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Anxiolytic and Anti-depressive Like Effects of Translocator Protein (18 kDa) Ligand YL-IPA08 in a Rat Model of Postpartum Depression

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Abstract

Translocator protein 18 kDa (TSPO) is mainly distributed in the outer mitochondrial membrane of steroid-synthesizing cells in the central and peripheral nervous systems. It mediates cholesterol transportation across the phospholipid membrane, which is a prerequisite for neurosteroid synthesis. Though the ligand of TSPO has clinical value in the diagnosis and treatment of neuropsychiatric disorders, the pharmacological study of TSPO for anti-postpartum depression has not been reported. In this study, the classical method of reproductive hormone withdrawal was used to construct a rat model of postpartum depression (PPD). The effect of YL-IPA08, a new ligand compound of TSPO, on PPD was evaluated using multiple behavioral tests at progressive time points. Additionally, real-time quantitative PCR, Western-blotting and an enzyme linked immunosorbent assay were conducted to elucidate the potential molecular mechanism of such effect. We report that the levels of TSPO and neurosteroids in the hippocampus and prefrontal cortex were significantly decreased in PPD rats compared to healthy controls. After 3 weeks of drug treatment, the levels of TSPO and neurosteroids in the hippocampus of PPD rats were increased, and anxiety and depressive like behaviors were alleviated. Meanwhile, compared with sertraline treatment, a positive control in this study, YL-IPA08 treatment had a shorter onset time. Our results suggest that the anxiolytic and anti-depressive activity of YL-IPA08 has significant value in the treatment of PPD and that TSPO may be a potential new target for the treatment of PPD.

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Abbreviations

TSPO:

Translocator protein (18 kDa)

PPD:

Postpartum depression

HPA axis:

Hypothalamic-pituitary-adrenal axis

SSRIs:

Selective serotonin reuptake inhibitors

OVX:

Ovariectomy

HSP:

Hormone simulated pregnancy

E:

Estradiol

P:

Progesterone

Ser:

Sertraline

OFT:

Open field test

EPM:

Elevated plus maze

SPT:

Sucrose preference test

FST:

Forced swimming test

ACTH:

Adrenocorticotropic

CORT:

Corticosterone

CRH:

Corticotropin releasing hormone

GABA:

G-aminobutyric acid

CBR:

Central benzodiazepine receptor

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Funding

This study was supported by the National Natural Science Foundation of China (No. 817010172), Beijing Municipal Science & Technology Comission (No. Z181100001718002) and PLA Youth Training Project for Medical Science (16QNP002).

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Author notes

  1. Peng Ren, Li Ma and Jing-Ya Wang have contributed equally.

Authors and Affiliations

  1. Department of Anesthesiology, Seventh Medical Center of PLA General Hospital, 5 Nanmencang Road, Dongcheng, Beijing, 100070, China

    Peng Ren, Li Ma, Hang Guo, Li Sun, Ming-Long Gao, Yong-Zhe Liu, Ya-Qun Ma & Wen-Zhi Guo

  2. Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China

    Peng Ren & Yun-Feng Li

  3. Department of Physiology, Guizhou Medical University, Guiyang, 550025, China

    Jing-Ya Wang

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  1. Peng Ren
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Contributions

PR and LM designed the research, data analysis, and wrote the manuscript. J-YW, HG and LS performed the behavioral tests. M-LG and Y-ZL participated in the molecular and cellular mechanisms of YL-IPA08. Y-QM performed the chemical synthesis of YL-IPA08. Y-FL and W-ZG contributed to the research design, data analysis, and manuscript revision. All authors reviewed the content and approved the final version of the manuscript.

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Correspondence to Yun-Feng Li or Wen-Zhi Guo.

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Ren, P., Ma, L., Wang, JY. et al. Anxiolytic and Anti-depressive Like Effects of Translocator Protein (18 kDa) Ligand YL-IPA08 in a Rat Model of Postpartum Depression. Neurochem Res 45, 1746–1757 (2020). https://doi.org/10.1007/s11064-020-03036-9

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  • DOI: https://doi.org/10.1007/s11064-020-03036-9

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