Uro-Protective Role of Lacosamide Against Cyclophosphamide-Induced Cystitis via Notch1/NICD/NF-κB Pathway: Network...

Cystitis, characterized by bladder inflammation, represents a significant clinical challenge in cancer chemotherapy, particularly with cyclophosphamide administration. Drug repurposing, which involves applying existing pharmaceuticals to new therapeutic areas, offers increased efficiency, reduced costs, and lower risks. This study investigated the molecular mechanisms underlying the uro-protective application of lacosamide, an FDA-approved antiepileptic drug, against cyclophosphamide-induced cystitis via suppression of the Notch-1/NICD/NF-κB inflammatory pathway. Network pharmacology analysis identified key molecular targets and pathways involved in lacosamide's protective mechanisms, followed by molecular docking studies that validated the binding interactions between lacosamide and target proteins. In vivo validation was performed using adult male Wistar rats with cyclophosphamide-induced cystitis. Network analysis revealed Notch-1 as a primary target for lacosamide's uroprotective action. Experimental validation demonstrated that lacosamide pretreatment significantly attenuated oxidative bladder injury by decreasing malondialdehyde levels while enhancing superoxide dismutase activity and reduced glutathione content. Lacosamide substantially downregulated pro-inflammatory mediators including TNF-α, IL-1β, and IL-6 via NF-κB suppression. Additionally, lacosamide suppressed the Notch-1/NICD/NF-κB pathway, elevated Bcl-2 expression, and reduced Bax protein and caspase-3 levels. Histopathological examination corroborated biochemical findings. Lacosamide demonstrates significant uro-protective efficacy through coordinated anti-inflammatory, antioxidant, and anti-apoptotic mechanisms through modulation of Notch-1/NICD/NF-κB pathway.