对小鼠进行治疗，同时使用或不使用α-2肾上腺素能受体拮抗剂育亨宾。采集小鼠海马进行蛋白质印迹分析。采用新物体识别试验和莫里斯水迷宫来测量认知功能。我们使用双因素和单因素方差分析（ANOVA）以及曼-惠特尼U检验分析主要结果，以确定右美托咪定、可乐定和育亨宾治疗后七氟醚对幼鼠磷酸化tau蛋白量、突触后致密蛋白95及认知功能的影响。

结果

右美托咪定和可乐定均减轻了七氟醚诱导的磷酸化tau蛋白量增加（右美托咪定加七氟醚组为94±16.3%，而溶剂加七氟醚组为240±67.8%，P<.001；可乐定加七氟醚组为125±13.5%，而溶剂加七氟醚组为355±57.6%，P<.001；均值±标准差）、七氟醚诱导的突触后致密蛋白95减少（右美托咪定加七氟醚组为82±6.6%，而溶剂加七氟醚组为31±12.4%，P<.001；可乐定加七氟醚组为95±6.4%，而溶剂加七氟醚组为62±18.4%，P<.001）以及幼鼠的认知功能障碍。有趣的是，育亨宾逆转了右美托咪定和可乐定对减轻七氟醚诱导的磷酸化tau蛋白、突触后致密蛋白95及认知功能变化的作用。