Effects Of Exposure To Sevoflurane In Neonatal Mice On Adolescent Learning And Memory And Hippocampal Myelin Injury

Background: Every year,millions of children in the world receive surgical treatment or auxiliary examinations under general anesthesia,and the effect of general anesthesia drugs on children’s central nervous system is currently unclear.A number of clinical retrospective studies and prospective studies have found that children’s repeated exposure to general anesthetics will have a negative impact on the central nervous system and reduce children’s motor coordination ability.In addition,a large number of animal studies have shown that multiple exposures to general anesthetics may damage the normal structure and function of the central nervous system of young rats,and increase the risk of cognitive dysfunction.At present,most of the research on the mechanism of neurodevelopmental toxicity of general anesthetics focuses on the development of neurons,and the myelin sheath of the central nervous system also plays an important role in the process of learning and memory.Recent studies have shown that exposure to sevoflurane in neonatal mice can cause damage to the myelin sheath of the central nervous system,leading to cognitive dysfunction.Sevoflurane is one of the most commonly used volatile general anesthetics for children.Sevoflurane can inhibit the phosphorylation of GSK3β(Ser9)in the hippocampal GSK3β/β-catenin signaling pathway,thereby impairing memory consolidation in adult rats.This signaling pathway plays a key role in the expression of myelin genes.However,the exact mechanism of neonatal mice’s repeated exposure to sevoflurane on their learning and memory impairment and central nervous system myelin damage is still unclear.Objective: To explore the effects of multiple exposures to sevoflurane in neonatal mice on adolescent learning and memory,and explore the mechanism of sevoflurane injury to the myelin sheath of the central nervous system of mice during this process,and provide certain guidance for clinical children’s anesthesia.Methods: 6-day-old C57BL/6 mice were randomly divided into control group(CON group),sevoflurane group(SEVO group),control + lithium chloride group(Li Cl group),sevoflurane + lithium chloride group(SEVO + Li Cl group).The SEVO group was exposed to 3% sevoflurane for 3 consecutive days(from the 6th day to the 8th day after birth),once a day for 2 hours each time,the CON group was a 60% oxygen control,and the SEVO + Li Cl group was exposed to sevoflurane 30 minutes before exposure glycogen synthase kinase 3β(GSK3β)inhibitor lithium chloride(100mg/kg)was intraperitoneally injected,and the Li Cl group was the control of intraperitoneal injection of lithium chloride(100mg/kg)30 minutes before exposure to 60% oxygen.New object recognition experiment and Y maze experiment were used to detect the learning and memory ability of mice from day 30 to day 32;Western blot was used to detect the content of myelin basic protein(MBP),β-catenin protein and p GSK3β/GSK3β ratio changes.Results: Behavioral experiment results show that lithium chloride can improve the learning and memory impairment of neonatal mice after exposure to sevoflurane.In the new object recognition test,the discrimination index of mice in the SEVO group was lower than that in the CON group(P<0.05).After lithium chloride pretreatment,the discrimination index of mice in the SEVO + Li Cl group was higher than that in the SEVO group(P<0.05).In the Y maze experiment,the % number in novel arm of the SEVO group was lower than that of the CON group(P<0.05).After lithium chloride pretreatment,the % number in novel arm of the SEVO + Li Cl group was higher than that of the SEVO group(P<0.05).Western blot results showed that the expression of MBP protein,β-catenin protein and the ratio of p GSK3β/GSK3β in the hippocampus of the SEVO group were lower than those in the CON group(P<0.05).After pretreatment with lithium chloride,compared with the SEVO group,the expression of MBP protein,β-catenin protein and the ratio of p GSK3β/GSK3β increased in the hippocampus of the SEVO + Li Cl group(P<0.05).Conclusions: Repetitive exposure to sevoflurane in neonatal mice leads to impaired learning and memory in adolescence,which may be related to the hippocampal myelin damage caused by the inhibition of GSK3β/β-catenin signaling pathway GSK3β(Ser9)phosphorylation.