Liu Zhuo, Han Yuanshan, Zhao Hongqing, Luo Weixu, Jia Ling, Wang Yuhong
Hunan University of Chinese Medicine, Training Bases, Hunan Key Laboratory of Chinese Materia Medical Powder and Innovative Drugs Established by Province and Ministry, Changsha 410208, Hunan, China.
First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan, China.
Evid Based Complement Alternat Med. 2019 Jun 10;2019:3710363. doi: 10.1155/2019/3710363. eCollection 2019.
Diabetes mellitus is frequently accompanied by depression (diabetes-depression, DD), and DD patients are at higher risk of diabetes-related disability and mortality than diabetes patients without depression. Hippocampal degeneration is a major pathological feature of DD. Here, we investigated the contribution of the Glu-mGluR2/3-ERK signaling pathway to apoptosis of hippocampal neurons in DD model rats.
The DD model was established by high-fat diet (HFD) feeding and streptozotocin (STZ) injection followed by chronic unpredictable mild stress (CUMS). Other groups were subjected to HFD + STZ only (diabetes alone) or CUMS only (depression alone). Deficits in hippocampus-dependent memory were assessed in the Morris water maze (MWM), motor activity in the open field test (OFT), and depression-like behavior in the forced swim test (FST). Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) was used to estimate the rate of hippocampal neuron apoptosis. Hippocampal glutamate (Glu) content was measured by high performance liquid chromatography. Hippocampal expression levels of mGluR2/3, ERK, and the apoptosis effector caspase-3 were estimated by immunohistochemistry and Western blotting.
DD model rats demonstrated more severe depression-like behavior in the FST, greater spatial learning and memory deficits in the MWM, and reduced horizontal and vertical activity in the OFT compared to control, depression alone, and diabetes alone groups. All of these abnormalities were reversed by treatment with the mGluR2/3 antagonist LY341495. The DD group also exhibited greater numbers of TUNEL-positive hippocampal neurons than all other groups, and this increased apoptosis rate was reversed by LY341495. In addition, hippocampal expression levels of caspase-3 and mGluR2/3 were significantly higher, ERK expression was lower, and Glu was elevated in the DD group. The mGluR2//3 antagonist significantly altered all these features of DD.
Comorbid diabetes and depression are associated with enhanced hippocampal neuronal apoptosis and concomitantly greater hippocampal dysfunction. These pathogenic effects are regulated by the Glu-mGluR2/3-ERK signaling pathway.
糖尿病常伴有抑郁症（糖尿病-抑郁症，DD），与无抑郁症的糖尿病患者相比，DD患者发生糖尿病相关残疾和死亡的风险更高。海马体退化是DD的主要病理特征。在此，我们研究了Glu-mGluR2/3-ERK信号通路在DD模型大鼠海马神经元凋亡中的作用。
通过高脂饮食（HFD）喂养和链脲佐菌素（STZ）注射，随后进行慢性不可预测轻度应激（CUMS）建立DD模型。其他组仅接受HFD+STZ（仅糖尿病组）或仅接受CUMS（仅抑郁症组）。在莫里斯水迷宫（MWM）中评估海马依赖性记忆缺陷，在旷场试验（OFT）中评估运动活动，在强迫游泳试验（FST）中评估抑郁样行为。采用末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记法（TUNEL）评估海马神经元凋亡率。通过高效液相色谱法测量海马谷氨酸（Glu）含量。通过免疫组织化学和蛋白质印迹法评估海马mGluR2/3、ERK和凋亡效应因子caspase-3的表达水平。
与对照组、仅抑郁症组和仅糖尿病组相比，DD模型大鼠在FST中表现出更严重的抑郁样行为，在MWM中存在更大的空间学习和记忆缺陷，在OFT中的水平和垂直活动减少。用mGluR2/3拮抗剂LY341495治疗可逆转所有这些异常。DD组TUNEL阳性海马神经元数量也比所有其他组更多，LY341495可逆转这种升高的凋亡率。此外，DD组中caspase-3和mGluR2/3的海马表达水平显著升高，ERK表达降低，Glu升高。mGluR2/3拮抗剂显著改变了DD的所有这些特征。
糖尿病合并抑郁症与海马神经元凋亡增加及随之而来的更严重海马功能障碍有关。这些致病作用受Glu-mGluR2/3-ERK信号通路调节。
