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Intranasal Insulin Prevents Anesthesia-induced Cognitive Impairments in Aged Mice

[ Vol. 16 , Issue. 1 ]

Author(s):

Xing Li, Xiaoqin Run*, Zhen Wei, Kuan Zeng, Zhihou Liang, Fang Huang, Dan Ke, Qun Wang, Jian-Zhi Wang, Rong Liu, Bin Zhang* and Xiaochuan Wang*   Pages 8 - 18 ( 11 )

Abstract:


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.

Keywords:

Postoperative cognitive dysfunction (POCD), insulin, propofol, tau hyperphosphorylation, cognitive impairments, memory deficit.

Affiliation:

Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030



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