Objective:To investigate the mechanism of dexmedetomidine preventing sevoflurane-indued neurotoxicity to neonatal mice and the relationship with Tau phosphorylation.Methods:Seventy-two SPF healthy newly born C57BL/6 wild-type mice of both sexes, aged 6 days, were divided into 4 groups ( n=18 each) using a random number table method: normal control group (C group), dexmedetomidine control group (D group), sevoflurane-induced neurotoxicity group (S group), and dexmedetomidine prevention group (SD group). Mice inhaled 2.1%-3.3% sevoflurane 2 h daily on postnatal days 6, 9 and 12, and dexmedetomidine 10 μg/kg was intraperitoneally injected at 30 min before anesthesia in group SD.Six mice were randomly selected after the end of injection, and the hippocampus tissues were removed for determination of the expression of phosphorylated Tau protein (AT8) and Tau46 protein at Tau-PS202 and Tau-PT205 sites by Western blot.The new object recognition test was performed on postnatal days 29-30 (the discrimination ratio of new objects was observed), and the Morris water maze test was performed from postnatal day 31 to 37 (the escape latency and the times of crossing the platform were observed). The hippocampi were harvested under anesthesia to detect the expression of postsynapatic density-95 by Western blot. Results:Compared with group C, the expression of AT8 was significantly up-regulated, the expression of PSD-95 was down-regulated, the number of crossing the platform and new object discrimination ratio were decreased ( P<0.05), and no significant change was found in Tau46 protein expression or escape latency in group S ( P>0.05). There was no significant difference in the indexes mentioned above between group D and group SD ( P>0.05). Compared with group S, the expression of AT8 was significantly down-regulated, the expression of postsynapatic density-95 was up-regulated, the number of crossing the platform and new object discrimination ratio were increased ( P<0.05), and no significant change was found in Tau46 protein expression and escape latency in group SD ( P>0.05). Conclusions:The mechanism of dexmedetomidine preventing sevoflurane-induced neurotoxicity to neonatal mice is related to the inhibition of Tau phosphorylation.