The Role And Mechanism Of FKBP51 In Postoperative Cognitive Dysfunction

Objective: Enhanced inflammation response has been increasingly reported in association with postoperative cognitive dysfunction(POCD).Glucocorticoid receptor(GR)signal is essential for suppression of inflammation.The obstacle of GR signaling may amplify the neuroinflammation induced by surgeries and increase the risk of POCD.The following study evaluates GR signaling in elderly patients undergoing selective operation.Methods: Part? 126 elderly patients undergoing elective hip fracture surgery with general anesthesia between May,2017 and August 2017 were enrolled.Plasma cortisol levels and the expression levels of GR and FK506 binding protein 51(FKBP51)in leukocytes were determined 1 day before and 7 days after operation.Postoperative pain was assessed following surgery,while neuropsychological tests were performed before surgery and 1 week post-operation.POCD.Part? C57BL/6mouse was selected for POCD model by stable tibia fracture.The changes of memory,cortisol,inflammatory factors,FKBP51 and GR were detected.We use the highly specific FKBP51 inhibitor SAFit2 to block FKBP51 activity and than evaluate whether SAFit2 can reverse the changes of memory,cortisol,inflammatory factors,FKBP51 and GR in POCD model mice.Results: One week after surgery,POCD incidence was 28.8%.Furthermore,significantly higher cortisol and FKBP51 levels were found in POCD patients compared with non-POCD patients(P<0.05).In addition,12 h after surgery,visual analogue pain scale(VAS)scores were significantly lower in POCD patients compared to non-POCD patients(P<0.05).Also,no significant difference in expression levels of GR was found between POCD and non-POCD patients.POCDmodel mice showed higher levels of cortisol,inflammatory factors,FKBP51 and GR?and dysmnesia.SAFit2 reversed higher levels of cortisol,inflammatory factors,FKBP51 and GR? and alleviated dysmnesia.Conclusions: High expression of FKBP51 are associated with POCD in patients and experimental animals.FKBP51 up-regulation may enhance surgery-induced neuroinflammation by inhibiting GR signaling,which,in turn,result in the POCD development.FKBP51 may be one of potential therapeutic targets in tackling of POCD.