Hippocampal PPARα Plays a Role in the Pharmacological Mechanism of Vortioxetine, a Multimodal-Acting Antidepressant.
Hippocampal PPARα Plays a Role in the Pharmacological Mechanism of Vortioxetine, a Multimodal-Acting Antidepressant.
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海马 PPAR α 在多模式抗抑郁药沃替西汀的药理机制中发挥作用
DOI：
10.3389/fphar.2021.673221
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发表时间：
2021
影响因子：
5.6
通讯作者：
Jiang B
中科院分区：
文献类型：
--
作者：
Wang Y;Gu JH;Liu L;Liu Y;Tang WQ;Ji CH;Guan W;Zhao XY;Sun YF;Xu DW;Jiang B
作为一种著名的多通道抗抑郁药，伏替西汀被认为是针对几种5-羟色胺(5-HT)受体和5-羟色胺转运体。近年来，除5-羟色胺外，越来越多的蛋白质被报道参与伏替西汀的抗抑郁机制。作为一种广为人知的核激素受体，过氧化物酶体增殖物激活受体α(PPARα)具有转录活性，在大脑中起着非常重要的作用。一些报告表明，海马区PPARα与抗抑郁反应有关。我们推测，海马区PPARα可能参与了伏替西汀的抗抑郁机制。本研究采用慢性不可预见性轻度应激(CUMS)、慢性社会失败应激(CSDS)、行为学测试、Western blotting和腺病毒相关病毒(AAV)介导的基因敲除方法。结果发现，伏替西汀可显著逆转中草药和西药对海马区PPARα表达的抑制作用。药物阻断PPARα可显著阻断伏替西汀的抗抑郁作用。此外，海马区PPARα的基因敲除也显著阻断了伏替西汀对慢性阻塞性肺疾病和慢性阻塞性肺疾病的保护作用。因此，伏替西汀在小鼠体内的抗抑郁作用需要海马PPARα。
As a well-known multimodal-acting antidepressant, vortioxetine is thought to aim at several serotonin (5-HT) receptors and the 5-HT transporter. However, recently more and more proteins besides 5-HT are being reported to participate in the antidepressant mechanism of vortioxetine. As a widely known nuclear hormone receptor, peroxisome proliferator activated receptor α (PPARα) possesses transcriptional activity and is very important in the brain. Several reports have suggested that hippocampal PPARα is implicated in antidepressant responses. Here we speculate that hippocampal PPARα may participate in the antidepressant mechanism of vortioxetine. In this study, chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), behavioral tests, the western blotting and adenovirus associated virus (AAV)-mediated gene knockdown methods were used together. It was found that vortioxetine administration significantly reversed the inhibitory actions of both CUMS and CSDS on the hippocampal PPARα expression. Pharmacological blockade of PPARα notably prevented the antidepressant actions of vortioxetine in the CUMS and CSDS models. Moreover, genetic knockdown of PPARα in the hippocampus also significantly blocked the protecting effects of vortioxetine against both CUMS and CSDS. Therefore, the antidepressant effects of vortioxetine in mice require hippocampal PPARα.
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影响因子：
5.4
作者：
Grygiel-Górniak B
通讯作者：
Grygiel-Górniak B
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影响因子：
4.5
作者：
Li, Yuanye;Chen, Gang;Xu, Guangfei
通讯作者：
Xu, Guangfei
影响因子：
7.3
作者：
Kilkenny, Carol;Browne, William;Altman, Douglas G.
通讯作者：
Altman, Douglas G.
影响因子：
10.6
作者：
Jiang, Bo;Wang, Hao;Li, Jun-Xu
通讯作者：
Li, Jun-Xu
过氧化物酶体增殖物激活的受体α在小鼠的行为重复和认知灵活性中起着至关重要的作用。
影响因子：
8.1
作者：
D'Agostino G;Cristiano C;Lyons DJ;Citraro R;Russo E;Avagliano C;Russo R;Raso GM;Meli R;De Sarro G;Heisler LK;Calignano A
通讯作者：
Calignano A