PMID- 25388293 OWN - NLM STAT- MEDLINE DCOM- 20151120 LR - 20181113 IS - 1432-2072 (Electronic) IS - 0033-3158 (Linking) VI - 232 IP - 9 DP - 2015 May TI - WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway. PG - 1629-42 LID - 10.1007/s00213-014-3802-0 [doi] AB - RATIONALE: Current anti-depressants are clinically effective only after several weeks of administration and always produce side effects. OBJECTIVES: 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. 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. FAU - Jiang, Bo AU - Jiang B AD - Department of Pharmacology, Nantong University Pharmacy College, 19 Qixiu Road, Nantong, Jiangsu, China, 226001. FAU - Huang, Chao AU - Huang C FAU - Zhu, Qing AU - Zhu Q FAU - Tong, Li-Juan AU - Tong LJ FAU - Zhang, Wei AU - Zhang W LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141113 PL - Germany TA - Psychopharmacology (Berl) JT - Psychopharmacology JID - 7608025 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (PPAR alpha) RN - 0 (Peroxisome Proliferators) RN - 0 (Pyrimidines) RN - 86C4MRT55A (pirinixic acid) RN - W980KJ009P (Corticosterone) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Corticosterone/metabolism MH - Depression/*drug therapy/metabolism MH - Depressive Disorder/metabolism MH - Hindlimb Suspension MH - Hippocampus/drug effects/metabolism MH - Male MH - Mice MH - Neurogenesis/drug effects MH - PPAR alpha/agonists MH - Peroxisome Proliferators/pharmacology/*therapeutic use MH - Pyrimidines/pharmacology/*therapeutic use MH - Signal Transduction/*drug effects MH - Stress, Psychological/*drug therapy/metabolism MH - Swimming EDAT- 2014/11/13 06:00 MHDA- 2015/12/15 06:00 CRDT- 2014/11/13 06:00 PHST- 2014/06/23 00:00 [received] PHST- 2014/10/27 00:00 [accepted] PHST- 2014/11/13 06:00 [entrez] PHST- 2014/11/13 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] AID - 10.1007/s00213-014-3802-0 [doi] PST - ppublish SO - Psychopharmacology (Berl). 2015 May;232(9):1629-42. doi: 10.1007/s00213-014-3802-0. Epub 2014 Nov 13.