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Antidepressant-Like and Anxiolytic-Like Effects of ZBD-2, a Novel Ligand for the Translocator Protein (18 kDa)

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Abstract

Activation of translocator protein (18 kDa) (TSPO) plays an important role to mediate rapid anxiolytic efficacy in stress response and stress-related disorders by the production of neurosteroids. However, little is known about the ligand of TSPO on the anxiety-like and depressive behaviors and the underlying mechanisms in chronic unpredictable mild stress (UCMS) mice. In the present study, a novel ligand of TSPO, ZBD-2 [N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide] synthesized by our laboratory, was used to evaluate the anxiolytic and antidepressant efficacy and to elucidate the underlying mechanisms. ZBD-2 (3 mg/kg) significantly attenuated anxiety-like and depressive behaviors in the UCMS mice, which was blocked by TSPO antagonist PK11195 (3 mg/kg). Treatment of ZBD-2 reversed the decrease in biogenic amines (norepinephrine, dopamine, and serotonin) in the brain region of hippocampus in the UCMS mice. The decreases in TSPO, GluN2B-containing N-methyl-d-aspartate (NMDA) receptors, GluA1, p-GluA1-Ser831, p-GluA1-Ser845, PSD-95, and GABAA-a2 were integrated with the increases of CaMKII and iNOS levels in the hippocampus of the UCMS mice. ZBD-2 significantly reversed the changes of above proteins. However, ZBD-2 or PK11195 treatment did not affect the levels of GluN2A-containing NMDA receptors and the total levels of GAD67. Our study provides strong evidences that ZBD-2 has a therapeutic effect on chronic stress-related disorders such as depression and anxiety through regulating the biogenic amine levels and the synaptic proteins in the hippocampus.

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Abbreviations

5-HT:

Serotonin

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

CNS:

Central nervous system

DA:

Dopamine

EPM:

Elevated plus maze

FST:

Forced swim test

GABA:

γ-Aminobutyric acid

NE:

Norepinephrine

NMDA:

N-Methyl-d-aspartate

OF:

Open field

SSRIs:

Selective serotonin reuptake inhibitors

TSPO:

Translocator protein (18 kDa)

TST:

Tail suspension test

UCMS:

Chronic unpredictable mild stress

ZBD-2:

N-Benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide

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Acknowledgments

This work was supported by the National Natural Science Foundation of China Nos. 81325022, 31470052, 2011ZXJ09106-01C, and Clinical Science and Technology Project Funding in Jiangsu Province (No. BL2012002).

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    Authors and Affiliations

    1. Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Nanjing University, Nanjing, 210002, China

      Dong-sheng Wang, Wen-bo Kang, Jian-ning Zhao & Gang Liu

    2. Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi’an, 710032, China

      Jing Han, Shuo Li, Ting Sun, Yan-yan Guo, Zhen Tian, Shui-bing Liu & Ming-gao Zhao

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    1. Dong-sheng Wang
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    Dong-sheng Wang, Jing Han and Shuo Li have contributed equally to this work.

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    Wang, Ds., Han, J., Li, S. et al. Antidepressant-Like and Anxiolytic-Like Effects of ZBD-2, a Novel Ligand for the Translocator Protein (18 kDa). Neuromol Med 19, 57–68 (2017). https://doi.org/10.1007/s12017-016-8425-7

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