Varenicline improved laparotomy-induced cognitive impairment by restoring mitophagy in aged mice

Growing incidence of postoperative cognitive dysfunction (POCD) in the elderly populations after major surgery challenges us to provide stable and effective treatments. Mitochondria dysfunction is essential in the pathogenesis of aging and neurodegenerative diseases. It is hypothesized that varenicline improves cognitive impairment through restoring mitophagy and tau phosphorylation. Wild type C57BL/6 mice (male, 18-month-old) were subjected to laparotomy with or without chronic varenicline administration. Postoperative cognition and anxiety were determined by Morris water maze and elevated plus maze tests. Meanwhile, oxidative stress, mitochondria function, mitophagy and tau phosphorylation, as well as the correlation of PKR and STAT3 were characterized. In aged mice following laparotomy, persistent cognitive dysfunction in spatial learning and memory were indicated by longer escape latency and less crossing frequency in the target quadrant. Laparotomy also induced anxiety responses deficits. After postoperative 14 days, significant ROS accumulation and smaller mitochondria with impaired function were presented in the hippocampus. Simultaneously, there were abundant of neuronal apoptosis and translocation of tau phosphorylation in the mitochondria. Enhanced mitophagy and down regulated ChAT activity were distributed in the mice subjected to laparotomy. PKR signaling was activated and required for subcellular activation of STAT3 in the brain. After chronic varenicline administration (1 mg/kg/day), cognitive dysfunction, hippocampal oxidative stress, as well as fragile mitophagy were improved. Our results highlight that laparotomy caused cognitive impairment with persistent oxidative stress, mitochondria dysfunction and autophagy dysregulation. PKR/STAT3 maybe the potential mechanism, and perioperative varenicline treatment could be an efficient therapeutic strategy for POCD.