Exendin-4 Improves Surgery-induced Behaviorial Deficits Via GLP-1/GLP-1R Signaling

Objective: Postoperative cognitive dysfunction(POCD)is a well-known complication characterized by the progressive deterioration of cognitive function following major surgery in elderly patients.An international multicenter trial of POCD estimated the overall incidence of POCD at 25.8% at 1 week and 9.9% after 3 months in patients with the age of more than 60 years old.POCD is associated with prolonged hospitalization,delayed recovery,and an increased risk of disability and mortality.Advancing age is considered the major risk factor for the development of POCD.Therefore,it is crucial to identify underlying mechanisms of POCD and develop strategies to treat or prevent surgery-induced behavioral deficits.Recent studies indicate that glucagon-like peptide 1(GLP-1)receptor(GLP-1R)agonists exhibit neurotrophic and neuroprotective effects.The aim of this study was to explore whether the GLP-1R agonist Exendin-4 can alter surgery-induced behavioral deficits and exert neuroprotective effects via the activation of the hippocampal GLP-1/GLP-1R pathway.Methods: 120 male Sprague-Dawley rats(aged 18–20 months old)were randomly divided into four groups: control group,Exendin-4 group,surgery group,and surgery + Exendin-4 group.The animals received either Exendin-4(5 ?g/kg/day)or saline intra-peritoneally for 14 days,and then were subjected to partial hepatectomy 24 h after the last injection.Behavioral changes were evaluated with Morris Water Maze and Open field testing on postoperative days 7 and 14.The levels of IL-1?,NF-?B,Iba-1,Synaptophysin,GLP-1/GLP-1R,GSK-3?,p-GSK-3?(Ser9),p-Tau(Ser396),and pTau(Ser202/199)in the hippocampus were measured at the same time point.Results: Surgical trauma induced an exacerbated spatial learning and memory impairment,increased the levels of depressive performance,and enhanced hippocampal NF-?B and IL-1? expression in the aged rats on postoperative day 7.A corresponding decline in GLP-1R was also found following surgical challenge on postoperative day 7.Exendin-4 treatment partly reversed surgery-induced postoperative behavioral impairment,downregulated the levels of NF-?B and IL-1?,ameliorated tau hyperphosphorylation and enhanced the activity of p-GSK-3?(Ser9).Together,the downregulation of GLP-1R exacerbated surgery-induced behavior deficits.Exendin-4 treatment attenuated these effects by inhibiting neuroinflammation and tau hyperphosphorylation.Conclusion: The current study provide evidence that GLP-1R signaling plays a pivotal role in reducing surgery-induced spatial learning and memory impairment,as well as reducing anxiety-like behavior in this surgical rat model.In particular,Exendin-4 treatment was shown to attenuate surgery-induced behavior deficits and to reduce tau hyperphosphorylation.Finally,this study suggests that the apparent neuroprotective effect of Exendin-4 is mediated by the inhibition of microglial activation and the concomitant release of pro-inflammatory cytokines.Therefore,Exendin-4 is a potential adjuvant neuroprotective agent for the prevention/or treatment of POCD in the elderly...