Jiang Bo, Huang Chao, Zhu Qing, Tong Li-Juan, Zhang Wei
Department of Pharmacology, Nantong University Pharmacy College, 19 Qixiu Road, Nantong, Jiangsu, China, 226001.
Psychopharmacology (Berl). 2015 May;232(9):1629-42. doi: 10.1007/s00213-014-3802-0. Epub 2014 Nov 13.
Current anti-depressants are clinically effective only after several weeks of administration and always produce side effects.
WY14643 is a selective agonist of peroxisome proliferator-activated receptor-α with neuroprotective and neurotrophic effects. Here, we investigated the anti-depressant effects of WY14643 in mice models of depression.
We assessed the anti-depressant effects of WY14643 in the forced swim test (FST), tail suspension test (TST) and chronic social defeat stress (CSDS) model. Western blotting and immunohistochemistry studies were further performed to detect the effects of WY14643 on the brain-derived neurotrophic factor (BDNF) signaling pathway and hippocampal neurogenesis. The anti-BDNF antibody, BDNF signaling inhibitor, and tryptophan hydroxylase inhibitor were also used to explore the anti-depressant mechanisms of WY14643.
WY14643 exhibited robust anti-depressant effects in the FST and TST and also protected against the CSDS stress in mice models. Moreover, WY14643 reversed the stress-induced elevation of corticosterone, deficiency of BDNF signaling pathway, and hippocampal neurogenesis. Blockade of BDNF signaling cascade, not the monoaminergic system, abolished all the anti-depressant effects of WY14643.
These data provide the first evidence that WY14643 exerts anti-depressant-like activity through promoting the BDNF signaling pathway.
目前的抗抑郁药物在给药几周后才具有临床疗效，并且总会产生副作用。
WY14643是过氧化物酶体增殖物激活受体-α的选择性激动剂，具有神经保护和神经营养作用。在此，我们研究了WY14643在抑郁症小鼠模型中的抗抑郁作用。
我们在强迫游泳试验（FST）、悬尾试验（TST）和慢性社会挫败应激（CSDS）模型中评估了WY14643的抗抑郁作用。进一步进行蛋白质免疫印迹和免疫组织化学研究，以检测WY14643对脑源性神经营养因子（BDNF）信号通路和海马神经发生的影响。还使用抗BDNF抗体、BDNF信号抑制剂和色氨酸羟化酶抑制剂来探索WY14643的抗抑郁机制。
WY14643在FST和TST中表现出强大的抗抑郁作用，并且在小鼠模型中还能抵御CSDS应激。此外，WY14643逆转了应激诱导的皮质酮升高、BDNF信号通路缺陷和海马神经发生。阻断BDNF信号级联反应而非单胺能系统，消除了WY14643的所有抗抑郁作用。
这些数据首次证明WY14643通过促进BDNF信号通路发挥抗抑郁样活性。
