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Hippocampal PPAR? is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice.

ABSTRACT:

Background and purpose

Developing novel pharmacological targets beyond the monoaminergic system is now a popular strategy for treating depression. PPAR? is a nuclear receptor protein that functions as a transcription factor,-regulating gene expression. We have previously reported that both WY14643 and fenofibrate, two pharmacological agonists of PPAR?, have antidepressant-like effects in mice, implying that PPAR? is a potential antidepressant target.

Experimental approach

We first used various biotechnological methods to evaluate the effects of chronic stress and fluoxetine on hippocampal PPAR?. The viral-mediated genetic approach was then employed to explore whether hippocampal PPAR? was an antidepressant target. PPAR? inhibitors, PPAR?-knockout (KO) mice and PPAR?-knockdown (KD) mice were further used to determine the role of PPAR? in the antidepressant effects of fluoxetine.

Key results

Chronic stress significantly decreased mRNA and protein levels of PPAR? in the hippocampus, but not other regions, and also fully reduced the recruitment of hippocampal PPAR? to the cAMP response element-binding (CREB) promoter. Genetic overexpression of hippocampal PPAR? induced significant antidepressant-like actions in mice by promoting CREB-mediated biosynthesis of brain-derived neurotrophic factor. Moreover, fluoxetine notably restored the stress-induced negative effects on hippocampal PPAR?. Using PPAR? antagonists fully blocked the antidepressant effects of fluoxetine in mice, and similarly, both PPAR?-KO and PPAR?-KD abolished the effects of fluoxetine. Besides, PPAR?-KO and PPAR?-KD aggravated depression in mice.

Conclusions and implications

Hippocampal PPAR? is a potential novel antidepressant target that mediates the antidepressant actions of fluoxetine in mice.

SUBMITTER: Song L

PROVIDER: S-EPMC6016645 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice.

Song Lu L Wang Hao H Wang Ying-Jie YJ Wang Jin-Liang JL Zhu Qing Q Wu Feng F Zhang Wei W Jiang Bo B

British journal of pharmacology 20180603 14

<h4>Background and purpose</h4>Developing novel pharmacological targets beyond the monoaminergic system is now a popular strategy for treating depression. PPARα is a nuclear receptor protein that functions as a transcription factor,-regulating gene expression. We have previously reported that both WY14643 and fenofibrate, two pharmacological agonists of PPARα, have antidepressant-like effects in mice, implying that PPARα is a potential antidepressant target.<h4>Experimental approach</h4>We first ...[more]

PMID: 29722018

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