Miquelianin and spiraeoside from Filipendula ulmaria mitigate α-synuclein accumulation in C.elegans and reduce the expression of neuroinflammatory cytokines in human microglia

INTRODUCTION: Chronic neuroinflammation and impaired proteostasis are increasingly recognized as interconnected drivers of Parkinson's disease (PD). Due to their pleiotropic character, multicomponent herbal remedies combining anti-inflammatory and proteostatic activity may counteract these disease-promoting processes. This study investigated a hydroethanolic extract of Filipendula ulmaria (FE) for its ability to modulate neuroinflammation, proteostasis, and aging-associated mechanisms relevant to PD. METHODS: The effects of FE on lifespan and health span were assessed in wild-type and on α-syn::YFP fluorescence, survival and thermoresistance in transgenic NL5901 Caenorhabditis elegans. FE was fractionated by flash chromatography, and bioactivity was assigned to individual constituents using LC-MS dereplication and a ¹H NMR-based biochemometric approach. Identified constituents were further examined for their capacity to reduce α-syn::YFP fluorescence and enhance thermotolerance in NL5901. To assess their relevance in neuroinflammation, all samples were examined in LPS-stimulated human microglial HMC3 cells for their effects on pro-inflammatory gene expression. RESULTS: FE extended lifespan, improved health span and reduced α-syn::YFP fluorescence in NL5901 by up to 25% at 200 μg/mL. In HMC3 cells, FE significantly downregulated IL-1β, IL-6, and MCP-1 expression at 100 μg/mL without cytotoxicity. Biochemometric and LC-MS analyses identified the flavonoid glycosides spiraeoside and miquelianin as key constituents, reducing the α-syn::YFP fluorescence by 32% and 35% at 200 μg/mL, respectively, while simultaneously increasing thermotolerance in NL5901 and suppressing pro-inflammatory cytokine expression in microglia. CONCLUSIONS: FE represents a promising source of neuroprotective agents targeting both neuroinflammation and proteostasis, supporting spiraeoside and miquelianin as hit candidates for preventive strategies against early neurodegenerative mechanisms.