Dexmedetomidine alleviates sevoflurane-induced neurotoxicity via mitophagy signaling
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ORIGINAL ARTICLE
Dexmedetomidine alleviates sevoflurane-induced neurotoxicity via mitophagy signaling Liangyuan Suo1 · Mingyu Wang1 Received: 9 May 2020 / Accepted: 25 September 2020 © Springer Nature B.V. 2020
Abstract Dexmedetomidine, a class of α2-adrenergic agonist, was reported to exert a neuroprotective effect on sevoflurane-induced neurotoxicity. However, the specific mechanisms have not been fully clarified yet. The aim of our study is to uncover the role of dexmedetomidine in sevoflurane-induced neurotoxicity. The rats pretreated with dexmedetomidine and/or Rapamycin 3-Methyladenine were housed in a box containing 30% O2, 68% N2 and 2% sevoflurane for 4 h for anesthesia. 24 h after drug injection, Morris water maze test was used to evaluate rats’ learning and memory ability. Hematoxylin & eosin (H&E) staining was adopted to analyze the pathological changes of hippocampus. TUNEL assay was performed to measure cell apoptosis in hippocampus. Immunofluorescent assay was utilized to detect HSP60 level. The protein levels of LC3I, LC3II, Beclin-1, CypD, VDAC1 and Tom20 were examined by western blot. 5 weeks after drug injection, Morris water maze test was used to evaluate rats’ learning and memory ability again. Dexmedetomidine alleviated sevoflurane-induced nerve injury and the impairment of learning and memory abilities. Additionally, dexmedetomidine inhibited sevoflurane-induced cell apoptosis in hippocampus. In mechanism, dexmedetomidine activated mitophagy to mitigate neurotoxicity by enhancing LC3II/LC3I ratio, HSP60, Beclin-1, CypD, VDAC1 and Tom20 protein levels in hippocampus. Dexmedetomidine alleviates sevofluraneinduced neurotoxicity via mitophagy signaling, offering a potential strategy for sevoflurane-induced neurotoxicity treatment. Keywords Sevoflurane · Dexmedetomidine · Mitophagy · Neurotoxicity Abbreviations Con + NS + DMSO Control + normal saline + DMSO Sev + NS + DMSO Sevoflurane + normal saline + DMSO Sev + Dex + DMSO Sevoflurane + dexmedetomidine + DMSO Sev + NS + Rapam Sevoflurane + rapamycin + normal saline Sev + dex + 3-MA Sevoflurane + dexmedetomidine + 3-Methyladenine PVDF Polyvinylidene fluoride PBS Phosphate buffer saline MWM Morris water maze IF Immunofluorescent CSU Confocal scanner unit CypD Cyclophilin D * Mingyu Wang [email protected] 1
Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital, No. 44 Xiaoheyan road, Dadong district, Shenyang 110042, Liaoning, China
TUNEL Terminal deoxynucleotidyltransferase dUTP nick end labeling H&E Hematoxylin & eosin
Introduction Recently, multiple clinical studies indicated that children who experienced repeated exposures or prolonged duration of general anesthesia before 4-year-old have a poorer intelligent performance than those did not experience general anesthesia [1, 2]. Sevoflurane, a category of volatile anesthetic, has been widely used for pediatric patients in clinic [3]. The preclinical evidence suggested that sevoflurane inhale may result in neurodegenerative
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