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.

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.