Comparative Efficacy of Donepezil and Lamotrigine in Modulating NFκB, PPARγ, and NLRP3 Inflammasome Pathways in Experimental Colitis.

Ulcerative colitis (UC) is a persistent inflammatory bowel disorder characterized by systemic inflammation and oxidative stress. This study compared the therapeutic potential of lamotrigine and donepezil in an acetic acid (AA)-induced UC rat model. Fifty-six male Wistar rats were divided into seven groups: control, AA (4% v/v), donepezil (5 mg/kg), lamotrigine (10 mg/kg), prednisolone + AA, donepezil + AA, and lamotrigine + AA. Treatments were trans-rectally administered for 12 days before and 2 days after UC induction. Macroscopic and histological damage, oxidative stress markers (myeloperoxidase, malondialdehyde, and nitric oxide), antioxidant levels (glutathione), cytokines, and apoptotic markers were assessed. Donepezil and lamotrigine reduced AA-induced damage, decreased oxidative stress, and restored the glutathione level. Both drugs lowered proinflammatory cytokines (e.g., interleukin-1β and tumor necrosis factor-α) and increased interleukin-10. Mechanistically, they activated peroxisome proliferator-activated receptor-gamma (PPARγ), inhibited nuclear factor kappa B (NFκB), and modulated apoptosis (BAX/Bcl-2 ratio, caspase-1). Donepezil and lamotrigine show promise in UC therapy by targeting oxidative stress, inflammation, and apoptosis, supporting their potential repurposing for inflammatory bowel disease treatment. Further research is needed for clinical validation.