Trigonelline Alleviates Neuroinflammation in AAV‐SynA53T Parkinson's Disease Model Mice: Involvement of PI3K/AKT–NF‐κB Signaling and Gut Microbial‐Metabolic Remodeling

ABSTRACT Trigonelline (TG), a major alkaloid in fenugreek seed and coffee, has anti‐inflammatory and antioxidant activities. We investigated whether TG ameliorates Parkinson's disease (PD)‐related synucleinopathy and whether these effects are associated with inflammatory signaling and gut microbial–metabolic alterations. Two‐sample Mendelian randomization (MR) was used to examine the relationship between genetically predicted circulating TG and α‐synuclein. In vivo, AAV‐SynA53T C57BL/6J mice received oral TG (5 mg/kg/day) for 30 days, followed by assessment of motor behavior, pSer129‐α‐syn pathology, dopaminergic markers, inflammatory readouts, intestinal barrier proteins, 16S rRNA profiles, and colon‐content metabolomics. MR supported a potential protective association between genetically predicted serum TG and reduced α‐synuclein. TG improved motor performance, reduced midbrain pSer129‐α‐syn signals, preserved dopaminergic markers, and attenuated inflammatory responses, accompanied by modulation of PI3K/AKT and NF‐κB signaling. TG also improved intestinal barrier‐associated features and altered the gut microbiota and metabolomic profile. A metabolomic feature tentatively annotated as Ganolucidic acid B was increased following TG treatment and correlated with several taxa enriched in the TG group; conditional network pharmacology suggested that its predicted targets were enriched in PD‐relevant inflammatory and PI3K–AKT‐related pathways. Overall, TG may ameliorate synucleinopathy‐associated phenotypes in AAV‐SynA53T mice, accompanied by attenuated inflammation and gut microbiota–metabolism remodeling. Further targeted metabolomic validation and causal intervention studies are warranted to clarify the contributions of specific metabolites and gut‐associated mechanisms.