Ponicidin ameliorates Alzheimer's disease through dual inhibition of RIPK1-mediated neuroinflammation and necroptosis.
Hu H, Cheng Q, Li D, Li Y, Li X
Summary
PubMedA plant-derived compound called ponicidin, isolated from Rabdosia rubescens, shows promise as a potential Alzheimer's disease treatment by binding to and inhibiting a key inflammation-triggering protein (RIPK1) in the brain. Testing in cells and mice suggests it could reduce neuroinflammation and neuronal death.
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Key Findings
Ponicidin binds RIPK1 with high affinity, confirmed by bio-layer interferometry and DARTS assays
In microglial and neuronal cells, ponicidin reduced inflammatory markers and necroptosis (programmed cell death)
Therapeutic efficacy demonstrated in 5×FAD transgenic mouse model of Alzheimer's disease through behavioral and biochemical improvements
Original Abstract
Ponicidin (Pon), a diterpenoid isolated from Rabdosia rubescens, exhibits a broad range of pharmacological activities, including anti-inflammatory effects. However, its therapeutic potential in Alzheimer's disease (AD), particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains underexplored. This study aims to investigate the mechanism through which Pon targets RIPK1 to alleviate AD pathogenesis. The interaction between Pon and RIPK1 was confirmed using bio-layer interferometry (BLI) and drug affinity responsive target stability (DARTS) assays. In vitro, the effects of Pon on inflammatory responses and necroptosis were evaluated in BV2 microglial cells (BV2 cells) and HT22 hippocampal neuronal cells (HT22 cells) using Enzyme-linked immunosorbent assay (ELISA), Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting (WB), and flow cytometry. In vivo, Pon's therapeutic efficacy was assessed in the 5 × FAD transgenic mouse model of AD through behavioral tests, histological analysis, and biochemical assays. Pon was found to bind RIPK1 with high affinity (K
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