Dexmedetomidine And Clonidine Attenuate Sevoflurane-Induced Tau Phosphorylation And Cognitive Impairment In Young Mice Via Alpha-2 Adrenergic Receptor

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 alpha-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 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 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 alpha-2 adrenergic receptor. More studies are needed to confirm the results and to determine the clinical relevance of these findings.