Downregulation of CDK5 Restores Sevoflurane-Induced Cognitive Dysfunction by Promoting SIRT1-Mediated Autophagy

  • Xiaoyu Yang
  • Wei Zhang
  • Heng Wu
  • Shubin Fu
  • Junjun Yang
  • Su Liu
  • Yanhong Zhao
  • Xiaoqing Zhang
  • Jianhui LiuEmail author
Original Research


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.


Roscovitine Sevoflurane CDK5 Cognitive dysfunction Autophagy Sirt1 



This study was supported Tongji Medical School, Shanghai Tongji Hospital, Tongji University.

Author Contributions

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.

Ethical Approval

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.


  1. Alkire MT, Gruver R, Miller J, McReynolds JR, Hahn EL, Cahill L (2008) Neuroimaging analysis of an anesthetic gas that blocks human emotional memory. Proc Natl Acad Sci USA 105(5):1722–1727. CrossRefPubMedGoogle Scholar
  2. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Fan L, Chen D, Wang J, Wu Y, Li D, Yu X (2017) Sevoflurane ameliorates myocardial cell injury by inducing autophagy via the deacetylation of LC3 by SIRT1. Anal Cell Pathol (Amst) 2017:6281285. CrossRefGoogle Scholar
  4. 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. CrossRefPubMedGoogle Scholar
  5. Ghatge S, Lee J, Smith I (2003) Sevoflurane: an ideal agent for adult day-case anesthesia? Acta Anaesthesiol Scand 47(8):917–931CrossRefGoogle Scholar
  6. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221(1):3–12. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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. CrossRefPubMedGoogle Scholar
  8. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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
  10. Komita M, Jin H, Aoe T (2013) The effect of endoplasmic reticulum stress on neurotoxicity caused by inhaled anesthetics. Anesth Analg 117(5):1197–1204. CrossRefPubMedGoogle Scholar
  11. Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Li X, Wu Z, Zhang Y, Xu Y, Han G, Zhao P (2017) Activation of autophagy contributes to sevoflurane-induced neurotoxicity in fetal rats. Front Mol Neurosci 10:432. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Lin D, Zuo Z (2011) Isoflurane induces hippocampal cell injury and cognitive impairments in adult rats. Neuropharmacology 61(8):1354–1359. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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. CrossRefPubMedGoogle Scholar
  15. 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. CrossRefPubMedGoogle Scholar
  16. Lv X, Yan J, Jiang J, Zhou X, Lu Y, Jiang H (2017) MicroRNA-27a-3p suppression of peroxisome proliferator-activated receptor-gamma contributes to cognitive impairments resulting from sevoflurane treatment. J Neurochem 143(3):306–319. CrossRefPubMedGoogle Scholar
  17. Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404(1):1–13. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Ou X, Lee MR, Huang X, Messina-Graham S, Broxmeyer HE (2014) SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells 32(5):1183–1194. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Qiu R, Li W, Liu Y (2018) MicroRNA-204 protects H9C2 cells against hypoxia/reoxygenation-induced injury through regulating SIRT1-mediated autophagy. Biomed Pharmacother 100:15–19. CrossRefPubMedGoogle Scholar
  20. Rohan D, Buggy DJ, Crowley S, Ling FK, Gallagher H, Regan C, Moriarty DC (2005) Increased incidence of postoperative cognitive dysfunction 24 hr after minor surgery in the elderly. Can J Anaesth 52(2):137–142. CrossRefPubMedGoogle Scholar
  21. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Stunkel W, Campbell RM (2011) Sirtuin 1 (SIRT1): the misunderstood HDAC. J Biomol Screen 16(10):1153–1169. CrossRefPubMedGoogle Scholar
  23. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Wang Y, Wang W, Li D, Li M, Wang P, Wen J, Liang M, Su B, Yin Y (2014) IGF-1 alleviates NMDA-induced excitotoxicity in cultured hippocampal neurons against autophagy via the NR2B/PI3K-AKT-mTOR pathway. J Cell Physiol 229(11):1618–1629. CrossRefPubMedGoogle Scholar
  25. Wiklund A, Granon S, Faure P, Sundman E, Changeux JP, Eriksson LI (2009) Object memory in young and aged mice after sevoflurane anaesthesia. NeuroReport 20(16):1419–1423. CrossRefPubMedGoogle Scholar
  26. Xiao X, Zhu Y, Bu J, Li G, Liang Z, Yang L, Hou B (2017) The autophagy inhibitor 3-methyladenine restores sevoflurane anesthesiainduced cognitive dysfunction and neurons apoptosis. Pharmazie 72(4):214–218. CrossRefPubMedGoogle Scholar
  27. Yang L, Gu X, Zhang W, Zhang J, Ma Z (2014) Cdk5 inhibitor roscovitine alleviates neuropathic pain in the dorsal root ganglia by downregulating N-methyl-D-aspartate receptor subunit 2A. Neurol Sci 35(9):1365–1371. CrossRefPubMedGoogle Scholar
  28. 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. CrossRefGoogle Scholar
  29. 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. CrossRefPubMedGoogle Scholar
  30. 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. CrossRefGoogle Scholar
  31. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Zhou YF, Wang QX, Zhou HY, Chen G (2016) Autophagy activation prevents sevoflurane-induced neurotoxicity in H4 human neuroglioma cells. Acta Pharmacol Sin 37(5):580–588. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Anesthesiology, Shanghai Tongji Hospital, Tongji Medical SchoolTongji UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Medical ImagingRenji Hospital, Medical School of Jiaotong UniversityShanghaiPeople’s Republic of China
  3. 3.Department of Psychology, Shanghai Tongji Hospital, Tongji Medical SchoolTongji UniversityShanghaiPeople’s Republic of China
  4. 4.Department of Animal Genetics Breeding and Reproduction, College of Animal ScienceSouthwest UniversityChongqingPeople’s Republic of China

Personalised recommendations