Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression.
Alleviative effects of fluoxetine on depressive-like behaviors by epigenetic regulation of BDNF gene transcription in mouse model of post-stroke depression.
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氟西汀通过表观遗传调控 BDNF 基因转录对中风后抑郁小鼠模型抑郁样行为的缓解作用
DOI：
10.1038/s41598-017-13929-5
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发表时间：
2017-11-02
影响因子：
4.6
通讯作者：
Hu B
中科院分区：
文献类型：
--
作者：
Jin HJ;Pei L;Li YN;Zheng H;Yang S;Wan Y;Mao L;Xia YP;He QW;Li M;Yue ZY;Hu B
氟西汀是一种选择性5-羟色胺再摄取抑制剂（SSRI）类抗抑郁药，被认为对脑卒中后抑郁（PSD）有较好的治疗作用。近年来的研究表明氟西汀可能通过增加脑源性神经营养因子（BDNF）的水平发挥抗抑郁作用，但其机制尚不清楚。本研究采用雄性C57 BL/6 J小鼠，采用光凝法结合隔离饲养建立PSD模型。在此过程中，我们证实氟西汀可以改善PSD小鼠的抑郁样行为，并上调海马BDNF的表达。然而，通过在海马中转染慢病毒衍生的shBDNF来消耗BDNF抑制氟西汀的作用。此外，我们证明了氟西汀诱导的BDNF表达调控的表观遗传机制。我们发现PSD小鼠海马中Bdnf启动子IV的特定CpG位点（位点2）的DNA甲基化有统计学显著性增加。我们还发现，氟西汀治疗可以通过蛋白激酶A（PKA）在Ser 421处磷酸化MeCP 2来解离MeCP 2-CREB-Bdnf启动子IV复合物。我们的研究强调了氟西汀在调节脑源性神经营养因子表达方面的重要性，这可能是预防脑卒中后抑郁的潜在策略。
Fluoxetine, one of the selective serotonin reuptake inhibitor (SSRI) antidepressants, has been thought to be effective for treating post-stroke depression (PSD). Recent work has shown that fluoxetine may exert an antidepressive effect through increasing the level of brain-derived neurotrophic factor (BDNF), but the underlying mechanism still remains unclear. In the present study, we successfully established the PSD model using male C57BL/6 J mice by photothrombosis of the left anterior cortex combined with isolatied-housing conditions. In the process, we confirmed that fluoxetine could improve the depression-like behaviors of PSD mice and upregulate the expression of BDNF in the hippocampus. However, depletion of BDNF by transfecting lentivirus-derived shBDNF in hippocampus suppressed the effect of fluoxetine. Furthermore, we demonstrated the epigenetic mechanisms involved in regulation of BDNF expression induced by fluoxetine. We found a statistically significant increase in DNA methylation at specific CpG sites (loci 2) ofBdnfpromoter IV in the hippocampus of PSD mice. We also found that fluoxetine treatment could disassociate the MeCP2-CREB-Bdnfpromoter IV complex via phosphorylation of MeCP2 at Ser421 by Protein Kinase A (PKA). Our research highlighted the importance of fluoxetine in regulating BDNF expression which could represent a potential strategy for preventing PSD.
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