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WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway

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Abstract

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-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.

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Abbreviations

AKT:

Protein kinase B

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

CMS:

Chronic mild stress

CREB:

cAMP response element-binding protein

CSDS:

Chronic social defeat stress

DCX:

Doublecortin

DG:

Dendrite gyrus

ERK:

Extracellular regulated protein kinase

FST:

Forced swimming test

mPFC:

Medial prefrontal cortex

PCPA:

p-Chlorophenylalanine methyl ester

PPAR-α:

Peroxisome proliferator-activated receptor-α

5-HT:

Serotonin

SSRIs:

Selective serotonin reuptake inhibitors

TMP:

Tetramethylpyrazine

TrkB:

Tyrosine kinase B

TST:

Tail suspension test

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Acknowledgments

This work was supported by the National Natural Science Foundation of China to Professor Wei Zhang (No. 81070197) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Author contributions

Bo Jiang, Chao Huang, and Wei Zhang conceived and designed the study. Bo Jiang, Chao Huang, and Li-Juan Tong performed the experiments. Bo Jiang and Wei Zhang wrote the manuscript. Bo Jiang, Qing Zhu, and Wei Zhang reviewed and edited the manuscript. All authors read and approved the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Nantong University Pharmacy College, 19 Qixiu Road, Nantong, Jiangsu, China, 226001

    Bo Jiang, Chao Huang, Qing Zhu, Li-Juan Tong & Wei Zhang

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  1. Bo Jiang
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  2. Chao Huang
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  3. Qing Zhu
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  4. Li-Juan Tong
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  5. Wei Zhang
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Corresponding author

Correspondence to Wei Zhang.

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Jiang, B., Huang, C., Zhu, Q. et al. WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway. Psychopharmacology 232, 1629–1642 (2015). https://doi.org/10.1007/s00213-014-3802-0

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  • DOI: https://doi.org/10.1007/s00213-014-3802-0

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