Hyperibone J exerts antidepressant effects by targeting ADK to inhibit microglial P2X7R/TLR4-mediated neuroinflammation

作者：Ting Li, Yawei Li, Jinhu Chen, Miao-Miao Nan, Xin Zhou, Lifang Yang, Wen‐Jun Xu, Chao Zhang, Lingyi Kong · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.07.015 · 被引用次数：49 · 研究领域：Tryptophan and brain disorders、Neuroinflammation and Neurodegeneration Mechanisms、Natural Compound Pharmacology Studies

INTRODUCTION: The antidepressant properties of Hypericum species are known. Hyperibone J, a principal component found in the flowers of Hypericum bellum, exhibited in vitro anti-inflammatory effects. However, the antidepressant effects and mechanisms of Hyperibone J remain to be elucidated. Adenosine kinase (ADK) is upregulated in epilepsy and depression and has been implicated in promoting neuroinflammation. OBJECTIVES: This study aimed to explore the impact of Hyperibone J on neuroinflammation-mediated depression and the mechanism underlying this impact. METHODS: This study employed acute and chronic in vivo depression models and an in vitro LPS-induced depression model using BV-2 microglia. The in vivo antidepressant efficacy of Hyperibone J was assessed through behavioral assays. Techniques such as RNA-seq, western blot, qPCR and ELISA were utilized to elucidate the direct target and mechanism of action of Hyperibone J. RESULTS: Compared with the model group, depression-like behaviors were significantly alleviated in the Hyperibone J group. Furthermore, Hyperibone J mitigated hippocampal neuroinflammation and neuronal damage. RNA-seq suggested that Hyperibone J predominantly influenced inflammation-related pathways. In vitro experiments revealed that Hyperibone J reversed the LPS-induced overexpression and release of inflammatory factors. Network pharmacology and various molecular biology experiments revealed that the potential binding of Hyperibone J at the ASN-312 site ...