中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (4): 727-733.doi: 10.4103/1673-5374.296418

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

海马神经血管单元中谷氨酸-代谢型谷氨酸受体2/3-磷酸肌醇3-激酶通路异常可诱发糖尿病抑郁

  

  • 出版日期:2021-04-15 发布日期:2020-12-21
  • 基金资助:

    中国国家自然科学基金项目(8157396581874464);湖南省自然科学基金项目(2017JJ3241);湖南省教育厅科研基金项目(17C1229

Abnormal Glu/mGluR2/3/PI3K pathway in the hippocampal neurovascular unit leads to diabetes-related depression

Jian Liu1, Yuan-Shan Han1, Lin Liu1, Lin Tang1, Hui Yang1, Pan Meng2, 3, 4, Hong-Qing Zhao3, 4, Yu-Hong Wang2, 3, 4, *#br#   

  1. 1 The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan Province, China;  2 Institute of Innovation and Applied Research, Hunan University of Chinese Medicine, Changsha, Hunan Province, China;  3 Key Laboratory of Chinese Material Medical Power and Innovation Drugs Established by Human Provincial Government and Ministry, Hunan University of Chinese Medicine, Changsha, Hunan Province, China;  4 The Domestic First Class Construction Discipline of Chinese Medicine in Hunan University of Chinese Medicine, Changsha, Hunan Province, China
  • Online:2021-04-15 Published:2020-12-21
  • Contact: Yu-Hong Wang, MD, wyh_107@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81573965 (to YHW), 81874464 (to YHW); the Natural Science Foundation of Hunan Province of China, No. 2017JJ3241 (to JL); and the Education Department Scientific Research Foundation of Hunan Province of China, No. 17C1229 (to JL).

摘要:

继发现谷氨酸和海马神经元凋亡分别是糖尿病并发抑郁的关键信号和直接因素后,海马神经血管单元的结构和功能损伤也被认为与糖尿病并发抑郁有关,但其作用机制仍然不明。实验假设糖尿病并发抑郁的发生可能与海马神经血管单元中糖皮质激素受体激活的谷氨酸-代谢型谷氨酸受体2/3-磷酸肌醇3-激酶通路有关。为验证这一假设,以大鼠海马神经元、星形胶质细胞和脑微血管内皮细胞构建海马神经血管单元模型,并以150 mM葡萄糖和200μM皮质酮模拟糖尿病并发抑郁。结果发现在糖尿病并发抑郁条件下,海马神经血管单元受损,导致其屏障功能降低,谷氨酸水平升高,糖皮质激素受体、谷氨酸转运蛋白和代谢型谷氨酸受体2/3异常表达,细胞外信号调节激酶/神经胶质细胞源性神经营养因子/磷酸肌醇3-激酶信号通路关键蛋白表达失衡,同时神经元活性明显降低,神经元凋亡以及凋亡蛋白Caspase-3和Caspase-9表达明显增加。提示海马神经血管单元中糖皮质激素受体诱导的谷氨酸-代谢型谷氨酸受体2/3-磷酸肌醇3-激酶通路参与调节海马神经元凋亡,且这可能与糖尿病并发抑郁的发生有关。实验于2019年11月12日经湖南中医药大学附属第一医院实验动物伦理委员会批准,批准号HN-ZYFY-2019-11-12。

https://orcid.org/0000-0001-6877-9725 (Jian Liu)

关键词: 海马, 神经血管单元, 蛋白, 因子, 通路, 糖尿病, 抑郁, 体外

Abstract: Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression, and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetes-related depression. However, the underlying mechanism remains unclear. We hypothesized that diabetes-related depression might be associated with the glutamate (Glu)/metabotropic glutamate receptor2/3 (mGluR2/3)/phosphoinositide 3-kinase (PI3K) pathway, activated by glucocorticoid receptors in the hippocampal neurovascular unit. To test this hypothesis, rat hippocampal neurovascular unit models, containing hippocampal neurons, astrocytes, and brain microvascular endothelial cells, were treated with 150 mM glucose and 200 µM corticosterone, to induce diabetes-related depression. Our results showed that under conditions of diabetes complicated by depression, hippocampal neurovascular units were damaged, leading to decreased barrier function; elevated Glu levels; upregulated glucocorticoid receptor, vesicular glutamate transporter 3 (VGLUT-3), and metabotropic glutamate receptor 2/3 (mGluR2/3) expression; downregulated excitatory amino acid transporter 1 (EAAT-1) expression; and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase (ERK)/glial cell-derived neurotrophic factor (GDNF)/PI3K signaling pathway. Moreover, the viability of neurons was dramatically reduced in the model of diabetes-related depression, and neuronal apoptosis, and caspase-3 and caspase-9 expression levels, were increased. Our results suggest that the Glu/mGluR2/3/PI3K pathway, induced by glucocorticoid receptor activation in the hippocampal neurovascular unit, may be associated with diabetes-related depression. This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine, China (approval No. HN-ZYFY-2019-11-12) on November 12, 2019.

Key words: diabetes-related depression, factor, hippocampus, in vitro, neurovascular unit, pathways, protein