期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 175, 期 14, 页码 2968-2987出版社
WILEY
DOI: 10.1111/bph.14346
关键词
-
资金
- National Natural Science Foundation of China [81401116, 81670243]
- Natural Science Foundation of Jiangsu Province [BK20161284]
- graduate student scientific research innovation projects of Jiangsu Province [KYCX17-1929]
Background and PurposeDeveloping 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 ApproachWe 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 ResultsChronic 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 ImplicationsHippocampal PPAR is a potential novel antidepressant target that mediates the antidepressant actions of fluoxetine in mice.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据