Chrysotoxine attenuates sevoflurane-induced neurotoxicity in vitro via regulating PI3K/AKT/GSK pathway

Objective: The aim of this study is to investigate the neuroprotective effect of chrysotoxine (CTX) on sevoflurane-treated nerve cells and uncover the potential regulation mechanism.

Methods: Nerve cells treated with sevoflurane and CTX were subjected to MTT and apoptotic detection. Cell apoptosis and oxidative stress were detected by flow cytometry (FCM) and ELISA assays. In addition, immunoblot assay was performed to study the signaling pathway affected by CTX treatment.

Results: CTX treatment promoted the cell viability and suppressed the apoptosis of sevoflurane-treated SH-SY5Y cells. In addition, CTX inhibited the sevoflurane-induced oxidative stress response and inflammatory response in nerve cells. Mechanically, CTX ameliorated neurotoxicity through activating the PI3K/AKT/GSK signaling pathway.

Conclusion: Therefore, CTX can serve as a promising drug target for treating anesthetics-induced neurotoxicity.

Sevoflurane; Chrysotoxine (CTX); Neurotoxicity; Apoptosis; PI3K/AKT/GSK pathway

[1] Jildenstål P, Widarsson Norbeck D, Snygg J, Ricksten S, Lannemyr L. Cerebral autoregulation in infants during sevoflurane anesthesia for craniofacial surgery. Pediatric Anesthesia. 2021; 31: 563–569.

[2] Ward CG, Loepke AW. Anesthetics and sedatives: Toxic or protective for the developing brain? Pharmacological Research. 2012; 65: 271–274.

[3] Bittner EA, Yue Y, Xie Z. Brief review: anesthetic neurotoxicity in the elderly, cognitive dysfunction and Alzheimer’s disease. Canadian Journal of Anaesthesia. 2011; 58: 216–223.

[4] León-Valenzuela Á, Román Malo C, González López M, Sánchez Palacios J, Sánchez Tarifa P, Del Pino Algarrada R. Sevoflurane sedation protocol in children with cerebral palsy undergoing botulinum toxin-A injections. Rehabilitacion. 2021; S0048-7120(20)30114-6. (In Spanish)

[5] Jiang W, Wang Q, Yajing Liao YL, Sun Y, Yang R. The effect of sevoflurane on the spatial recall ability and expression of apolipoprotein E and beta amyloid in the hippocampus in rats. Cellular and Molecular Biology. 2020; 66: 35–43.

[6] 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 Neuro-science. 2021; 81: 1–9.

[7] Kim JH, Oh AY, Choi YM, Ku SY, Kim YY, Lee NJ, et al. Isoflurane decreases death of human embryonic stem cell-derived, transcriptional marker Nkx2.5+ cardiac progenitor cells. Acta Anaesthesiologica Scan-dinavica. 2011; 55: 1124–1131.

[8] Şimşek HO, Kocatürk O, Demetoğlu U, Gürsoytrak B. Propofol based total intravenous anesthesia versus sevoflurane based inhalation anesthesia: the postoperative characteristics in oral and maxillofacial surgery. Journal of Cranio-Maxillofacial Surgery. 2020; 48: 880–884.

[9] Zhao S, Chen F, Wang D, Han W, Zhang Y, Yin Q. NLRP3 inflammasomes are involved in the progression of postoperative cognitive dysfunction: from mechanism to treatment. Neurosurgical Review. 2020.

[10] Wang Y, Yin CP, Tai YL, Zhao ZJ, Hou ZY, Wang QJ. Apoptosis inhibition is involved in improvement of sevoflurane-induced cognitive impairment following normobaric hyperoxia preconditioning in aged rats. Experimental and Therapeutic Medicine. 2021; 21: 203.

[11] Piao M, Wang Y, Liu N, Wang X, Chen R, Qin J, et al. Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species. Frontiers in Cellular Neuroscience. 2020; 14: 583782.

[12] Tang XL, Wang X, Fang G, Zhao YL, Yan J, Zhou Z, et al. Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-kappaB pathway in neonatal mice. Journal of Nutritional Biochemistry. 2020; 90: 108579.

[13] Bhummaphan N, Pongrakhananon V, Sritularak B, Chanvorachote P. Cancer Stem Cell-Suppressing Activity of Chrysotoxine, a Bibenzyl from Dendrobium pulchellum. The Journal of Pharmacology and Experimental Therapeutics. 2018; 364: 332–346.

[14] Fan J, Guan L, Kou Z, Feng F, Zhang Y, Liu W. Determination of chrysotoxine in rat plasma by liquid chromatography-tandem mass spectrometry and its application to a rat pharmacokinetic study. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2014; 967: 57–62.

[15] Song JX, Shaw PC, Sze CW, Tong Y, Yao XS, Ng TB, et al. Chrysotoxine, a novel bibenzyl compound, inhibits 6-hydroxydopamine induced apoptosis in SH-SY5Y cells via mitochondria protection and NF-kappaB modulation. Neurochemistry International. 2010; 57: 676–689.

[16] Song J, Shaw P, Wong N, Sze C, Yao X, Tang C, et al. Chrysotoxine, a novel bibenzyl compound selectively antagonizes MPP+, but not rotenone, neurotoxicity in dopaminergic SH-SY5Y cells. Neuroscience Letters. 2012; 521: 76–81.

[17] Xu L, Shen J, Dai S, Sun L, Chen X. Tetramethylpyrazine Attenuated Sevoflurane-Induced Neurotoxicity by Enhancing Autophagy through GPR50/CREB Pathway in SH-SY5Y Cells. The American Journal of Chinese Medicine. 2020; 48: 945–966.

[18] Nam DJ, Kim SH, Park SH, Lee H, Kang BB, Lee JH. Does desflurane need more irrigating-pump pressure for the visibility in arthroscopic shoulder surgery than sevoflurane? Anesthesia and Pain Medicine. 2020; 15: 35–40.

[19] Zheng J, Du L, Zhang L. Seizure-like movements caused by residual sevoflurane inside the anesthesia machine: A case report. Medicine. 2021; 100: e24495.

[20] Orden C, Santos M, Ceprian M, Tendillo FJ. The effect of cannabidiol on sevoflurane minimum alveolar concentration reduction produced by morphine in rats. Veterinary Anaesthesia and Analgesia. 2021; 48: 74–81.

[21] Sung T, Lee D, Bang J, Choi J, Shin S, Kim T. Remifentanil-based propofol-supplemented vs. balanced sevoflurane-sufentanil anesthesia regimens on bispectral index recovery after cardiac surgery: a random-ized controlled study. Anesthesia and Pain Medicine. 2020; 15: 424–433.

[22] Yamamoto H, Uchida Y, Chiba T, Kurimoto R, Matsushima T, Inotsume M, et al. Transcriptome analysis of sevoflurane exposure effects at the different brain regions. PLoS ONE. 2020; 15: e0236771.

[23] Marra A, Rossi D, Pignataro L, Bigogno C, Canta A, Oggioni N, et al. Toward the identification of neuroprotective agents: g-scale synthesis, pharmacokinetic evaluation and CNS distribution of (R)-RC-33, a promising Sigma1 receptor agonist. Future Medicinal Chemistry. 2016; 8: 287–295.

[24] Choi Y, Kim D, Kim Y, Yang S, Lee K, Ryu JH, et al. Synthesis and Evaluation of Neuroprotective Selenoflavanones. International Journal of Molecular Sciences. 2015; 16: 29574–29582.

[25] Li H, Li J, Yu Q, Dai C, Gu J, Peng S, et al. Sevoflurane-induced neuronal apoptosis in neonatal mice is prevented with intranasal administration of insulin. American Journal of Translational Research. 2020; 12: 8175–8184.

[26] Wainszelbaum MJ, Charron AJ, Kong C, Kirkpatrick DS, Srikanth P, Barbieri MA, et al. The Hominoid-specific Oncogene TBC1D3 Activates Ras and Modulates Epidermal Growth Factor Receptor Signaling and Trafficking. Journal of Biological Chemistry. 2008; 283: 13233–13242.