WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway.
BACKGROUND
Current anti-depressants are clinically effective only after several weeks of administration and always produce side effects.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These data provide the first evidence that WY14643 exerts anti-depressant-like activity through promoting the BDNF signaling pathway.
Department of Pharmacology, Nantong University Pharmacy College, 19 Qixiu Road, Nantong, Jiangsu, China, 226001.
Bo
B
Jiang
Chao
C
Huang
Qing
Q
Zhu
Li-Juan
LJ
Tong
Wei
W
Zhang
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003345:Corticosterone / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D003866:Depressive Disorder / Q000378:metabolism; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists; D020025:Peroxisome Proliferators / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism; D013550:Swimming
D019208:Brain-Derived Neurotrophic Factor; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C006253:pirinixic acid; D003345:Corticosterone