title: The role of hippocampal insulin signaling on postoperative cognitive dysfunction in an aged rat model of abdominal surgery.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan. Electronic address: takashika@kochi-u.ac.jp.
authors: Takashi
authors: T
authors: Kawano
authors: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan.
authors: Hideki
authors: H
authors: Iwata
authors: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan.
authors: Bun
authors: B
authors: Aoyama
authors: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan.
authors: Atsushi
authors: A
authors: Nishigaki
authors: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan.
authors: Daiki
authors: D
authors: Yamanaka
authors: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan.
authors: Hiroki
authors: H
authors: Tateiwa
authors: Department of Dental Anesthesiology, Tokushima University School of Dentistry, Japan.
authors: Satoru
authors: S
authors: Eguchi
authors: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan.
authors: Fabricio M
authors: FM
authors: Locatelli
authors: Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Nankoku, Japan.
authors: Masataka
authors: M
authors: Yokoyama
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D011184:Postoperative Period; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D007328:Insulin; D038362:Glycogen Synthase Kinase 3
keywords: Insulin; Microglia; Neuroinflammation; Postoperative cognitive disorders