Effect Of Anesthetics On Congnitive Function In Old Rats And Its Possible Mechanism

Objective:In this study,we investigate the enhancement of amyloid-beta proteinl-40(Aβ1-40)in oligomerization and fibril formation by isoflurane/sevoflurane/propofol as well as the changes in cognitive function and p-CaMKⅡ,p-CREB,p-JNK,p-p38 and p-tau expression in hippocampus after isoflurane/sevoflurane/propofol anesthesia on encephalocoele injected rats.Methods:①Control group:Aβ1-40 incubated in PBS.Group I/S/P:Aβ1-40 incubated in PBS with 1.3MAC isoflurane/sevoflurane or 3ug/ml propofol dissolved.The oligmerization of Aβ1-40 was observed by fluorimetric analysis and transmission electron microscope.②One hundred 20 months old rats were randomly divided into 10 groups respectively.10ul normal saline/Aβ1-40 monomer/solubility Aβ1-40 oligomer/insolubility Aβ1-40 fiber was injected into encephalocoele in rats(group control/Aβ1/Aβ2/Aβ3).Rats in group I+NS/I+Aβ1 inhaled 1.3MAC isoflurane for 4h after the injection of NS or Aβ1-40 monomer.Rats in group S+NS/S+Aβ1 inhaled 1.3MAC sevoflurane for 4h after the injection of NS or Aβ1-40 monomer.Rats in group P+NS/P+Aβ1 were anesthetized by propofol for 4h after the injection of NS or Aβ1-40 monomer.All the rats performed Morris Water Maze(MWM)test to assess the congnitve function after 2 weeks.The animals were killed immediately after the test,and the hipppocapus was isolated to determine the express of p-CaMKⅡ, p-CREB,p-JNK,p-p38 and p-tau using western-blot technique.Results:①Fluorescence intensity in groupⅠwas remarkably increased at all time points while in group S,it was greatly increased at all time points except 4d and 5d.Fluorescence intensity in group P was not remarkably increased at all time points except 30min(P＜0.05).②A higher density of fibrillar Aβ1-40 aggregation was observed at 4d in groupⅠcompared with that at 7d in control group and a massive aggregation was observed at 7d in groupⅠ.Fibrillar Aβ1-40 aggregation was hardly observed at 4d in group S but a higher density of fibrillar Aβ1-40 aggregation was observed at 7d in group S than that at 7d in control group.Aβ1-40 at 4d in group P also showed amorphous aggregation, while at 7d in group P showed a little fibrillar aggregation.③According to the performances of MWM,we found the cognitive function were decreased in rats of group Aβ2,Aβ3,I+NS and S+NS(P＜0.05).The cognitive function was bad in rats of group I+Aβ1 and group S+Aβ1 than that in group I+NS and group S+NS(P＜0.05).The cognitive functions were remarkably decreased in rats of group P+NS and P+Aβ1 and there was no difference between them.④The results of western-blot showed:the express of p-CaMKⅡand p-CREB was significantly decreased in group Aβ2,Aβ3,I+NS,I+Aβ1,S+NS,S+Aβ1 and P+NS while only p-CaMKⅡwas decreased in group P+Aβ1(P＜0.05).The express of p-JNK and p-p38 was significantly higher in group Aβ2,Aβ3,I+NS,I+ Aβ1 and S+Aβ1 while only p-p38 was significantly higher in S+NS(P＜0.05). The express of p-tau was positive in group Aβ2,Aβ3,I+Aβ1 and S+Aβ1.Conclusion:Both isoflurane and sevoflurane enhance amyloid-beta protein in oligomerization while propofol does not have the same effect on it in vitro.The spatial memory was impaired and the expression of p-CaMKⅡand p-CREB involve in learning and memory process was inhibited by isoflurane/sevoflurane /propofol for at least 2 weeks.Solubility Aβ1-40 monomer inhibit the signal system too and lead to the express of p-tau.Both isoflurane and sevoflurane maybe enhance Aβ1-40 in oligomerization to influence the spatial memory and signal system.