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

Area of Science:

• Neuroimmunology
• Gastroenterology
• Pharmacology

Background:

• Ulcerative colitis (UC) causes gut-brain axis disruption, leading to neuroinflammation and motor deficits.
• The Dectin-1/leucine-rich repeat kinase 2 (LRRK2)/α-synuclein (αSyn) signaling pathway is implicated in exacerbating UC inflammation.
• Existing research highlights a potential link between this pathway and UC-related motor dysfunction.

Purpose of the Study:

• To investigate the therapeutic effect of trimetazidine (TMZ) on UC progression and associated motor deficits in a mouse model.
• To explore the modulation of the Dectin-1/LRRK2/αSyn pathway by TMZ.
• To evaluate the binding interactions of TMZ with Dectin-1, LRRK2, and αSyn using computational methods.

Main Methods:

• Utilized a BALB/c mouse model of ulcerative colitis treated with trimetazidine (TMZ).
• Assessed behavioral changes, serum inflammatory markers (IFN-γ, NF-kB), colonic inflammation (fecal calprotectin, occult blood), and protein expression (Dectin-1, LRRK2, αSyn, P62, LAMP2).
• Employed molecular docking and molecular dynamics simulations to analyze TMZ-protein interactions.

Main Results:

• TMZ treatment significantly improved motor behavior and reduced colonic inflammation markers in UC mice.
• TMZ decreased serum IFN-γ and NF-kB levels and downregulated Dectin-1, LRRK2, and αSyn expression.
• The drug restored autophagic flux and computational analyses confirmed TMZ binding to Dectin-1, LRRK2, and αSyn.

Conclusions:

• The Dectin-1/LRRK2/αSyn pathway is a potential molecular link between UC and motor dysfunction.
• TMZ demonstrates therapeutic potential in managing colonic inflammation and associated neurological manifestations.
• Further validation is warranted to establish TMZ's role in treating UC-related neurological deficits.