Background: Preclinical and clinical evidence suggests that elderly individuals are at increased
risk of cognitive decline after general anesthesia. General anesthesia is also believed to be a risk
factor for Postoperative Cognitive Dysfunction (POCD) and Alzheimer’s Disease (AD). Intranasal administration
of insulin, which delivers the drug directly into the brain, improves memory and cognition
in both animal studies and small clinical trials. However, how insulin treatment improves cognitive
function is poorly understood.
Methods: Aged mice were pretreated with intranasal insulin or saline before anesthesia. Propofol was
added intraperitoneally to the mice from 7th day of insulin/saline treatment, and general anesthesia was
induced and maintained for 2 hours/day for 5 consecutive days. Mice were evaluated at 26th day when
the mice were continued on insulin or saline administration for another 15 days.
Results: We found that intranasal insulin treatment prevented anesthesia-induced cognitive impairments,
as measured by novel object recognition test and contextual-dependent fear conditioning test. Insulin
treatment also increased the expression level of Post-synaptic Density Protein 95 (PSD95), as well as
upregulated Microtubule-associated Protein-2 (MAP-2) in the dentate gyrus of the hippocampus. Furthermore,
we found that insulin treatment restored insulin signaling disturbed by anesthesia via activating
PI3K/PDK1/AKT pathway, and attenuated anesthesia-induced hyperphosphorylation of tau at multiple
AD-associated sites. We found the attenuation of tau hyperphosphorylation occurred by increasing
the level of GSK3β phosphorylated at Ser9, which leads to inactivation of GSK-3β.
Conclusion: Intranasal insulin administration might be a promising therapy to prevent anesthesiainduced
cognitive deficit in elderly individuals.