• Yang Yu, Yongyan Yang, Hong Tan, Myriam Boukhali, Ashok Khatri, Yonghao Yu, Fuzhou Hua, Ling Liu, Mengzhu Li, Guang Yang, Yuanlin Dong, Yiying Zhang, Wilhelm Haas, and Zhongcong Xie.
• From the Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, China (Yang Yu, Y. Yang, Yonghao Yu) the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts (Yang Yu, Y. Yang, H.T., F.H., L.L., M.L., Y.D., Y.Z., Z.X.) the Department of Anesthesia, Xinhua Hospital of Shanghai Jiaotong University, Shanghai, China (H.T.) the Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (M.B., W.H.) the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (A.K.) the Department of Anesthesia, Second Affiliated Hospital of Nanchang University, Nanchang, China (F.H.) Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (L.L.) Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China (M.L.) the Department of Anesthesiology, Columbia University Medical Center, New York, New York (G.Y.).
• Anesthesiology. 2020 Sep 1; 133 (3): 595610595-610.

BackgroundSevoflurane anesthesia induces Tau phosphorylation and cognitive impairment in neonatal but not in adult mice. This study tested the hypothesis that differences in brain Tau amounts and in the activity of mitochondria-adenosine triphosphate (ATP)-Nuak1-Tau cascade between the neonatal and adult mice contribute to the age-dependent effects of sevoflurane on cognitive function.Methods6- and 60-day-old mice of both sexes received anesthesia with 3% sevoflurane for 2 h daily for 3 days. Biochemical methods were used to measure amounts of Tau, phosphorylated Tau, Nuak1, ATP concentrations, and mitochondrial metabolism in the cerebral cortex and hippocampus. The Morris water maze test was used to evaluate cognitive function in the neonatal and adult mice.ResultsUnder baseline conditions and compared with 60-day-old mice, 6-day-old mice had higher amounts of Tau (2.6 ± 0.4 [arbitrary units, mean ± SD] vs. 1.3 ± 0.2; P < 0.001), Tau oligomer (0.3 ± 0.1 vs. 0.1 ± 0.1; P = 0.008), and Nuak1 (0.9 ± 0.3 vs. 0.3 ± 0.1; P = 0.025) but lesser amounts of ATP (0.8 ± 0.1 vs. 1.5 ± 0.1; P < 0.001) and mitochondrial metabolism (74.8 ± 14.1 [pmol/min] vs. 169.6 ± 15.3; P < 0.001) in the cerebral cortex. Compared with baseline conditions, sevoflurane anesthesia induced Tau phosphorylation at its serine 202/threonine 205 residues (1.1 ± 0.4 vs. 0.2 ± 0.1; P < 0.001) in the 6-day-old mice but not in the 60-day-old mice (0.05 ± 0.04 vs. 0.03 ± 0.01; P = 0.186). The sevoflurane-induced Tau phosphorylation and cognitive impairment in the neonatal mice were both attenuated by the inhibition of Nuak1 and the treatment of vitamin K2.ConclusionsHigher brain Tau concentrations and lower brain mitochondrial metabolism in neonatal compared with adult mice contribute to developmental stage-dependent cognitive dysfunction after sevoflurane anesthesia.

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