The Role And Mechanism Of Adult Hippocampal Neurogenesis In Sevoflurane-induced Cognitive Impairment In Aged Mice

IntroductionPerioperative neurocognitive disorders(PND)refer to the slight damage of higher cerebral cortical functions like memory,issue handling abilities and attention,which happened in the perioperative time.PND prolongs the time of hospital stay and increases the expense of inpatient care.It affects the prognosis of patients and increases the postoperative mortality rate.Sevoflurane is an inhaled anesthetic which is commonly used in hospital.However,sevoflurane tends induce PND.At present,the factors affecting the cognitive impairment induced by sevoflurane and the related mechanisms are still unclear.Clinical studies have confirmed that sevoflurane inhalation can increase the incidence of PND in elderly patients.Animal experiments confirmed that rats exposed to high concentration(3.6%)of sevoflurane tends to suffer cognitive impairment.Thus,the factors that affect the occurance of cognitive impairment induced by sevoflurane may be sevoflurane concentration and the age of the object exposed.Adult hippocampal neurogenesis(AHN)occurs in the subgranular zone(SGZ)of the hippocampal dentate gyrus(DG)which is related to hippocampal-mediated learning and memory functions.The inhibition of AHN may lead to cognitive impairment.Whether sevoflurane exposure leads to AHN inhibition and the related mechanism are still unclear.Brain-derived neurotrophic factor(BDNF)and neurotrophin-3(NT-3)play an important role in regulating AHN whose receptors are tyrosine receptor kinase B(TrkB)and tropomyosin receptor kinase C(TrkC).Whether BDNF/TrkB and NT-3/TrkC pathways are associated with cognitive impairment and AHN inhibition induced by sevoflurane are still unclear.MethodsSevoflurane exposure:adult(8-month-old)or aged(18-month-old)C57BL/6 mice were divided into 3 groups:control group(CON group),1.5%sevoflurane exposure group(1.5%Sevo group)and 3%sevoflurane exposure group(3.0%Sevo group)randomly.Mice in the 1.5%Sevo group and 3.0%Sevo group were inhaled with 1.5%or 3%sevoflurane for 3 hours per day.They were inhaled for 3 days.The CON group was inhaled with O2 for the same duration as the sevoflurane-exposed group.Cognitive evaluation:Morris water maze test(MWM)and the Y-maze test was used to evaluate cognitive function.AHN test:Immunofluorescence of BrdU/DCX double-labeled staining was used to detect AHN in hippocampal SGZ.Expression of BDNF/TrkB and NT-3/TrkC pathways:Western blotting was used to detect the expression of BDNF/TrkB and NT-3/TrkC pathways.BDNF/NT-3 microinjection:Aged mice were randomly divided into control group(CON group),3%sevoflurane group(3.0%Sevo group),BDNF or NT-3 microinjection group(BDNF group or NT-3 group).3.0%Sevo group,BDNF group and NT-3 group were exposed to 3%sevoflurane and the CON group was exposed to oxygen.24 hours after exposure,BDNF/NT-3 were injected into the hippocampus with a stereotaxic.Immunofluorescence was used to detect AHN.MWM and Y-maze were used to detect the cognitive function.ResultsCognitive evaluation:The cognitive function of mice in 3.0%Sevo group was decreased significantly(p<0.05)compared with the mice in CON group in aged mice.There was no statistical difference between mice in 1.5%Sevo group and CON group in cognitive function.There was no significant difference in cognitive function among three groups in adult mice.AHN test:Compared with the mice in CON group AHN of mice in 3.0%Sevo group was significantly decreased(p<0.05)in aged mice.There was no statistical difference in AHN between mice in 1.5%Sevo group and CON group.There was no significant difference in AHN among three groups in adult mice.Expression of BDNF/TrkB and NT-3/TrkC pathways:Compared with the mice in CON group the expression of BDNF/TrkB and NT-3/TrkC of mice in 3.0%Sevo group was significantly decreased(p<0.05)in aged mice.There was no statistical difference between mice in 1.5%Sevo group and CON group in the expression of BDNF/TrkB and NT-3/TrkC.There was no significant difference among three groups in the expression of BDNF/TrkB and NT3/TrkC in adult mice.BDNF/NT-3 microinjection:The AHN and cognitive function of mice in BDNF group and NT-3 group increased significantly(p<0.05)compared with the mice in 3.0%Sevo group.Conclusions1.Cognitive impairment caused by sevoflurane is affected by the concentration of sevoflurane and the age of exposed subjects.Elderly subjects and high-concentration exposure are more likely to cause cognitive impairment.2.AHN palys a role in cognitive impairment induced by sevoflurane in the elderly through BDNF/TrkB and NT-3/TrkC pathways.