中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2018, Vol. 13 ›› Issue (11): 1995-2004.doi: 10.4103/1673-5374.239448

• 原著:退行性病与再生 • 上一篇    下一篇

新生2型糖尿病大鼠模型青年期可出现认知缺陷和阿尔茨海默样神经病理损伤

  

  • 收稿日期:2018-07-04 出版日期:2018-11-15 发布日期:2018-11-15
  • 基金资助:

    河南医学院博时启动基金项目（1001/0106），河南省科技项目（172102310105）

Cognitive deficits and Alzheimer-like neuropathological impairments during adolescence in a rat model of type 2 diabetes mellitus

Li Jin1, 2, Yi-Pei Li1, 2, Qiong Feng3, 4, Li Ren1, 2, Fang Wang1, 2, Guo-Jia Bo1, 2, Li Wang1, 2   

  1. 1 Department of Pathophysiology, Henan Medical College, Zhengzhou, Henan Province, China
    2 Henan Key Laboratory of Degenerative Brain Disease, Henan Medical College, Zhengzhou, Henan Province, China
    3 Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, Chinsa
    4 Department of Pathology, Wuhan Children’s Hospital, Wuhan, Hubei Province, China
  • Received:2018-07-04 Online:2018-11-15 Published:2018-11-15
  • Contact: Li Wang, PhD, kyk02@126.com.
  • Supported by:

    This study was principally supported by the Initial Funding of PhD Research from Henan Medical College of China, No. 1001/0106; and in parts by the Science and Technology Project of Henan Province of China, No. 172102310105.

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摘要：

大量研究显示2型糖尿病患者存在认知功能障碍和神经元突触损伤，且越来越多的证据表明2型糖尿病与阿尔茨海默病神经变性和神经损伤的发生和进展紧密相关。但目前由2型糖尿病引起的代谢紊乱与阿尔茨海默病中神经退行性病变的关联仍未完全阐明。为此，实验设计SD大鼠出生后1，3，5，7，9d皮下注射4mg/g谷氨酸钠建立2型糖尿病动物模型，3月龄时，以巴恩斯迷宫和评价各组大鼠空间记忆功能，以微电极测试海马CA1区电生理功能，以Western blot检测海马组织中突触可塑性相关蛋白GluN2A和GluN2B的表达水平，以ELISA测量海马和大脑皮质中白细胞介素1β、肿瘤坏死因子α和白细胞介素6以及海马Aβ1-40和Aβ1-42水平。结果发现新生期暴露于谷氨酸钠的大鼠Barnes迷宫潜伏期延长，错误次数增加，Morris水迷宫中潜伏期增加，停留在逃逸平台所在的象限较短，且跨越平台的次数也减少，海马高频刺激后的突触传递受到抑制，海马组织中GluN2A和GluN2B表达减弱，海马和皮质中白细胞介素1β、白细胞介素6和肿瘤坏死因子α表达增加，海马中Aβ1-40和Aβ1-42水平增加。表明谷氨酸钠暴露诱导的2型糖尿病大鼠能够引起阿尔茨海默样神经病理学改变，并进一步导致青年期的认知缺陷和神经变性。

orcid:0000-0001-6205-5881(Li Wang)

 

关键词: 2型糖尿病, 阿尔茨海默病, 谷氨酸钠, 新生儿期认知缺陷, 高血糖, 高胰岛素血症, 胰岛素抵抗, 神经再生

Abstract:

Numerous studies have shown that many patients who suffer from type 2 diabetes mellitus exhibit cognitive dysfunction and neuronal synaptic impairments. Therefore, growing evidence suggests that type 2 diabetes mellitus has a close relationship with occurrence and progression of neurodegeneration and neural impairment in Alzheimer’s disease. However, the relationship between metabolic disorders caused by type 2 diabetes mellitus and neurodegeneration and neural impairments in Alzheimer’s disease is still not fully determined. Thus, in this study, we replicated a type 2 diabetic animal model by subcutaneous injection of newborn Sprague-Dawley rats with monosodium glutamate during the neonatal period. At 3 months old, the Barnes maze assay was performed to evaluate spatial memory function. Microelectrodes were used to measure electrophysiological function in the hippocampal CA1 region. Western blot assay was used to determine expression levels of glutamate ionotropic receptor NMDA type subunit 2A (GluN2A) and GluN2B in the hippocampus. Enzyme-linked immunosorbent assay was used to determine levels of interleukin-1β, tumor necrosis factor α, and interleukin-6 in the hippocampus and cerebral cortex, as well as hippocampal amyloid beta (Aβ)1–40 and Aβ1–42 levels. Our results showed that in the rat model of  type 2 diabetes mellitus caused by monosodium glutamate exposure during the neonatal period, latency was prolonged and the number of errors increased in the Barnes maze. Further, latency was increased and time in the escape platform quadrant shortened. Number of times crossing the platform was also reduced in the Morris water maze. After high frequency stimulation of the hippocampus, synaptic transmission was inhibited, expression of GluN2A and GluN2B were decreased in the hippocampus, expression of interleukin 1β, interleukin 6, and tumor necrosis factor α was increased in the hippocampus and cortex, and levels of Aβ1–40 and Aβ1–42 were increased in the hippocampus. These findings confirm that type 2 diabetes mellitus induced by neonatal monosodium glutamate exposure results in Alzheimer-like neuropathological changes and further causes cognitive deficits and neurodegeneration in young adulthood.

Key words: nerve regeneration, type 2 diabetes mellitus, Alzheimer’s disease, monosodium glutamate, neonatal period, cognitive deficits, hyperglycemia, hyperinsulinemia, insulin resistance, neural regeneration