Varenicline modulates autophagy through PKR/STAT3 pathway to improve postoperative cognitive dysfunction / 中国药理学通报

ABSTRACT

Aim To evaluate whether varenicline could regulate autophagy through PKR/STAT3 pathway to improve postoperative cognitive dysfunction. Methods Forty healthy male C57BL/6J mice, aged 18 months and weighing (27. 5 ± 2. 5) g, were randomly divided into four groups (n = 10) j 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 (1 mg kg"1 d"1) one day before operation and lasted until 13th day after operation. The other two groups were treated with equal amount of normal saline instead of varenicline. The model of postoperative cognitive dysfunction was established by laparotomy under sevofiurane anesthesia. The novel object recognition task was performed on 10th ~ 12th day after laparotomy, and the Y-maze test was performed on 14th day after laparotomy to detect the cognitive function of the mice. The expression levels of AT8 and LC3B in hippocampus were detected by Western blot and immunofluorescence staining. The expression levels of p-PKR and p-STAT3 were detected by Western blot, and the interaction between STAT3 and PKR was detected by double labeled immunofluorescence staining. Results Compared with CON group, the error numbers and the latency in LAP group increased, the discrimination index decreased, accompanied with the increased expression levels of AT8 and p-PKR, the decreased expression levels of LC3 B and p-STAT3, and the increased interaction of STAT3 and PKR. Compared with LAP group, the error numbers and the latency in Var + LAP group decreased, and the discrimination index increased, associated with the decreased expression of AT8 and p-PKR, the increased expression of LC3B and p-STAT3, and the decreased interaction of STAT3 and PKR. Conclusions Vareni-cline regulates autophagy and eliminates hyperphospho-rylated tau through PKR/STAT3 pathway to improve postoperative cognitive dysfunction.