通过激活海马PPARa和BDNF信号通路,帕马替特治疗在CUMS和CRS模型中产生抗抑郁样作用。

IF 3.7 2区 医学 Q1 CLINICAL NEUROLOGY
Jin Zhou, Wei Zhao, Hua Fan, Si-Yi Zhou, Xiao-Li Zhang, Hui Xu, Bo Jiang, Wei Liu, Zhi-Ming Cui, Da-Wei Xu
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引用次数: 0

摘要

背景:过氧化物酶体增殖物激活受体α (PPARα)在抑郁症的发病机制中起着至关重要的作用。一些PPARα激动剂,包括WY14643、非诺贝特和吉非弗齐,已经报道通过PPARα介导的海马脑源性神经营养因子(BDNF)信号传导和神经发生增强,在小鼠模型中产生抗抑郁样作用。pemafbrate是一种新型的高度选择性的PPARα调节剂,因此,我们假设它也可能表现出类似抗抑郁药的功效。方法:采用两种已建立的抑郁症小鼠模型,慢性不可预测轻度应激(CUMS)和慢性约束应激(CRS),来评估培马哌特的潜在抗抑郁作用。采用Western blotting和免疫荧光法评估培马颤治疗是否抵消慢性应激诱导的海马PPARα、BDNF信号传导和神经发生的抑制。为了研究其作用机制,我们使用了药物抑制剂(用于PPARα的GW6471和用于BDNF信号传导的K252a)联合腺相关病毒(AAV)介导的基因敲低方法。结果:在两种模型中,反复给药可显著改善慢性应激诱导的抑郁样行为,恢复海马PPARα水平、BDNF信号和神经发生。同时给药GW6471或K252a后,这些抗抑郁作用明显减弱。同样,基因敲低海马PPARα或BDNF均可消除帕马哌特的抗抑郁作用。结论:培马布托通过促进海马PPARα和BDNF信号传导,在CUMS和CRS小鼠模型中均具有抗抑郁样作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pemafibrate treatment produces antidepressant-like effects in CUMS and CRS models through activation of hippocampal PPARα and BDNF signaling.

Background: It is well established that peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the pathogenesis of depression. Several PPARα agonists, including WY14643, fenofibrate, and gemfibrozil, have been reported to produce antidepressant-like effects in mouse models through PPARα-mediated enhancement of hippocampal brain-derived neurotrophic factor (BDNF) signaling and neurogenesis. Pemafibrate is a novel and highly selective modulator of PPARα; we therefore hypothesized that it might also exhibit antidepressant-like efficacy.

Methods: We employed 2 established mouse models of depression, chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS), to evaluate the potential antidepressant effects of pemafibrate. Western blotting and immunofluorescence were used to assess whether pemafibrate treatment counteracts chronic stress-induced suppression of hippocampal PPARα, BDNF signaling, and neurogenesis. To investigate the mechanism of action, we utilized pharmacological inhibitors (GW6471 for PPARα and K252a for BDNF signaling) combined with adeno-associated virus-mediated genetic knockdown approaches.

Results: Repeated pemafibrate administration significantly ameliorated chronic stress-induced depressive-like behaviors and restored hippocampal PPARα levels, BDNF signaling, and neurogenesis in both models. These antidepressant effects were markedly attenuated by co-administration of GW6471 or K252a. Similarly, genetic knockdown of either hippocampal PPARα or BDNF abolished pemafibrate's antidepressant-like actions.

Conclusions: Pemafibrate exerts antidepressant-like effects in both CUMS and CRS mouse models by promoting hippocampal PPARα and BDNF signaling.

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来源期刊
CiteScore
8.40
自引率
2.10%
发文量
230
审稿时长
4-8 weeks
期刊介绍: The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
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