Glu-mGluR2/3-ERK信号通路在糖尿病并发抑郁症大鼠前额叶皮质神经元凋亡中的作用
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摘要
目的探讨Glu-mGluR2/3-ERK信号通路在糖尿病并发抑郁症(diabetic depression, DD)大鼠前额叶皮质神经元凋亡中的作用。方法动物实验分为两部分,第一部分动物分为4组:对照组、糖尿病组、抑郁症组、DD组;第二部分动物分为3组:对照组、DD组、mGluR2/3阻断剂+DD组(LY341495组)。采用旷场实验和Morris水迷宫实验,评价大鼠的抑郁样行为,HE染色观察前额叶皮质区病理损伤情况;HPLC法检测谷氨酸含量;免疫组化法检测mGluR2/3、ERK、caspase-3蛋白的阳性表达情况。结果与对照组比较,DD模型组大鼠抑郁样行为明显,前额叶皮质神经元存在胞体肿胀、核固缩、排列紊乱、数量减少等病理损伤现象,凋亡执行蛋白caspase-3阳性表达明显上升,同时谷氨酸含量异常升高,其受体mGluR2/3表达增加,下游分子ERK表达降低,说明神经元凋亡可能与Glu-mGluR2/3-ERK通路有关。进一步研究发现,给予mGluR2/3阻断剂LY341495后,DD组大鼠前额叶皮质区mGluR2/3、ERK、caspase-3表达均得到逆转,病理损伤情况也得到一定程度缓解。结论 Glu-mGluR2/3-ERK信号通路参与了DD大鼠前额叶皮质神经元的凋亡过程。
Aim To investigate the key role of Glu-mGluR2/3-ERK signaling pathway in the apoptosis of prefrontal cortical neurons in diabetic rats with depression(DD).Methods Animal experiments were divided into two parts. The first part was divided into four groups: control, diabetes, depression and DD group; the second part was divided into three groups: control, DD, mGluR2/3 blocker+DD group(LY341495 group). Hormonal and Morris water maze tests were used to evaluate the depression-like behavior of rats. HE staining was used to observe the pathological damage in the prefrontal cortex. HPLC was applied to determine glutamate content, and immunohistochemistry was employed to assess the positive expression of mGluR2/3, ERK, and caspase-3.Results Compared with control group, the depression-like behavior of the rats in DD model group was obvious. The prefrontal cortical neurons had pathological lesions such as swelling of the cell body, nuclear condensation, disordered arrangement, and reduced number, and the positive expression of caspase-3 increased significantly. Meanwhile, glutamate content increased abnormally, its receptor mGluR2/3 expression increased, and downstream molecules ERK expression decreased, indicating that neuronal apoptosis may be related to Glu-mGluR2/3-ERK pathway. Further study found that after the administration of mGluR2/3 blocker LY341495, the expression of mGluR2/3, ERK and caspase-3 in the prefrontal cortex of rats in DD group was reversed, and the pathological damage was alleviated to some extent.Conclusions The Glu-mGluR2/3-ERK signaling pathway is involved in the process of apoptosis of prefrontal cortical neurons in DD rats.
Aim To investigate the key role of Glu-mGluR2/3-ERK signaling pathway in the apoptosis of prefrontal cortical neurons in diabetic rats with depression(DD).Methods Animal experiments were divided into two parts. The first part was divided into four groups: control, diabetes, depression and DD group; the second part was divided into three groups: control, DD, mGluR2/3 blocker+DD group(LY341495 group). Hormonal and Morris water maze tests were used to evaluate the depression-like behavior of rats. HE staining was used to observe the pathological damage in the prefrontal cortex. HPLC was applied to determine glutamate content, and immunohistochemistry was employed to assess the positive expression of mGluR2/3, ERK, and caspase-3.Results Compared with control group, the depression-like behavior of the rats in DD model group was obvious. The prefrontal cortical neurons had pathological lesions such as swelling of the cell body, nuclear condensation, disordered arrangement, and reduced number, and the positive expression of caspase-3 increased significantly. Meanwhile, glutamate content increased abnormally, its receptor mGluR2/3 expression increased, and downstream molecules ERK expression decreased, indicating that neuronal apoptosis may be related to Glu-mGluR2/3-ERK pathway. Further study found that after the administration of mGluR2/3 blocker LY341495, the expression of mGluR2/3, ERK and caspase-3 in the prefrontal cortex of rats in DD group was reversed, and the pathological damage was alleviated to some extent.Conclusions The Glu-mGluR2/3-ERK signaling pathway is involved in the process of apoptosis of prefrontal cortical neurons in DD rats.
引文
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[11] Schmitz S K, King C, Kortleven C, et al. Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1[J]. EMBO J, 2016, 35(11): 1236-50.
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[13] Podkowa K, Pochwat B, Branski P, et al. Group II mGlu receptor antagonist LY341495 enhances the antidepressant-like effects of ketamine in the forced swim test in rats[J]. Neuropharmacology, 2016,233(15):2901-14.
[2] Ates M, Dayi A, Kiray M, et al. Anxiety- and depression-like behavior are correlated with leptin and leptin receptor expression in prefrontal cortex of streptozotocin-induced diabetic rats[J]. Biotech Histochem, 2014,89(3):161-71.
[3] 薛 曼, 杨云惠, 索占伟, 等. 蛋白酪氨酸磷酸酶SHP-2在Ⅰ型代谢型谷氨酸受体诱发痛觉超敏中的作用[J]. 中国药理学通报, 2017, 33(2): 171-4.[3] Xue M, Yang Y H, Suo Z W, et al. Role of protein tyrosine phosphatase SHP-2 in group Ⅰ metabotropic glutamate receptors-induced allodynia[J]. Chin Pharmacol Bull, 2017, 33(2): 171-4.
[4] Tsai C Y, Chang A Y, Chan J Y, et al. Activation of PI3K/Akt signaling in rostral ventrolateral medulla impairs brain stem cardiovascular regulation that underpins circulatory depression during mevinphos intoxication[J]. Biochem Pharmacol, 2014,88(1):75-85.
[5] Gleason S D, Li X, Smith I A, et al. mGlu2/3 agonist-induced hyperthermia: an in vivo assay for detection of mGlu2/3 receptor antagonism and its relation to antidepressant-like efficacy in mice[J]. CNS Neurol Disord Drug Targets, 2013,12(5):554-66.
[6] Umegaki H, Makino T, Shimada H, et al. Cognitive dysfunction in urban-community dwelling prefrail older subjects[J]. J Nutr Health Aging, 2018,22(4):549-54.
[7] Wu Y J, Lin C C, Yeh C M. Repeated transcranial direct current stimulation improves cognitive dysfunction and synaptic plasticity deficit in the prefrontal cortex of streptozotocin-induced diabetic rats[J]. Brain Stimul, 2017,10(6):1079-87.
[8] Mangia S, Kumar A F, Moheet A A, et al. Neurochemical profile of patients with type 1 diabetes measured by 1H-MRS at 4 T[J]. J Cereb Blood Flow Metab, 2013,33(5):754-9.
[9] 吴文宝, 孔庆宏, 阚祥绪, 等. 凋亡通路及caspases在阿尔茨海默病中作为治疗靶点的研究[J].中国药理学通报,2015,31(11):1496-501.[9] Wu W B, Kong Q H, Kan X X, et al.Research progress of apoptosis pathways and caspases as therapeutic targets involved in Alzheimer′s disease[J].Chin Pharmacol Bull, 2015, 31(11):1496-501.
[10] Zeng W, Chen G, Guo Y, et al. Production of poly-γ-glutamic acid by a thermotolerant glutamate-independent strain and comparative analysis of the glutamate dependent difference[J]. AMB Express, 2017, 7(1): 213.
[11] Schmitz S K, King C, Kortleven C, et al. Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1[J]. EMBO J, 2016, 35(11): 1236-50.
[12] Lin C H, You J R, Wei K C. Stimulating ERK/PI3K/NFκB signaling pathways upon activation of mGluR2/3 restores OGD-induced impairment in glutamate clearance in astrocytes[J]. Eur J Neurosci, 2014, 39(1): 83-96.
[13] Podkowa K, Pochwat B, Branski P, et al. Group II mGlu receptor antagonist LY341495 enhances the antidepressant-like effects of ketamine in the forced swim test in rats[J]. Neuropharmacology, 2016,233(15):2901-14.