2. Academic Validation
  3. The impact and mechanisms of YL-IPA08, a potent ligand for the translocator protein (18 kDa) on protection against LPS-induced depression and cognitive dysfunction in rodents

The impact and mechanisms of YL-IPA08, a potent ligand for the translocator protein (18 kDa) on protection against LPS-induced depression and cognitive dysfunction in rodents

  • Metab Brain Dis. 2025 Mar 6;40(3):137. doi: 10.1007/s11011-025-01565-2.
Lin-Yu Cui 1 2 3,  Jing-Yao Duan 1,  Jiao-Zhao Yan 4,  Jing-Ya Wang 5,  Peng Ren 6,  Li-Ming Zhang 1,  Wen-Zhi Guo 7,  Wei Dai 8,  Yun-Feng Li 9
Affiliations

Affiliations

  • 1 Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 2 Department of Anesthesiology, Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Capital Medical University, Beijing, 100013, China.
  • 3 College of Anaesthesia, Shanxi Medical University, 86 Xinjiannan Road, Taiyuan, 030001, Shanxi, China.
  • 4 Lingang Laboratory, ShanghaiTech University, 555 Qiangye Road, Shanghai, 201210, China.
  • 5 Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
  • 6 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 7 Department of Anesthesiology, Seventh Medical Center of PLA General Hospital, 5 Nanmencang Road, Dongcheng, Beijing, 100070, China. elite2005gg@163.com.
  • 8 Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. twotou3@126.com.
  • 9 Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. lyf619@aliyun.com.
PMID: 40047959 DOI: 10.1007/s11011-025-01565-2
Abstract

Translocator protein (18 kDa) (TSPO) has been implicated in the development of depression and cognitive dysfunction. This study aimed to investigate the anti-depression/anti-anxiety and cognitive enhancing impacts and potential mechanisms of TSPO ligand YL-IPA08 in lipopolysaccharide (LPS)-induced inflammatory model. The effects of YL-IPA08 in LPS induced mice were identified by behavioral tests, and the target of YL-IPA08 was validated using the TSPO antagonist PK11195. The microglia in PFC were analyzed by immunofluorescence, and the inflammatory cytokines (IL-6, IL-1β and TNF-α) and anti-inflammatory factors (IL-4, IL-10, TGF-β1) in PFC was detected by ELISA or WB. Effect of TGF-β1 inhibitor Repsox on the actions of YL-IPA08 in LPS-treated mice was further verified. We found that YL-IPA08 administration ameliorated LPS-induced depression/anxiety-like behaviors and cognitive impairment, which were blocked by PK11195. YL-IPA08 reversed the increased number and inflammatory morphological changes of microglia in PFC of LPS mice by targeting TSPO. YL-IPA08 reversed the increased inflammatory cytokines (IL-6, IL-1β and TNF-α) and decreased anti-inflammatory factors (IL-4, IL-10) in the PFC of LPS mice by TSPO activation. In addition, YL-IPA08 elevated the suppressed levels of TGF-β1 and SMAD3 (member of TGF-β1 pathway) in PFC of LPS mice by TSPO activation. TGF-β1 inhibitor Repsox blocked the anti-depression/anxiety and cognition enhancing effects of YL-IPA08 in LPS mice. Our data implicated that central inflammation regulation and TSPO-TGF-β1/Smad pathway activation contributed to the anti-depressant/anxiety and cognitive promoting impacts of YL-IPA08.

Keywords

Anxiety; Cognitive dysfunction; Depression; Transforming growth factor-β1 (TGF-β1); Translocator protein (18 kDa).

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