Identification of Prolyl endopeptidase as a novel anti-depression target of Genipin-1-b-D-gentiobioside in brain tissues

Abstract

Depression is a serious mood disease that causes global impairment and mortality. In traditional Chinese medicine, herb compounds decoction with Gardenia jasminoides (GJ) as the main ingredient to treat depression has a history of hundreds of years in East Asian countries. Although the antidepressant effect of GJ has been well established, the antidepressant effect and target of its main component Genipin-1-b-D-gentiobioside (GG) remain unknown. In the present study, using a mouse chronic unpredictable mild stress (CUMS) model, we first examined the antidepressant effectiveness of GG. Next, we identified potential target proteins of GG in brain tissue using liquid chromatography-mass spectrometry (LC-MS)-based drug affinity responsive target stability (DARTS), and we intersected these targets with databases of depression targets to obtain GG's antidepressant protein targets. Finally, Prolyl endopeptidase (PREP) was initially confirmed as a potential antidepressant target of GG in brain tissue by molecular docking and biolayer interferometry (BLI). The results showed that GG administration reduced depression-like behavior in CUMS mice and increased the mRNA and protein expression levels of BDNF in the hippocampus of CUMS mice. Subsequently, there was an overlapping protein target between LC-MS-based DARTS and the databases of depression targets. Finally, molecular docking and BLI kinetic analysis indicated that GG specifically bound to PREP. According to the aforementioned research, PREP is a potential antidepressant protein target of GG in the brain. This conclusion could offer a chemical and biological foundation for future research on treating depression by focusing on PREP.