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A New Perspective on Ameliorating Depression-Like Behaviors: Suppressing Neuroinflammation by Upregulating PGC-1α

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Abstract

Inflammation plays an important role in depression pathology, making it a promising target for ameliorating depression-like behaviors. The peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional coactivator being able to constrain inflammatory events through NF-κB signaling. However, the role of PGC-1α in depression is not yet clear. This study was designed to investigate the role of PGC-1α in depression and explore the underlying mechanisms. Mice modeled with chronic unpredictable mild stimulation (CUMS) were explored for the relationship between depression-like behaviors and PGC-1α. Baicalin was used to evaluate the effect regulating PGC-1α. Furthermore, the anti-neuroinflammatory effect of baicalin was investigated both in BV2-SH-SY5Y co-culture system and in mice by LPS challenge. The role of PGC-1α in neuroinflammation was explored in cell co-culture systems under gene silencing conditions targeting NF-κB signaling. We found that the expression of PGC-1α was inhibited in the hippocampus of mice exposed to CUMS or LPS, while baicalin could increase the expression of PGC-1α and alleviate the depression-like behaviors. Furthermore, baicalin attenuated neuroinflammation in the hippocampus of mice and BV2-SH-SY5Y co-culture system by LPS challenge via regulating NF-κB signaling; however, knockdown of the PGC-1α could reverse the effect of baicalin on neuroinflammation and NF-κB signaling. Our results revealed a vital role for PGC-1α in attenuating neuroinflammation in depression, indicating that PGC-1α might be a therapeutic target for depression.

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Abbreviations

CUMS:

Chronic unpredictable mild stimulation

BA:

Baicalin

CNS:

Central nervous system

LPS:

Lipopolysaccharide

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha

NF-κB:

Transcription factor nuclear factor kappa light-chain-enhancer of activated B cells

IL-1β:

Interleukin-1 beta

TNF-α:

Tumor necrosis factor alpha

IL-6:

Interleukin-6

PBS:

Phosphate-buffered saline

SPT:

Sucrose preference test

TST:

Tail suspension test

FST:

Forced swimming test

MOD:

Mean optical density

T2DM:

Type 2 diabetes mellitus

NC:

Negative control

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Acknowledgments

The authors would like to express their gratitude to all those who contributed to the thesis. The authors acknowledge the help of a supervisor, Professor Shiping Ma, who has offered suggestions in academic studies. The authors also have a special debt of gratitude to all the teachers in Department of Chinese Medicine Pharmacology of China Pharmaceutical University.

Funding

This work is funded by the National Natural Science Foundation of China (No. 81703735, No. 81573701) and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 639, Longmian Road, Nanjing, 211198, People’s Republic of China

    Xinxin Fu, Jie Jiao, Tingting Qin, Jiayu Yu, Qiang Fu, Xueyang Deng, Shiping Ma & Zhanqiang Ma

  2. Qinba Traditional Chinese Medicine Resources Research and Development Center, AnKang University, AnKang, 725000, People’s Republic of China

    Shiping Ma

  3. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 211100, People’s Republic of China

    Zhanqiang Ma

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  1. Xinxin Fu
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  2. Jie Jiao
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  4. Jiayu Yu
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Correspondence to Shiping Ma or Zhanqiang Ma.

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Highlights

CUMS downregulated the expression of PGC-1α in hippocampus of mice.

Baicalin upregulated the expression of PGC-1α in SH-SY5Y cells.

The amelioration of baicalin for depression-like behaviors in LPS-induced mice is related to the attenuation of neuroinflammation.

PGC-1α/NF-κB signaling pathway involves in the anti-neuroinflammatory effect of baicalin.

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Fu, X., Jiao, J., Qin, T. et al. A New Perspective on Ameliorating Depression-Like Behaviors: Suppressing Neuroinflammation by Upregulating PGC-1α. Neurotox Res 39, 872–885 (2021). https://doi.org/10.1007/s12640-020-00292-z

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  • DOI: https://doi.org/10.1007/s12640-020-00292-z

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