Abstract
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. 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. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. 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. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. 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.
Highlights
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
We show that intranasal insulin prevents apoptosis of hippocampal cells by activating the mechanistic target of rapamycin complex 1 (mTORC1) pathway, since the beneficial effect of insulin on apoptosis was abolished by the mTORC1 inhibitor, temsirolimus
Mice were exposed to anesthesia on postnatal days 15–17, which correlate to ~ 2-year-old children based on weaning age and lifespan[26], to avoid metabolic derangement and hypercarbia, which are often observed during anesthesia in younger (e.g. PD 7) rodents[27]
Summary
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. 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. 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. The hippocampus is highly vulnerable to n eurotoxicity[15] and is one of the first regions where cells undergo apoptosis upon general anesthesia in juvenile a nimals[16] It has central roles in acquisition and consolidation of different types of memory, spatial and contextual memory[17], an early life damage to the hippocampus results in long-lasting memory impairments[18]
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