This approach has been recently tested and found effective in several studies as a potential treatment for cognitive deficits in Alzheimer’s disease, brain injury and other brain disorders 9, 10, 11, 12, 13. Intranasal insulin allows a non-invasive and efficient delivery of insulin into the brain. In juvenile animals, repeated general anesthesia induces cell death in the brain via apoptosis 2, which is a proposed mechanism underlying persistent dysfunction of neuronal circuits, impaired synaptic plasticity, and long-term memory formation in adulthood. The mechanisms of repeated anesthesia-induced cognitive deficits remain elusive and no treatment to prevent memory deficits is available. FDA Drug Safety Communication to issue an alert on the pediatric use of anesthetic and sedative agents, warning that they may negatively impact brain development upon repeated or prolonged administration to young children (or the fetus during the third trimester of pregnancy) 8. The accumulating evidence in animal and human studies prompted the U.S. Although short anesthetic exposure in children does not lead to cognitive impairment 4, animal studies and pediatric epidemiological reports linked repeated or prolonged general anesthesia to cognitive and behavioral abnormalities, including neurodevelopmental delay, learning disabilities, and attention deficit/hyperactivity disorder 5, 6, 7. Repeated general anesthesia during the early postnatal period causes neurotoxicity and long-lasting cognitive deficits in a wide range of animal species 1, 2, 3. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available.
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