Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation
Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation
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二甲双胍通过激活 AMPK/CREB 介导的组蛋白乙酰化增强 BDNF 的表达来改善应激诱导的抑郁样行为
DOI：
10.1016/j.jad.2019.09.013
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发表时间：
2020-01-01
影响因子：
6.6
通讯作者：
Chen Xiaochun
中科院分区：
文献类型：
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作者：
Fang Wenting;Zhang Jing;Chen Xiaochun
背景：据报道，二甲双胍是一种一线抗血糖药物，对2型糖尿病患者具有抗抑郁作用。但是，仍然需要研究其确切的作用和潜在机制。方法：C57BL/6J小鼠遭受慢性社会失败压力（SDS）和药物管理局（对照 +车辆，SDS +车辆，SDS + MET（200 mg kg） （-1），SDS + Fluox（3 mg kg（-1）），SDS + MET + Fluox）。并通过蔗糖偏好测试，社交相互作用，尾悬架测试和强迫游泳测试评估抑郁型表型。通过使用染色质免疫沉淀，定量的实时PCR mRNA表达分析和体内和原发性培养的海马神经元中的二甲双胍对抑郁作用的潜在机制进行了讨论：二甲双胍治疗对抑郁症样行为的发展进行了反应在单独施用时患有SD的小鼠中，与氟西汀的抗抑郁作用增强氟西汀。进一步的RNA测序分析表明，二甲双胍治疗阻止了动物和高尔基体染色的内侧前额叶皮层（MPFC）的转录变化，表明在CAL锥体神经元的神经突多形中有良好的形态变化，这些神经元的神经层可变性近似于未应激小鼠中发现的那些。在分子水平上，二甲双胍通过与BDNF启动子一起增加组蛋白乙酰化，从而显着上调了脑衍生的神经营养因子（BDNF）的表达，这归因于AMP激活的蛋白激酶（AMPK）和Camp-Response的激活元素结合蛋白（CREB）。结论：我们的发现表明二甲双胍可以产生抗抑郁药效果，它为二甲双胍在预防和抑郁症治疗中的临床价值提供了经验见解。
Background: Metformin, a first-line antiglycemic drug, has been reported to have anti-depressant effects in patients with type 2 diabetes; however, its exact role and underlying mechanism still need to be investigated.Method: C57BL/6J mice were subjected to the Chronic social defeat stress (SDS) and drug administration (Control + Vehicle, SDS + Vehicle, SDS + MET (200 mg kg(-1)), SDS + FLUOX (3 mg kg(-1)), SDS + MET + FLUOX). And the depression phenotypes were evaluated by the sucrose preference test, social interaction, tail suspension test and forced swimming test. The potential mechanisms underlying the effects of metformin on depression was discussed by using Chromatin immunoprecipitation, Quantitative real-time PCR mRNA expression analysis and Western blot in vivo and in primary cultured hippocampal neurons.Result: The metformin treatment counteracted the development of depression-like behaviors in mice suffering SDS when administered alone and enhanced the anti-depressant effect of fluoxetine when combined with fluoxetine. Further RNA sequencing analysis revealed that metformin treatment prevented the transcriptional changes in the medial prefrontal cortex (mPFC) of the animals and Golgi staining indicated favorable morphological changes in the neurite plasticity of CAl pyramidal neurons, which approximated to those found in unstressed mice. At a molecular level, metformin significantly upregulated the expression of the brain-derived neurotrophic factor (BDNF) by increasing the histone acetylation along with the BDNF promoter, which was attributed to the activation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB).Conclusion: Our findings suggest that metformin can produce antidepressant effects, which provides empirical insights into the clinical value of metformin in the prevention and therapy of depression.