Intranasal Insulin Prevents Anesthesia-induced Cognitive Impairments in Aged Mice

被引:33
作者
Li, Xing [1 ]
Run, Xiaoqin [2 ]
Wei, Zhen [1 ]
Zeng, Kuan [1 ]
Liang, Zhihou [3 ]
Huang, Fang [1 ]
Ke, Dan [1 ]
Wang, Qun [1 ]
Wang, Jian-Zhi [1 ,4 ]
Liu, Rong [1 ]
Zhang, Bin [5 ]
Wang, Xiaochuan [1 ,4 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Educ Minist China Neurol Disorders, Dept Pathophysiol,Sch Basic Med,Key Lab, Wuhan 430030, Hubei, Peoples R China
[2] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Vasc Surg, Wuhan, Hubei, Peoples R China
[3] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Neurol, Wuhan, Hubei, Peoples R China
[4] Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong 226001, JS, Peoples R China
[5] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
基金
中国国家自然科学基金;
关键词
Postoperative cognitive dysfunction (POCD); insulin; propofol; tau hyperphosphorylation; cognitive impairments; memory deficit; ALZHEIMERS-DISEASE; SEVOFLURANE ANESTHESIA; ISOFLURANE ANESTHESIA; THERAPEUTIC TARGET; IMPROVES MEMORY; PROTEIN-TAU; BRAIN; YOUNG; HYPERPHOSPHORYLATION; PHOSPHORYLATION;
D O I
10.2174/1567205015666181031145045
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 gyms 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 GSK3 beta phosphorylated at Ser9, which leads to inactivation of GSK-3 beta. Conclusion: Intranasal insulin administration might be a promising therapy to prevent anesthesia-induced cognitive deficit in elderly individuals.
引用
收藏
页码:8 / 18
页数:11
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