Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3β activation in young mice.
BACKGROUND
Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane is a commonly used anesthetic in children. Tau phosphorylation contributes to cognitive dysfunction. The authors therefore assessed the effects of sevoflurane on Tau phosphorylation and the underlying mechanisms in young mice.


METHODS
Six-day-old wild-type and Tau knockout mice were exposed to sevoflurane. The authors determined the effects of sevoflurane anesthesia on Tau phosphorylation, levels of the kinases and phosphatase related to Tau phosphorylation, interleukin-6 and postsynaptic density protein-95 in hippocampus, and cognitive function in both young wild-type and Tau knockout mice.


RESULTS
Anesthesia with 3% sevoflurane 2 h daily for 3 days induced Tau phosphorylation (257 vs. 100%, P = 0.0025, n = 6) and enhanced activation of glycogen synthase kinase 3β, which is the kinase related to Tau phosphorylation in the hippocampus of postnatal day-8 wild-type mice. The sevoflurane anesthesia decreased hippocampus postsynaptic density protein-95 levels and induced cognitive impairment in the postnatal day-31 mice. Glycogen synthase kinase 3β inhibitor lithium inhibited the sevoflurane-induced glycogen synthase kinase 3β activation, Tau phosphorylation, increased levels of interleukin-6, and cognitive impairment in the wild-type young mice. Finally, the sevoflurane anesthesia did not induce an increase in interleukin-6 levels, reduction in postsynaptic density protein-95 levels in hippocampus, or cognitive impairment in Tau knockout young mice.


CONCLUSIONS
These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3β activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice. Future studies will dissect the cascade relation of these effects.
From the Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China (G.T.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R China (J.Z.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, and Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, P. R. China (L.Z.); Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts (Y.D., Y.Z., Z.X.); Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China (B.Y.); and Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (G.C., D.J.C.).
Guorong
G
Tao
Jie
J
Zhang
Lei
L
Zhang
Yuanlin
Y
Dong
Buwei
B
Yu
Gregory
G
Crosby
Deborah J
DJ
Culley
Yiying
Y
Zhang
Zhongcong
Z
Xie
D000375:Aging; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced; D004789:Enzyme Activation; D004924:Escape Reaction / Q000187:drug effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood; D008094:Lithium / Q000494:pharmacology; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D000077149:Sevoflurane; D016875:tau Proteins / Q000378:metabolism
D018685:Anesthetics, Inhalation; D015850:Interleukin-6; D008738:Methyl Ethers; D016875:tau Proteins; D000077149:Sevoflurane; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3