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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.
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Details
1 McGill University, Department of Anesthesia and Faculty of Dentistry, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, School of Human Nutrition, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
2 McGill University, Department of Anesthesia and Faculty of Dentistry, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
3 McGill University, Department of Pharmacology and Therapeutics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
4 McGill University Health Centre Glen Site, Royal Victoria Hospital, Department of Anesthesia, Montreal, Canada (GRID:grid.416229.a) (ISNI:0000 0004 0646 3575)
5 University of Illinois at Chicago, Department of Pharmacology and Regenerative Medicine, Chicago, USA (GRID:grid.185648.6) (ISNI:0000 0001 2175 0319)
6 McGill University, Department of Pharmacology and Therapeutics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, Alan Edwards Centre for Research on Pain, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, Department of Anatomy and Cell Biology, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
7 University Campus, Division of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Ioannina, Greece (GRID:grid.14709.3b)
8 McGill University, Department of Physiology, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
9 McGill University, School of Human Nutrition, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
10 McGill University, Department of Anesthesia and Faculty of Dentistry, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, Alan Edwards Centre for Research on Pain, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)