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

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.