Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1

被引:9
作者
Roque, Patricia Soriano [1 ,2 ]
Hooshmandi, Mehdi [1 ]
Neagu-Lund, Laura [1 ]
Yin, Shelly [1 ]
Yousefpour, Noosha [3 ]
Sato, Hiroaki [4 ]
Sato, Tamaki [4 ]
Nakadate, Yosuke [4 ]
Kawakami, Akiko [4 ]
Tahmasebi, Soroush [5 ]
Ribeiro-da-Silva, Alfredo [3 ,6 ,7 ]
Gkogkas, Christos G. [8 ]
Prager-Khoutorsky, Masha [9 ]
Schricker, Thomas [4 ]
Wykes, Linda [2 ]
Khoutorsky, Arkady [1 ,6 ]
机构
[1] McGill Univ, Dept Anesthesia & Fac Dent, Montreal, PQ, Canada
[2] McGill Univ, Sch Human Nutr, Montreal, PQ, Canada
[3] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada
[4] McGill Univ, Royal Victoria Hosp, Hlth Ctr Glen Site, Dept Anesthesia, Montreal, PQ, Canada
[5] Univ Illinois, Dept Pharmacol & Regenerat Med, Chicago, IL 60612 USA
[6] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ, Canada
[7] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada
[8] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Div Biomed Res, Univ Campus, Ioannina 45110, Greece
[9] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada
基金
加拿大健康研究院;
关键词
DEVELOPING RAT-BRAIN; GENERAL-ANESTHESIA; EARLY EXPOSURE; HIPPOCAMPUS; NEURODEGENERATION; PHOSPHORYLATION; MITOCHONDRIA; ASSOCIATION; CHILDREN; HUMANS;
D O I
10.1038/s41598-021-94849-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:12
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