Varenicline Reduces Oxidative Stress And Tau Hyperphosphorylation To Improve Postoperative Cognitive Dysfunction By Modulating Autophagy

Objective Postoperative cognitive dysfunction(POCD)is a common complication of the central nervous system in elderly patients after surgery.It is characterized by impaired memory,decreased information processing ability and decreased attention,accompanied by changes in mood and personality.A POCD model was prepared by laparotomy in elderly mice and varenicline was given gavage during perioperative period to evaluate whether varenicline can reduce oxidative stress and Tau hyperphosphorylation to improve postoperative cognitive dysfunction by modulating autophagy,and whether its function of modulating autophagy is associated with the PKR/STAT3 signaling pathway.Methods 80 healthy C57BL/6J mice,aged 18 months and weighing 25-30 g,were randomly divided into four groups(n = 20): control group(CON group),laparotomy group(LAP group),laparotomy with varenicline administration group(Var + LAP group)and varenicline group(Var group).The mice in Var + LAP group and Var group were treated with varenicline(1mg/kg/d)one day before operation and lasted until the 13 th day after operation.The other two groups were treated with equal amount of saline instead of varenicline.The postoperative cognitive dysfunction model is prepared by placing mice in a rodent inhalation anesthesia device,after induction of anesthesia with a concentration of 5% sevoflurane(oxygen flow rate 0.8 L /min),the anesthesia was maintained with 2.5% sevoflurane.Disinfect the abdomen and prepare skin and cut a 2.5 cm long longitudinal incision down 0.5 cm below the xiphoid of the midline of the abdomen.Approximately 10 cm of the intestine was exteriorized and vigorously rubbed for 30 seconds.The intestine was exposed outside the abdominal cavity for 1 minute and then was replaced into the abdominal cavity,and the peritoneal,abdominal muscles and skin are sutured with Sterile chromic gut sutures.New object recognition experiment and Y maze test were performed on 10th-12 th day after laparotomy and 14 th day after laparotomy to detect the cognitive function of the mice.At the end of the behavioral experiments,the mice were killed by carbon dioxide asphyxiation method and the brain was taken,the frozen sections were prepared by continuous coronal sections,and the content of ROS in hippocampal CA3 region was detected by DHE staining.The mitochondria of hippocampus were extracted by differential centrifugation and the mitochondrial membrane potential was detected by JC-1 staining.Expression of AT8,LC3 B,STAT3 and PKR in hippocampus were detected by western blotting.The expression of AT8 and LC3 B and the co-localization of PKR and STAT3 in the CA3 region of hippocampus were detected by immunofluorescence staining.Results Compared with CON group,the error numbers and latency in LAP group increased,the discrimination index decreased,the ROS content in hippocampal CA3 region increased,mitochondrial membrane potential decreased,the expression of AT8 and p-PKR increased,the expression of LC3B-II/I and p-STAT3 decreased,the colocalization of PKR and STAT3 increased;Compared with the LAP group,the error numbers and latency in Var + LAP group decreased,the discrimination index increased,the ROS content in hippocampal CA3 region decreased,mitochondrial membrane potential increased,the expression of AT8 and p-PKR decreased,the expression of LC3B-II/I and p-STAT3 increased,the co-localization of PKR and STAT3 decreased.There was no significant difference between the indexes of Var group compared with CON group.Conclusion(1)Varenicline can improve postoperative cognitive dysfunction caused by laparotomy in elderly mice;(2)Varenicline can reduce ROS content and oxidative stress in hippocampal CA3 region of mice after laparotomy;restore mitochondrial membrane potential and reduce mitochondrial damage;reduce Tau hyperphosphorylation and attenuate its neurotoxicity;(3)Varenicline reduces oxidative stress and Tau hyperphosphorylation to improve postoperative cognitive dysfunction by modulating autophagy,which is related to PKR/STAT3 signaling pathway.