Effects And Related Mechanism Of Inhaled Anesthetic Agents On Recognition And Memory In Alzheimer's Disease Transgenic Mice (5xFAD) Model

Background:Advent of modern general anesthesia made it possible for the advancement of complicated surgery procedures for sever diseases.According to the specific need of operations,anesthetics can be divided into general anesthetics and local anesthetics.General anesthetics act on the central nervous system that stop the brain from responding to sensory messages travelling from the nerves in the body,cause unconsciousness,painless and unaware of the procedure.General anesthetics can be further divided into inhaled anesthetics and intravenous anesthetics.Inhaled anesthetics are a kind of chemically inactive gas or volatile liquid.It is inhaled into the alveoli after mixing with air at specific composition and diffuses into the bloodstream.Eventually it reaches the central nervous system to exert the anesthetic effect.Halothane,enflurane,isoflurane,desflurane,sevoflurane,and nitrous oxide are the most common used inhaled anesthetics.Although the rate of inhaled anesthetic uptake and elimination from the alveoli is fast,its side effects on nevous system have been widely reported.For instance,postoperative cognitive dysfunction(POCD),confusion,and delirium are commonly seen after surgery and general anesthesia in the elderly,and the symptoms may even last for months and years.These evidences illustrated that inhaled anesthetic may exert neurotoxicity and cognitive impairment.Alzheimer's disease(AD)is a neurological condition,accounts for 60-80%of dementia cases.It is characterized by memory loss and cognitive decline.With the progress of the disease,?-amyloid plaques and neurofibrillary tangles appear as the major pathological features.Studies have been revealed that aging brain,especially with contextual cognitive disorders,is much venerable with inhaled anesthetics exposure.More importantly,the pathological changes in AD brain precede the abnormal clinical manifestations.Thus,it is crucial to understand the effects of inhaled anesthetics on behavioral and pathological changes in AD population and elders with early signs which has clinical significance for risk assessment of anesthesia.Aim:In this study,we aimed to investigate both the short term and long term effects and the precise mechanisms of sevoflurane,isoflurane and desflurane in a Alzheimer's Disease mouse model(5xFAD).Methods:We used the male 5xFAD transgenic mouse model of AD at the pathological stage of disease,which showed amyloid ?(A?)deposition.Different doses(2.8%,1.4%,and 8%)of sevoflurane,isoflurane and desflurane were given respectively to 5xFAD mice.According to the experience in clinical practice,two different time periods(30 mins or 6 hours)were observed in this study.(1)To investigate the behavior changes of 5xFAD mice under different inhaled anesthetics,Y-maze and fear conditioning behavior tests were performed before and after exposure to inhaled anesthetic for cognitive memory function.(2)To investigate the pathological hallmarks of 5xFAD mice under different inhaled anesthetics,the immunohistochemistry was employed to detect the staining of A? plaques in hippocampus.(3)To investigate the activation of astrocytes in 5xFAD mice under different inhaled anesthetics,the immunohistochemistry was employed to detect the staining of GFAP in hippocampus and amygdala.(4)To investigate the expression patterns of insoluble A?,PSD-95,SVP,and active caspase-3 in 5xFAD mouse brain under different inhaled anesthetics,the Western blot was used to detect protein levels of the above proteins.Results:(1)Under the short term(30 min)exposure of sevoflurane,isoflurane,and desflurane,there were no significant difference in cognitive function and fear conditioned memory tests when compared with control mice.(2)Under the long term(6 hours)exposure of sevoflurane,isoflurane,and desflurane,isoflurane showed significant decrease in cognitive function and fear conditioned memory tests.Sevoflurane and desflurane only decreased in fear conditioned memory tests.(3)Increased A? deposition plaques were found in the CA1 and CA3 area but not DG area in hippocampus in three groups.However,Western blot results indicated the insoluble/soluble ratio of A? were increased in sevoflurane and isoflurane group.The expression of GFAP were increased in the amygdala in three groups.(4)Under the long term(6 hours)exposure of sevoflurane,isoflurane,and desflurane,the protein expression of PSD-95 were decreased in sevoflurane and isoflurane.Caspase-3 were activated in all groups but highly enhanced in isoflurane group.Conclusions:Our results suggest that short exposure of inhaled anesthetic reagents have no significant effect on AD cognitive and memory function.However,long exposure to common inhaled anesthetic reagents will worsen the AD cognitive and memory function and increase the A? plaques.