Intranasal insulin prevents anesthesia-induced spatial memory deficit in mice

Accumulating evidence indicates that exposure to general anesthesia may increase the incidence of postoperative cognitive dysfunction (POCD) and Alzheimer's disease (AD), especially in elderly individuals. The mechanisms leading to cognitive impairment after anesthesia are still largely unknown. Currently there are no effective strategies to treat or prevent postoperative cognitive dysfunction. We treated 17-18 month old mice (hybrid of C57BL/6 and 129/Sv mice) with daily intranasal administration of insulin (1.75 IU/mouse/day) or equal volume of saline for seven consecutive days. On the 8th day, the mice were then anesthetized with single intraperitoneal injection of propofol (150 mg/kg body weight) followed by sevoflurane (2.5%) inhalation for one hour. Morris water maze task was carried out to evaluate the cognitive function on days 9-13. The mice were sacrificed immediately after probe test on day 13th. The brains from 0, 24 and 120 hours after anesthesia were used for biochemical analysis. We found that anesthesia for one hour caused hyperphosphorylation of tau at several AD-related phosphorylation sites and spatial learning impairment and cognitive deficit. Intranasal administration of insulin attenuated anesthesia-induced hyperphosphorylation of tau, led to up-regulation of presynaptic proteins synapsin and synaptophysin and postsynaptic protein PSD95, and promoted brain insulin signaling. Furthermore, intranasal insulin prevented anesthesia-induced spatial learning deficits. Our results demonstrate that pretreatment with intranasal insulin attenuates anesthesia-induced tau hyperphosphorylation and prevents cognitive dysfunction in mice. These findings offer a potential therapeutic strategy for the prevention of anesthesia-induced cognitive dysfunction.