The Effect Of Propofol On NE2B/CaMK?? Signaling Pathway In Brain Injury Induced By Hepatic Ischemia-reperfusion In Preadolescent Mice

Objective Hepatic ischemia reperfusion(HIR)is one of the most important procedures in liver transplantation,which directly affects the prognosis and survival rate of patients.A large number of studies have confirmed that propofol can protect liver,kidney,myocardium and other important organs from ischemia-reperfusion injury.N-methyl-D-aspartic acid receptor(NMDA)is an ionic glutamate receptor,which plays an important role in the development of nervous system and is closely related to learning and memory.NR2 B is the earliest subunit of NMDA receptor and plays an important role in activating NMDA receptor.Overactivated NMDA receptor can produce neurotoxicity,while propofol has anti-NMDA toxicity.The aim of this study was to investigate the effects of propofol preconditioning on brain injury induced by HIR in young mice and whether the mechanisms were related to the signal pathway of NR2B/ CaMK??.Methods A total of 120 pathogen-free male C57BL/6 mice,aged 2 weeks,weighing 4?6 g,were randomly divided into 5 groups(n=24): sham group,hepatic ischemia-reperfusion group(HIR group),propofol + HIR group(P group),Ifenprodil + HIR group(Ifen group),KN-93 + HIR group(KN-93 group).Sham group only underwent switching abdominal surgery to free the hepatic portal vessels;HIR group was used to prepare 70% HIR injury model by clamping the left and middle lobes of the liver for 60 minutes;P group was injected 1% propofol 20 mg/kg intraperitoneally 30 minutes before modeling;Ifen group was injected 50% Ifenprodil solution 0.1 ml/day continuously 5 days before modeling;KN-93 group was injected 20% KN-93 solution 0.1 ml/day intraperitoneally 5 days before modeling,and the rest were operated on the same way as the HIR group.Three days after reperfusion,eight mice in each group were randomly killed.Serum ELISA was extracted to detect brain injury markers S100? and NSE.Histopathological damage was observed by HE staining.Apoptosis was observed by TUNEL.The expression levels of NR2 B,p-NR2 B,CaMK??,p-CaMK??,bax?bcl-2?caspase-3 were measured by Western blot.Mitochondrial damage in hippocampal neurons was observed by transmission electron microscopy.The remaining 8 mice were fed normally.Morris water maze test was performed 1 month later to observe the long-term effects of neurological function in mice.Results Compared with Sham group,the concentration of serum brain injury markers in HIR group was significantly increased(P < 0.05),the pathological damage of brain neurons was significant,apoptosis was serious,mitochondrial damage was serious,the escape latency of water maze results was prolonged,and the percentage of target platform quadrant residence time was decreased(P < 0.05),suggesting that HIR process could cause brain injury in mice.Compared with HIR group,the serum concentration of brain injury markers in P group was significantly lower(P < 0.05),the pathological damage and apoptosis of brain nerve cells were alleviated,the mitochondrial damage was alleviated by transmission electron microscopy,the escape latency of water maze results was shortened,the percentage of residence time of target platform quadrant was increased(P < 0.05),and the expression of p-NR2 B and p-CaMKIIa was down-regulated,while the expression of Bax and caspase-3 was lower,bcl-2 was higher(P < 0.05).These results suggest that propofol preconditioning has protective effect on brain injury induced by HIR.The results of Ifen group and KN-93 group were significantly alleviated than those of HIR group,the apoptotic index was lower(P < 0.05),the escape latency was shorter,the percentage of target platform quadrant residence time was increased(P < 0.05),the expression of p-NR2 B and p-CaMKIIa was down-regulated,the levels of bax,caspase-3 were decreased,bcl-2 was increased(P < 0.05),but there was no significant difference compared with P group(P > 0.05).The results suggest that the protective effect of propofol preconditioning on brain injury induced by HIR in mice is related to the inhibition of phosphorylation of NR2 B subunit of NMDA receptor and CaMKIIa.Conclusion The pathophysiological process of hepatic ischemia-reperfusion can induce brain injury in mice and cause long-term neurological dysfunction.Pretreatment with propofol has protective effect on brain injury.Its mechanism may be related to inhibiting the activity of NR2B/CaMKIIa signaling pathway in hippocampal CA1 region of brain tissue and inhibiting neuronal apoptosis.