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 3days. 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.
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 3days. 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.
Authors: Michael T Nedelcovych; Alexandra J Gadiano; Ying Wu; Arena A Manning; Ajit G Thomas; Saja S Khuder; Seung-Wan Yoo; Jiadi Xu; Justin C McArthur; Norman J Haughey; David J Volsky; Rana Rais; Barbara S Slusher Journal: ACS Chem Neurosci Date: 2018-01-04 Impact factor: 5.780