INTRANASAL ADMINISTRATION OF INSULIN PREVENTS ANESTHESIA-INDUCED COGNITIVE IMPAIRMENT AND CHRONIC NEUROBEHAVIORAL CHANGES

General anesthesia increases the risk for cognitive impairment post operation, especially in the elderly and vulnerable individuals. Recent animal studies on the impact of anesthesia on postoperative cognitive impairment have provided some valuable insights, but much remains to be understood. Aged (17–18 months old) and adult (7–8 months old) wild-type (WT) mice (a hybrid of 129/Sv and C57BL/6 mice) and adult (7–8 months old) 3xTg-AD mice (a triple transgenic mouse model of Alzheimer's disease) were anesthetized with intraperitoneal (i.p.) injection of propofol (150 mg/kg body weight) in combination with inhalation of 2.5% sevoflurane for 1 or 3 hrs. After awaken from anesthesia, the mice were returned to their home cages. Behavioral tests (Morris water maze, open field test, one-trial novel object recognition test, contextual and cued fear conditioning test, and elevated plus maze) were performed on various dates after anesthesia. We found that anesthesia with propofol and sevoflurane caused significant deficits in spatial learning and memory, as tested using Morris Water maze 2–6 days after anesthesia exposure, in aged (17–18 months old) wild-type (WT) mice and in adult (7–8 months old) 3xTg-AD mice, but not in adult WT mice. Anesthesia resulted in long-term neurobehavioral changes in the fear conditioning task carried out 65 days after exposure to anesthesia in 3xTg-AD mice. Importantly, daily intranasal administration of insulin (1.75 U/mouse/day) for only three days prior to anesthesia completely prevented the anesthesia-induced deficits in spatial learning and memory and the long-term neurobehavioral changes tested 65 days after exposure to anesthesia in 3xTg-AD mice. Our results indicate that aging and Alzheimer-like brain pathology increase the vulnerability to cognitive impairment after anesthesia and that intranasal treatment with insulin can prevent anesthesia-induced cognitive impairment.