Trimetazidine Attenuates Ulcerative Colitis-Linked Extrapyramidal Dysfunction by Mediated Dectin-1/LRRK2/α-Synuclein Autophagy Axis

Abstract

Chronic relapsing colonic inflammation, specifically ulcerative colitis (UC), causes persistent mucosal injury and disrupts the gut-brain axis. This disruption leads to basal ganglia neuroinflammation and ultimately extrapyramidal motor dysfunction. Dysregulation of the Dectin 1/leucine-rich repeat kinase 2 (LRRK2)/α-synuclein (αSyn) signaling exacerbates inflammation. This study investigated whether modulation of this pathway affects UC progression and is associated with motor deficits using trimetazidine (TMZ) treatment in a Bagg albino c (BALB/c) mice model. Furthermore, we examined the role of this pathway through molecular docking followed by molecular dynamics simulations to evaluate the plausibility of TMZ interactions with Dectin-1, LRRK2, and α-syn proteins. Our results indicate that TMZ improved behavioral changes and also significantly reduced serum interferone-γ (IFN-γ) and NF-kB levels, along with decreased Dectin-1, LRRK2, and αSyn expression. TMZ also mitigated colonic inflammation, as shown by reducing fecal calprotectin and fecal occult blood, supported by histological examinations. Furthermore, TMZ restored autophagic flux by reducing P62 accumulation and enhancing LAMP2 expression. Molecular docking and dynamics confirmed TMZ binding to Dectin-1, LRRK2, and αSyn, through hydrophobic and hydrophilic interactions. These findings suggest a potential molecular basis for the observed associations between the Dectin-1/LRRK2/α-synuclein axis and UC-related motor dysfunction, warranting further experimental validation, establishing TMZ's therapeutic potential for managing colonic inflammation and associated neurological manifestations.