Sabik Chowdhury

Introduction: With the incredible advances in surgical technique, there has been an increasing number of procedures performed in utero and in the first few years of life.¹¹ In neonates, this is a critical period of CNS development in which neurons are vulnerable to damage.⁷ Sevoflurane is a volatile anesthetic that is commonly used for the induction and maintenance of general anesthesia in this patient population.³ Repeated and prolonged exposure to Sevoflurane can cause damage to the cortex and hippocampus.⁷ The mechanism through which this occurs is complex and was previously not well understood. Recent advances in research have not only given insight to the mechanism of sevoflurane toxicity, but also pointed to adjuvant anesthetic Dexmedetomidine as a possible neuroprotective agent.^1,2  Methods: Western Blot analysis was performed to analyze levels of apoptotic, autophagic, and neuroinflammatory protein markers in developing rat brains after induction of sevoflurane.^1,2 In addition, the PI3K/Akt/mTOR pathway was analyzed and levels of protein markers were measured after the induction of sevoflurane.² Dexmedetomidine was then introduced as an adjuvant anesthetic and the effects were observed.^1,2 Results: Sevoflurane exposure caused an increase in autophagy, apoptosis, and neuroinflammation in a dose and time dependent manner.^1,2 These effects seem to be a result of the inhibition of the PI3K/Akt/mTOR pathway.² Dexmedetomidine antagonizes the harmful effects of sevoflurane by re-activating the PI3/Akt/mTOR pathway.² This can be seen in the decreased levels of neuroinflammation and autophagy after the administration of Dexmedetomidine.² An inhibitor of the PI3K/Akt/mTOR pathway was added to Dexmedetomidine to ensure that this signaling cascade was responsible for the negative effects of Sevoflurane exposure. After this was done, the levels of neuroinflammation and autophagy increased again, suggesting that the inhibition of this signaling cascade was in fact the causative agent of Sevoflurane neurotoxicity. Conclusion: Repeated or prolonged Sevoflurane exposure in developing brains causes apoptosis, autophagy, and neuroinflammation. This occurs due to the inhibition of the PI3K/Akt/mTOR signaling pathway. Anesthetic adjuvant Dexmedetomidine offers neuroprotection against Sevoflurane by re-activating the PI3K/Akt/mTOR pathway.

1. Shan Y, Sun S, Yang F, Shang N, Liu H. Dexmedetomidine protects the developing rat brain against the neurotoxicity wrought by sevoflurane: role of autophagy and Drp1–Bax signaling. Drug Design, Development and Therapy. 2018; Volume 12:3617-3624. doi:10.2147/dddt.s180343
2. Wang N, Wang M. Dexmedetomidine suppresses sevoflurane anesthesia-induced neuroinflammation through activating PI3K/Akt/mTOR pathway. BMC Anesthesiology. 2019. doi:10.21203/rs.2.194/v1
3. Xu L, Shen J, Yu L, et al. Role of autophagy in sevoflurane-induced neurotoxicity in neonatal rat hippocampal cells. Brain Research Bulletin. 2018;140:291-298. doi:10.1016/j.brainresbull.2018.05.020
4. Cui R-S, Wang K, Wang Z-L. Sevoflurane anesthesia alters cognitive function by activating inflammation and cell death in rats. Experimental and Therapeutic Medicine. 2018. doi:10.3892/etm.2018.5976
5. Shi M;Miao S;Gu T;Wang D;Zhang H;Liu J; Dexmedetomidine for the prevention of emergence delirium and postoperative behavioral changes in pediatric patients with sevoflurane anesthesia: a double-blind, randomized trial. Drug design, development and therapy. https://pubmed.ncbi.nlm.nih.gov/30936683/. Accessed March 18, 2021.
6. Andropoulos DB. Effect of Anesthesia on the Developing Brain: Infant and Fetus. Fetal Diagnosis and Therapy. 2017;43(1):1-11. doi:10.1159/000475928
7. Chen B, Liu Y, Cai Y, et al. Hippocampus is more vulnerable to neural damages induced by repeated sevoflurane exposure in the second trimester than other brain areas. Acta Biochimica et Biophysica Sinica. 2020;52(8):864-874. doi:10.1093/abbs/gmaa060
8. Neag M-A, Mitre A-O, Catinean A, Mitre C-I. An Overview on the Mechanisms of Neuroprotection and Neurotoxicity of Isoflurane and Sevoflurane in Experimental Studies. Brain Research Bulletin. 2020;165:281-289. doi:10.1016/j.brainresbull.2020.10.011
9. Olutoye OA, Baker BW, Belfort MA, Olutoye OO. Food and Drug Administration Warning on Anesthesia and Brain Development: Implications for Obstetric and Fetal Surgery. Obstetric Anesthesia Digest. 2018;38(4):180-181. doi:10.1097/01.aoa.0000547276.94540.6a
10. Zuo Y, Chang Y, Thirupathi A, Zhou C, Shi Z. Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism. International Journal of Developmental Neuroscience. 2020;81(1):1-9. doi:10.1002/jdn.10080
11. Li X, Wu Z, Zhang Y, Xu Y, Han G, Zhao P. Activation of Autophagy Contributes to Sevoflurane-Induced Neurotoxicity in Fetal Rats. Frontiers in Molecular Neuroscience. 2017;10. doi:10.3389/fnmol.2017.00432