Downregulation of CDK5 Restores Sevoflurane-Induced Cognitive Dysfunction by Promoting SIRT1-Mediated Autophagy
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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.
KeywordsRoscovitine Sevoflurane CDK5 Cognitive dysfunction Autophagy Sirt1
This study was supported Tongji Medical School, Shanghai Tongji Hospital, Tongji University.
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.
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).
Compliance with Ethical Standards
Conflict of interest
All authors declare that they have no competing interest.
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.
- Chang HC, Guarente L (2013) SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153(7):1448–1460. https://doi.org/10.1016/j.cell.2013.05.027S0092-8674(13)00594-1 CrossRefPubMedPubMedCentralGoogle Scholar
- Ge HW, Hu WW, Ma LL, Kong FJ (2015) Endoplasmic reticulum stress pathway mediates isoflurane-induced neuroapoptosis and cognitive impairments in aged rats. Physiol Behav 151:16–23. https://doi.org/10.1016/j.physbeh.2015.07.008S0031-9384(15)30023-8 CrossRefPubMedGoogle Scholar
- Guo X, Lv J, Lu J, Fan L, Huang X, Hu L, Wang J, Shen X (2018) Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy. Neuropharmacology 130:77–91. https://doi.org/10.1016/j.neuropharm.2017.11.033 CrossRefPubMedGoogle Scholar
- Gutierrez-Vargas JA, Munera A, Cardona-Gomez GP (2015) CDK5 knockdown prevents hippocampal degeneration and cognitive dysfunction produced by cerebral ischemia. J Cereb Blood Flow Metab 35(12):1937–1949. https://doi.org/10.1038/jcbfm.2015.150jcbfm2015150 CrossRefPubMedPubMedCentralGoogle Scholar
- Hong T, Ge Z, Meng R, Wang H, Zhang P, Tang S, Lu J, Gu T, Zhu D, Bi Y (2018) Erythropoietin alleviates hepatic steatosis by activating SIRT1-mediated autophagy. Biochim Biophys Acta 1863 6:595–603Google Scholar
- Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293. https://doi.org/10.1016/j.molcel.2010.09.023S1097-2765(10)00751-3 CrossRefPubMedPubMedCentralGoogle Scholar
- Lin D, Zuo Z (2011) Isoflurane induces hippocampal cell injury and cognitive impairments in adult rats. Neuropharmacology 61(8):1354–1359. https://doi.org/10.1016/j.neuropharm.2011.08.011S0028-3908(11)00344-3 CrossRefPubMedPubMedCentralGoogle Scholar
- Liu B, Xia J, Chen Y, Zhang J (2017a) Sevoflurane-induced endoplasmic reticulum stress contributes to neuroapoptosis and BACE-1 expression in the developing brain: the role of eIF2alpha. Neurotox Res 31(2):218–229. https://doi.org/10.1007/s12640-016-9671-z10.1007/s12640-016-9671-z CrossRefPubMedGoogle Scholar
- Liu J, Yang J, Xu Y, Guo G, Cai L, Wu H, Zhao Y, Zhang X (2017b) Roscovitine, a CDK5 inhibitor, alleviates sevoflurane-induced cognitive dysfunction via regulation tau/GSK3beta and ERK/PPARgamma/CREB signaling. Cell Physiol Biochem 44(2):423–435. https://doi.org/10.1159/000485008000485008 CrossRefPubMedGoogle Scholar
- Shen X, Dong Y, Xu Z, Wang H, Miao C, Soriano SG, Sun D, Baxter MG, Zhang Y, Xie Z (2013) Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology 118(3):502–515. https://doi.org/10.1097/ALN.0b013e3182834d77 CrossRefPubMedPubMedCentralGoogle Scholar
- Stunkel W, Campbell RM (2011) Sirtuin 1 (SIRT1): the misunderstood HDAC. J Biomol Screen 16(10):1153–1169. https://doi.org/10.1177/10870571114221031087057111422103 CrossRefPubMedGoogle Scholar
- Sun T, Jiao L, Wang Y, Yu Y, Ming L (2018) SIRT1 induces epithelial-mesenchymal transition by promoting autophagic degradation of E-cadherin in melanoma cells. Cell Death Dis 9(2):136. https://doi.org/10.1038/s41419-017-0167-410.1038/s41419-017-0167-4 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhang Q, Zhang P, Qi GJ, Zhang Z, He F, Lv ZX, Peng X, Cai HW, Li TX, Wang XM, Tian B (2018a) Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models. Biochim Biophys Acta 1862 6:1443–1451. https://doi.org/10.1016/j.bbagen.2018.03.021 CrossRefGoogle Scholar
- Zhang YP, Lou Y, Hu J, Miao R, Ma F (2018b) DHA supplementation improves cognitive function via enhancing Abeta-mediated autophagy in Chinese elderly with mild cognitive impairment: a randomised placebo-controlled trial. J Neurol Neurosurg Psychiatry 89(4):382–388. https://doi.org/10.1136/jnnp-2017-316176jnnp-2017-316176 CrossRefPubMedGoogle Scholar
- Zhang Z, Zhang P, Qi GJ, Jiao FJ, Wang QZ, Yan JG, He F, Zhang Q, Lv ZX, Peng X, Cai HW, Chen X, Sun N, Tian B (2018c) CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress. Biochim Biophys Acta 1864 2:533–541. https://doi.org/10.1016/j.bbadis.2017.11.012 CrossRefGoogle Scholar
- Zheng YL, Zhang X, Fu HX, Guo M, Shukla V, Amin ND, Jing E, Ba L, Luo HY, Li B, Lu XH, Gao YC (2016) Knockdown of expression of Cdk5 or p35 (a Cdk5 activator) results in podocyte apoptosis. PLoS ONE 11(8):e0160252. https://doi.org/10.1371/journal.pone.0160252PONE-D-15-43733 CrossRefPubMedPubMedCentralGoogle Scholar