Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes.
Anti-Depressant Fluoxetine Reveals its Therapeutic Effect Via Astrocytes.
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DOI：
10.1016/j.ebiom.2018.05.036
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发表时间：
2018-06
期刊：
影响因子：
11.1
通讯作者：
Koizumi S
中科院分区：
文献类型：
--
作者：
Kinoshita M;Hirayama Y;Fujishita K;Shibata K;Shinozaki Y;Shigetomi E;Takeda A;Le HPN;Hayashi H;Hiasa M;Moriyama Y;Ikenaka K;Tanaka KF;Koizumi S
虽然精神药物作用于神经元和神经胶质细胞，但神经胶质如何反应，以及神经胶质反应是否参与治疗效果还知之甚少。在这里，我们表明，氟西汀（FLX），一种抗抑郁药，介导其抗抑郁作用，通过增加ATP的胶质传递。FLX通过囊泡核苷酸转运蛋白（VNUT）增加ATP胞吐。FLX诱导的抗抑郁行为在星形胶质细胞选择性VNUT敲除小鼠或当VNUT在小鼠中缺失时降低，但当星形胶质细胞选择性VNUT在小鼠中过表达时增加。这表明VNUT依赖性星形胶质细胞ATP胞吐在FLX的治疗效果中具有关键作用。释放的ATP及其代谢产物腺苷作用于星形胶质细胞表达的P2 Y11和腺苷A2 b受体，导致星形胶质细胞中脑源性神经营养因子的增加。这些发现表明，除了神经元，FLX作用于星形胶质细胞，并通过增加ATP胶质传递介导其治疗效果。Anti-BMPFLX作用于星形胶质细胞并增加VNUT依赖性ATP胞吐作用。这种星形胶质细胞反应是FLX诱导的治疗效果的原因。星形胶质细胞ATP及其代谢产物腺苷可增加星形胶质细胞内BDNF的表达，并显示其治疗作用。Kinoshita等人证明星形胶质细胞是抗抑郁药氟西汀（FLX）的治疗靶点。他们发现FLX刺激星形胶质细胞释放VNUT依赖性ATP，导致BDNF介导的抗抑郁作用。这项研究证明了这种抗抑郁作用的星形胶质细胞调节，这补充了先前描述的FLX的传统机制。由于星形胶质细胞参与抑郁症的发病机制是目前的兴趣，这种新的见解星形胶质细胞的作用，抗抑郁作用应支持建立新的抑郁症治疗策略。
Although psychotropic drugs act on neurons and glial cells, how glia respond, and whether glial responses are involved in therapeutic effects are poorly understood. Here, we show that fluoxetine (FLX), an anti-depressant, mediates its anti-depressive effect by increasing the gliotransmission of ATP. FLX increased ATP exocytosis via vesicular nucleotide transporter (VNUT). FLX-induced anti-depressive behavior was decreased in astrocyte-selective VNUT-knockout mice or when VNUT was deleted in mice, but it was increased when astrocyte-selective VNUT was overexpressed in mice. This suggests that VNUT-dependent astrocytic ATP exocytosis has a critical role in the therapeutic effect of FLX. Released ATP and its metabolite adenosine act on P2Y11 and adenosine A2b receptors expressed by astrocytes, causing an increase in brain-derived neurotrophic factor in astrocytes. These findings suggest that in addition to neurons, FLX acts on astrocytes and mediates its therapeutic effects by increasing ATP gliotransmission. Anti-depressant FLX acts on astrocytes and increases VNUT-dependent ATP exocytosis. Such astrocytic responses are responsible for the FLX-induced therapeutic effects. Astrocytic ATP and its metabolite adenosine increase BDNF in astrocytes, and reveal the therapeutic effects. Kinoshita et al. demonstrated that astrocytes are a therapeutic target of the antidepressant, fluoxetine (FLX). They found that FLX stimulates VNUT-dependent ATP release from astrocytes leading to a BDNF-mediated anti-depressive effect. This study demonstrated the astrocytic regulation of this anti-depressive effect, which complements the previously described conventional mechanism of FLX. Because the involvement of astrocytes in the pathogenesis of depression is of current interest, this new insight into the role of astrocytes in anti-depressive effects should support the establishment of novel therapeutic strategies for depression.
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影响因子：
4.3
作者：
Harada K;Kamiya T;Tsuboi T
通讯作者：
Tsuboi T
DOI：
10.1126/science.1190721
发表时间：
2010-07-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gourine AV;Kasymov V;Marina N;Tang F;Figueiredo MF;Lane S;Teschemacher AG;Spyer KM;Deisseroth K;Kasparov S
通讯作者：
Kasparov S
影响因子：
4.8
作者：
Coco, S;Calegari, F;Verderio, C
通讯作者：
Verderio, C
星形胶质细胞衍生的 ATP 调节抑郁样行为
影响因子：
82.9
作者：
Cao, Xiong;Li, Liang-Ping;Gao, Tian-Ming
通讯作者：
Gao, Tian-Ming
影响因子：
3.4
作者：
Allaman, Igor;Fiumelli, Hubert;Martin, Jean-Luc
通讯作者：
Martin, Jean-Luc