WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway
WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway
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DOI：
10.1007/s00213-014-3802-0
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发表时间：
2015-05-01
影响因子：
3.4
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
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作者：
Jiang, Bo;Huang, Chao;Zhang, Wei
目前的抗抑郁药在临床上仅在给药数周后才有效，并且总是产生副作用。WY 14643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。本研究采用强迫游泳实验（FST）、悬尾实验（TST）和慢性社交失败应激（CSDS）模型，观察了WY 14643对抑郁症小鼠的抗抑郁作用。进一步采用免疫印迹和免疫组织化学方法检测WY 14643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。抗BDNF抗体、BDNF信号通路抑制剂、色氨酸羟化酶抑制剂等实验方法，探讨了WY 14643的抗脑缺血机制。WY 14643在小鼠的FST和TST中表现出较强的抗脑缺血作用，对CSDS应激也有保护作用。此外，WY 14643逆转应激诱导的皮质酮升高，BDNF信号通路的缺陷和海马神经发生。WY 14643的抗凋亡作用是通过阻断BDNF信号通路而不是单胺能系统而被阻断的。这些结果首次证明WY 14643通过促进BDNF信号通路发挥抗凋亡作用。
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-alpha 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.