Varenicline reduces DNA damage, tau mislocalization and post surgical cognitive impairment in aged mice

Postoperative cognitive dysfunction (POCD) occurs more frequently in elderly patients undergoing major surgery. Age associated cholinergic imbalance may exacerbate postoperative systemic and neuroinflammation, but the effect nicotinic acetylcholine receptor (nAchR) stimulation on the development of POCD remains unclear. Aged male C57BL/6N mice (18 months old) underwent a midline laparotomy or were exposed to sevoflurane anesthesia alone (4-5%), with or without concomitant varenicline, a partial nAchR, at 1 mg/kg/day. Laparotomy increased pro-inflammatory cytokines in the liver and hippocampus (IL-1 beta and MCP-1) and induced a decline in cognitive performance, indicated by lower discrimination index in the Novel Object Recognition test, greater error number and longer escape latency in the Y-maze test. Glia activation, aberrant tau phosphorylation (AT8) and accumulation of phosphorylated H2AX in the hippocampus were detectable up to postoperative day 14, with neuronal apoptosis seen in the hippocampus. Perioperative varenicline attenuated the cognitive decline and associated tau protein mislocalization, DNA damage and neuronal apoptosis. The modulation of JAK2/STAT3 signaling may play a critical role in this process. Neuroinflammation, tau phosphorylation and DNA damage contribute to the development of cognitive dysfunction following laparotomy. Cholinergic stimulation by varenicline attenuated these changes through preventing the mislocalization of phosphorylated tau and DNA damage.