Abstract
An increasing number of studies have found that use of traditional anesthetics may lead to cognitive impairment of the immature brain. Our previous studies verified that cyclin-dependent kinase 5 (CDK5) plays a role in sevoflurane-induced cognitive dysfunction. Autophagy was shown to protect against anesthesia-induced nerve injury. Therefore, the current study aimed to ascertain if autophagy participates in anesthesia-induced neurotoxicity. In this study, primary hippocampal neurons were isolated and utilized for experiments in vitro. We also performed in vivo experiments with 6-day-old wild-type mice treated with or without roscovitine (Rosc, a CDK5 inhibitor) or 3-methyladenine (3-Ma, an autophagy inhibitor) after exposure to sevoflurane. We used the Morris water maze to analyze cognitive function. Immunohistochemical staining was used to assess pathologic changes in the hippocampus. The results showed that suppressing CDK5 reversed sevoflurane-induced nerve cell apoptosis both in vivo and in vitro and demonstrated that inhibits CDK5 activation promoted Sirtuin 1 (Sirt1) expression, which functions importantly in induced autophagy activation. Suppression of Sirt1 expression inhibited the protective effect of Rosc on sevoflurane-induced nerve injury by inhibiting autophagy activation. Our in vivo experiments also found that pretreatment with 3-Ma attenuated the protective effect of Rosc on sevoflurane-induced nerve injury and cognitive dysfunction. We conclude that inhibits CDK5 activation restored sevoflurane-induced cognitive dysfunction by promoting Sirt1-mediated autophagy.
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Acknowledgements
This study was supported Tongji Medical School, Shanghai Tongji Hospital, Tongji University.
Funding
This study was supported by the National Natural Science Foundation (No. 81600934 to Jianhui Liu), National Natural Science Foundation of China (81974155 to Jianhui Liu), Pujiang Talent Programme (2019PJD049 to Jianhui Liu), the Natural Science Foundation of Shanghai, China (No. 16ZR1432200 to Jianhui Liu), and Medicine guidance of Science and Technology Commission of Shanghai Municipality (No. 16411967700 to Jianhui Liu).
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XZ and JL designed and conceived the study. XY, WZ, HW, SF, and JY performed the analysis and experiments. SL and YZ drafted the manuscript.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were approved by the Shanghai Tongji Hospital, Tongji Medical School, Tongji University. The experiments of this manuscript comply with the current laws of the country in which they were performed.
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Yang, X., Zhang, W., Wu, H. et al. Downregulation of CDK5 Restores Sevoflurane-Induced Cognitive Dysfunction by Promoting SIRT1-Mediated Autophagy. Cell Mol Neurobiol 40, 955–965 (2020). https://doi.org/10.1007/s10571-020-00786-6
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DOI: https://doi.org/10.1007/s10571-020-00786-6