• Qin-Qin He, Man Yang, Jing Huang, Wei Wu, Kuo Tang, Yong Zhang, Jian Zhou, Wei Ou, Maodi Xie, Yu Liang, Peilin Lu, Yunxia Zuo, Hai Yu, and Tao Li.
• Department of Anaesthesiology, Laboratory of Mitochondria and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, China.
• Br J Anaesth. 2022 Nov 1; 129 (5): 703-715.

BackgroundHypersensitivity to general anaesthetics predicts adverse postoperative outcomes in patients. Hypoxia exerts extensive pathophysiological effects on the brain; however, whether hypoxia influences sevoflurane sensitivity and its underlying mechanisms remain poorly understood.MethodsMice were acclimated to hypoxia (oxygen 10% for 8 h day-1) for 28 days and anaesthetised with sevoflurane; the effective concentrations for 50% of the animals (EC50) showing loss of righting reflex (LORR) and loss of tail-pinch withdrawal response (LTWR) were determined. Positron emission tomography-computed tomography, O-glycoproteomics, seahorse analysis, carbon-13 tracing, site-specific mutagenesis, and electrophysiological techniques were performed to explore the underlying mechanisms.ResultsCompared with the control group, the hypoxia-acclimated mice required higher concentrations of sevoflurane to present LORR and LTWR (EC50LORR: 1.61 [0.03]% vs 1.46 [0.04]%, P<0.01; EC50LTWR: 2.46 [0.14]% vs 2.22 [0.06]%, P<0.01). Hypoxia-induced reduction in sevoflurane sensitivity was correlated with elevation of protein O-linked N-acetylglucosamine (O-GlcNAc) modification in brain, especially in the thalamus, and could be abolished by 6-diazo-5-oxo-l-norleucine, a glutamine fructose-6-phosphate amidotransferase inhibitor, and mimicked by thiamet-G, a selective O-GlcNAcase inhibitor. Mechanistically, O-GlcNAcylation drives de novo synthesis of glutamine from glucose in astrocytes and promotes the glutamate-glutamine cycle, partially via glycolytic flux and activation of glutamine synthetase.ConclusionsIntermittent hypoxia exposure decreased mouse sensitivity to sevoflurane anaesthesia through enhanced O-GlcNAc-dependent modulation of the glutamate-glutamine cycle in the brain.Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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