Dexmedetomidine and Clonidine Attenuate Sevoflurane-Induced Tau Phosphorylation and Cognitive Impairment in Young Mice via α-2 Adrenergic Receptor.
Dexmedetomidine and Clonidine Attenuate Sevoflurane-Induced Tau Phosphorylation and Cognitive Impairment in Young Mice via α-2 Adrenergic Receptor.
复制标题
右美托咪定和可乐定通过α-2肾上腺素能受体减轻七氟烷诱导的幼龄小鼠Tau蛋白磷酸化和认知障碍。
DOI：
10.1213/ane.0000000000005268
复制
发表时间：
2021-03-01
影响因子：
5.7
通讯作者：
Xie Z
中科院分区：
文献类型：
--
作者：
Sun M;Dong Y;Li M;Zhang Y;Liang F;Zhang J;Soriano SG;Xie Z
麻醉剂七氟烷诱导幼龄小鼠Tau磷酸化和认知障碍。基本机制和有针对性的干预措施基本上仍未得到探讨。我们假设右美托咪定和可乐定通过作用于α-2肾上腺素能受体来减弱七氟烷诱导的Tau磷酸化和认知障碍。6日龄小鼠在出生后第6、9和12天每天接受2小时3%七氟烷麻醉。使用α-2肾上腺素能受体激动剂右美托咪定和可乐定治疗有和没有α-2肾上腺素能受体拮抗剂育亨宾的小鼠。收获小鼠海马并进行蛋白质印迹分析。采用新物体再认测验和Morris水迷宫测试认知功能。我们通过双因素和单因素方差分析以及Mann-Whitney U检验分析了主要结局，以确定七氟烷对右美托咪定、可乐定和育亨宾治疗后幼龄小鼠磷酸化Tau含量、突触后密度-95和认知功能的影响。右美托咪定和可乐定均减弱七氟烷诱导的磷酸化Tau含量增加[94 ± 16.3%]。（右美托咪定+七氟烷）与240 ± 67.8%（溶剂+七氟烷），P < 0.001; 125 ± 13.5%（可乐定+七氟烷）与355 ± 57.6%（溶媒+七氟烷），P < 0.001;平均值±标准差]，七氟烷诱导的突触后密度降低-95 [82 ± 6.6%（右美托咪定+七氟烷）与31 ± 12.4%（溶媒+七氟烷），P < 0.001; 95 ± 6.4%（可乐定+七氟烷）对比62 ± 18.4%（溶剂+七氟烷），P < 0.001]，以及幼龄小鼠的认知障碍。有趣的是，育亨宾逆转了右美托咪定和可乐定对减弱七氟烷诱导的磷酸化Tau、突触后密度-95和认知功能变化的影响。右美托咪定和可乐定可通过激活α 2肾上腺素能受体抑制七氟醚诱导的Tau蛋白磷酸化和认知障碍。需要更多的研究来证实这些结果，并确定这些发现的临床相关性。
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 alpha-2 adrenergic receptor. Six-day-old mice received anesthesia with 3% sevoflurane two 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 alpha-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 two-way and one-way 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. 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 < 0.001; 125 ± 13.5% (clonidine plus sevoflurane) versus 355 ± 57.6% (vehicle plus sevoflurane), P < 0.001; mean ± standard deviation], sevoflurane-induced reduction in postsynaptic density-95 [82 ± 6.6% (dexmedetomidine plus sevoflurane) versus 31 ± 12.4% (vehicle plus sevoflurane), P < 0.001; 95 ± 6.4% (clonidine plus sevoflurane) versus 62 ± 18.4% (vehicle plus sevoflurane), P < 0.001], 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. Dexmedetomidine and clonidine could inhibit the sevoflurane-induced Tau phosphorylation and cognitive impairment via activation of alpha-2 adrenergic receptor. More studies are needed to confirm the results and to determine the clinical relevance of these findings.