The role of hippocampal insulin signaling on postoperative cognitive dysfunction in an aged rat model of abdominal surgery

Aims This study aimed to investigate the role of central insulin signaling, including glycogen synthase kinase 3β (GSK-3β), and its therapeutic potential for the prevention of postoperative neurocognitive deficits. Main methods In non-insulin experiment, aged rats were divided into a sham group and abdominal surgery group. In insulin experiment, sham and surgically treated rats were distributed into two groups: an intranasal denatured insulin-treated group and intranasal insulin-treated group. Insulin administration started the day of surgery and continued for 3 days. Fourteen-days after surgery, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of pro-inflammatory cytokines, GSK-3β, and phosphorylated GSK-3β (pGSK-3β ser9 ). Under identical conditions, lipopolysaccharide (LPS)-induced cytokine release from isolated hippocampal microglia was also tested. Key findings In non-insulin experiment, compared with non-surgical animals, the rats that underwent abdominal surgery showed memory deficits and increased hippocampal cytokine levels. The hippocampal ratio of pGSK-3β ser9 /GSK-3β decreased after surgery, a ratio that was positively correlated with novel object recognition performance in the testing phase. Insulin experiment revealed that perioperative intranasal insulin administration could restore the surgery-induced hippocampal neuroinflammation and hyperactivation of GSK-3β, and prevent impairment in novel object recognition. Furthermore, ex vivo experiments indicated that intranasal insulin administration, as well as pretreatment with SB216763, a GSK-3β inhibitor, resulted in reduction of the surgery-related microglial hyper-reactivity to LPS. Significance Our findings in aged rats suggest that surgical procedures could impair central insulin signaling including GSK-3β, which makes the individual more susceptible to hippocampal neuroinflammation and related cognitive disorders.