State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
Department of Experimental Center for Medical Innovation, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
Eur J Pharmacol. 2021 Mar 15;895:173861. doi: 10.1016/j.ejphar.2021.173861. Epub 2021 Jan 16.
Clinical studies have shown that diabetes can present with underlying depression, and a combination of the two can lead to emotional, memory and cognitive disorders, closely associated with hippocampal neuroinflammation. However, the mechanism underlying the development of hippocampal neuroinflammation under the above condition remains elusive. The aims of this study were to explore the pathogenesis of diabetes combined with depression, and the effect of dexamethasone (Dex), a glucocorticoid receptor (GR) agonist, on hippocampal neuroinflammation in diabetic rats with chronic unpredictable mild stress (CUMS). Therefore, rats were intragastrically fed on a high-fat diet (10% cholesterol 10 ml/kg) for 14 days and thereafter injected with 38 mg/kg of streptozotocin on the 15th day to induce diabetes. Dex treatment of the diabetic and CUMS rats ameliorated the depression-associated behavior in the respective rats. Apart from enhanced depressive behavior, diabetes-depressed condition also up-regulated the expression of hippocampus microglia chemokine Ⅰ receptor (CX3CR1) and secretion of several pro-inflammatory factors, in particular, interleukin 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor - α (TNF-α). Hematoxylin-eosin staining revealed inflammatory damages in the hippocampus. Western blot analysis further revealed repression of GR proteins converse to the nuclear factor kappa-B (NF-κB) proteins, which were up-regulated. Intriguingly, Dex reversed the above events by inhibiting inflammatory reactions in the hippocampus. Consequently, played an antidepressant effect in diabetic and CUMS model rats. Overall, findings of this research suggest that the physiopathology of diabetes with stress cormobity are mediated by inflammatory reactions in the hippocampus. In particular, the responses are associated with regulation of GR/NF-κB signaling pathway.
临床研究表明，糖尿病可伴有潜在的抑郁，两者结合可导致情绪、记忆和认知障碍，与海马神经炎症密切相关。然而，上述情况下海马神经炎症发展的机制仍不清楚。本研究旨在探讨糖尿病合并抑郁的发病机制，以及糖皮质激素受体（GR）激动剂地塞米松（Dex）对慢性不可预测轻度应激（CUMS）糖尿病大鼠海马神经炎症的影响。因此，大鼠连续 14 天给予高脂肪饮食（10%胆固醇 10ml/kg），第 15 天给予 38mg/kg 链脲佐菌素诱导糖尿病。Dex 治疗糖尿病和 CUMS 大鼠改善了各自大鼠的抑郁相关行为。除了增强抑郁行为外，糖尿病抑郁状态还上调了海马小胶质细胞趋化因子 1 受体（CX3CR1）的表达和几种促炎因子的分泌，特别是白细胞介素 1β（IL-1β）、白细胞介素 6（IL-6）、白细胞介素 8（IL-8）和肿瘤坏死因子-α（TNF-α）。苏木精-伊红染色显示海马炎症损伤。Western blot 分析进一步显示，GR 蛋白被抑制，而核因子 kappa-B（NF-κB）蛋白被上调。有趣的是，Dex 通过抑制海马中的炎症反应逆转了上述事件。因此，在糖尿病和 CUMS 模型大鼠中发挥了抗抑郁作用。总的来说，这项研究的结果表明，应激共病糖尿病的病理生理学是由海马炎症反应介导的。特别是，这些反应与 GR/NF-κB 信号通路的调节有关。
