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TPPU, a sEH Inhibitor, Attenuates Corticosterone-Induced PC12 Cell Injury by Modulation of BDNF-TrkB Pathway

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Abstract

High level of corticosterone (CORT) is toxic to neurons and plays an important role in depression-like behavior and chronic stress. Our previous study showed that TPPU, a soluble epoxide hydrolase (sEH) inhibitor (sEHI), induces an antidepressant effect in animal models. However, the underlying mechanism is not clear. In this study, we investigated the protective effect of TPPU on PC12 cells against CORT-induced cytotoxicity and its underlying mechanism. We found that TPPU and the sEH substrate epoxyeicosatrienoic acids (EETs) protected PC12 cells from the CORT-induced injury by increasing cell viability and inhibiting apoptosis. Furthermore, TPPU and EETs also blocked the CORT-mediated downregulation of BDNF. Blocking the BDNF-TrkB pathway by the TrkB inhibitor K252a abolished the protective effect of TPPU. Taken together, our results suggest that sEHI could protect PC12 cells against the CORT-induced cytotoxicity via the BDNF-TrkB signaling pathway.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

CORT:

Corticosterone

DHET:

Dihydroxyeicosatrienoic acids

EET:

Epoxyeicosatrienoic acids

HPA:

Hypothalamic-pituitary-adrenal

PEG 400:

Polyethylene glycol 400

SEH:

Soluble epoxide hydrolase

SEHI:

Soluble epoxide hydrolase inhibitor

TPPU:

1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea or N-[1-(1-oxopropyl)-4-piperidinyl]-N′-[4-(trifluoromethoxy)phenyl]-urea

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Acknowledgments

We would like to thank all the members of our research team for their scientific support and helpful advice.

Funding

This work is partly supported by the Doctor Foundation of Luohe Medical College (grant numbers 2014-DF-004, to Dr Wu), and Plan subjects on science and technology of Henan province (grant number 172102310605 to Dr Wu).

Author information

Authors and Affiliations

  1. Department of Pathophysiology, Luohe Medical College, Luohe, China

    Qiong Wu

  2. Department of Medicine, Luohe Medical College, Luohe, China

    Jingfang Song & Danxin Meng

  3. Department of Physiology, Luohe Medical College, Luohe, 462000, China

    Quanzhong Chang

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  1. Qiong Wu
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  2. Jingfang Song
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  3. Danxin Meng
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  4. Quanzhong Chang
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Contributions

Quanzhong Chang and Qiong Wu contributed to the conception and design of the study, acquisition, analysis and interpretation of data, and manuscript drafting. Danxin Meng and Jingfang Song contributed to Hoechst analysis, Western blotting, CCK-8 analysis, and cell culture. All authors critically revised the manuscript and approved the final manuscript.

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Correspondence to Quanzhong Chang.

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Wu, Q., Song, J., Meng, D. et al. TPPU, a sEH Inhibitor, Attenuates Corticosterone-Induced PC12 Cell Injury by Modulation of BDNF-TrkB Pathway. J Mol Neurosci 67, 364–372 (2019). https://doi.org/10.1007/s12031-018-1230-z

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