Kappa opioid receptor agonists improve postoperative cognitive dysfunction in rats via the JAK2/STAT3 signaling pathway

摘要

Postoperative cognitive dysfunction (POCD) is a common and well-known complication following surgery, particularly cardiopulmonary bypass (CPB) surgery. There are currently no suitable treatments for POCD, which is associated with increased illness and mortality rates. The present study aimed to identify a novel treatment for POCD. The protective effect of kappa opioid receptor (KOR) agonists on POCD in rats following CPB was determined and the regulatory mechanism of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was examined. The rats were randomly divided into five groups: Sham operation (Sham group), CPB operation (CPB group), KOR agonist + CPB (K group), KOR agonist + norbinaltorphimine (nor-BNI) + CPB (NK group), and KOR agonist + JAK2-STAT3 specific pathway inhibitor + CPB (AG group). A water maze test and neurological function scores were used to evaluate POCD. Hematoxylin and eosin staining was used to observe hippocampal neurons. ELISA was used to detect the levels of inflammatory factors, oxidative stress factors and brain injury markers. Immunofluorescence was used to visualize the neurons. TUNEL staining and western blotting were used to detect neuronal apoptosis, and western blotting was also used to detect JAK2/STAT3 pathway-related proteins. The KOR agonists significantly improved POCD. S-100β and NSE detection revealed that KOR agonists alleviated brain damage in CPB rats, and this result was reversed by KOR antagonists. The KOR agonists led to a significantly reduced inflammatory response and oxidative stress, as determined by ELISA detection, and attenuated hippocampal neuronal apoptosis, as revealed by TUNEL staining and western blotting, compared with the results in the CPB group. Finally, the KOR agonists inhibited the expression levels of phosphorylated (p-)JAK2 and p-STAT3, rather than total JAK2 and STAT3, compared with levels in the CPB group. Taken together, KOR agonists improved POCD in rats with CPB by inhibiting the JAK2/STAT3 signaling pathway.