作者机构：
[Han, Yuan-Shan; Wang, Yu-Hong; Tang, Lin; Liu, Jian; Liu, Lin] Hunan Univ Chinese Med, Hosp 1, Changsha, Hunan, Peoples R China.;[Zhao, Hong-Qing; Yang, Hui] Hunan Univ Chinese Med, Inst Innovat & Appl Res, Changsha, Hunan, Peoples R China.;[Meng, Pan; Zhao, Hong-Qing; Yang, Hui] Hunan Univ Chinese Med, Key Lab Chinese Mat Med Power & Innovat Drugs Est, Changsha, Hunan, Peoples R China.;[Meng, Pan; Zhao, Hong-Qing; Yang, Hui] Hunan Univ Chinese Med, Domest First Class Construct Discipline Chinese M, Changsha, Hunan, Peoples R China.
通讯机构：
[Wang, Yu-Hong] H;Hunan Univ Chinese Med, Hosp 1, Changsha, Hunan, Peoples R China.
摘要：
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 diabetesrelated 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.
期刊：
European Journal of Pharmacology,2021年895(1):173861 ISSN：0014-2999
通讯作者：
Wang, Yu-Hong;Liu, Zhuo
作者机构：
[Wang, Yu-Hong; Zhao, Hong-Qing; Li, Zi-Rong] Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha 410208, Hunan, Peoples R China.;[Han, Yuan-Shan; Liu, Jian; Yang, Hui] Hunan Univ Chinese Med, Affiliated Hosp 1, Dept Expt Ctr Med Innovat, Changsha, Hunan, Peoples R China.;[Liu, Zhuo] Hunan Acad Tradit Chinese Med, Affiliated Hosp, Dept Educ & Sci, Changsha 410012, Hunan, Peoples R China.
通讯机构：
[Wang, Yu-Hong; Liu, Zhuo] H;Hunan Univ Chinese Med, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha 410208, Hunan, Peoples R China.;Hunan Acad Tradit Chinese Med, Affiliated Hosp, Dept Educ & Sci, Changsha 410012, Hunan, Peoples R China.
关键词：
Chronic unpredictable mild stress;Diabetic model rats;GR;Hippocampal;Inflammatory;NF-κB signaling pathway
摘要：
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 intra-gastrically 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 micmglia chemokine I receptor (CX3CR1) and secretion of several pro-inflammatory factors, in particular, interleukin 1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor - alpha (TNF-alpha). 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-kappa B) 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-kappa B signaling pathway.
作者机构：
[王宇红; 赵洪庆; 孟盼; 马明玥; 李姿蓉; 韩远山; 张尚霞; 吴梦瑶] Hunan University of Traditional Chinese Medicine, National Key Laboratory Breeding Base of Chinese Medicine Powders and Innovative Drugs/Technology Innovation Center, Changsha, 410208, China
作者机构：
[刘检; 韩远山; 刘林; 蔺晓源; 唐林; 杨蕙] First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China;[罗薇絮; 孟盼; 王宇红] Key Laboratory of Chinese Materia Medica Power and Innovation Drugs Established by Provincial and Ministry, Hunan University of Chinese Medicine, Changsha, 410007, China
通讯机构：
[Wang, Y.-H.] K;Key Laboratory of Chinese Materia Medica Power and Innovation Drugs Established by Provincial and Ministry, China
作者机构：
[Shi J.; Yu-Hong W.; Zi-Rong L.] State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;[Jian L.; Yuan-Shan H.] The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China;[Meng-Yao W.] Qianjin Pharmaceutical Co., Ltd., Zhuzhou, Hunan 412000, China;[Xi Z.] Hunan Provincial Brain Hospital, Changsha, Hunan 410007, China
通讯机构：
[Wang Yu-Hong] S;State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
期刊：
Journal of International Medical Research,2020年48(9) ISSN：0300-0605
通讯作者：
Wang, Yuhong
作者机构：
[Cai, Xiong; Ling, Chengli; Lei, Chang; Wang, Yuhong; Zou, Manshu; Xiang, Yun; Huang, Dan] Hunan Univ Chinese Med, Inst Innovat & Appl Res Chinese Med, Training Base Prov Minist Joint State Key Lab Chi, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.;[Xie, Yu] Hunan Univ Chinese Med, Affiliated Hosp 2, Changsha, Hunan, Peoples R China.;[Li, Xuran] Hunan Univ Chinese Med, Sch Pharm, Changsha, Hunan, Peoples R China.
通讯机构：
[Wang, Yuhong] H;Hunan Univ Chinese Med, Inst Innovat & Appl Res Chinese Med, Training Base Prov Minist Joint State Key Lab Chi, 300 Xueshi Rd, Changsha 410208, Hunan, Peoples R China.
关键词：
Cerebral ischemia;reperfusion;neuropharmacology;apigenin;flavonoids;PC12 cell model;oxidative stress;mitochondria;middle cerebral artery occlusion rat model
摘要：
Objective The therapeutic efficacy of apigenin in PC12 cells and rats remains uncertain. The aim of this study was to investigate the neuroprotective effects of apigenin against cerebral ischemia/reperfusion injury, both in vitro and in vivo. Methods We first treated PC12 cells with cobalt chloride (CoCl2) to create a model of oxidative stress injury. Cell viability was then determined using a multifunctional microplate reader. In addition, reactive oxygen species (ROS) levels, apoptosis, and mitochondrial membrane potentials (MMPs) were examined using high-content cytometer analysis. The efficacy of apigenin treatment was also analyzed in a rat middle cerebral artery occlusion (MCAO) model using TTC staining and neurological deficit scores. Results The half-inhibitory concentration of CoCl2 was 1.2 mM. Pretreatment with 10 µg ⋅ mL−1 apigenin significantly enhanced cell viability, reduced ROS levels, alleviated apoptosis, and improved MMP in PC12 cells with CoCl2-induced injury in vitro. In addition, apigenin treatment in vivo significantly improved neurological deficit scores and reduced infarct areas in MCAO rats. These results suggest that the neuroprotective mechanisms of apigenin may be related to mitochondrial activation. Conclusions Apigenin had excellent neuroprotective effects for the treatment of cerebral ischemia/reperfusion injury in vitro and in vivo.
