Abstract

ROFLUMILAST MITIGATES MALFD-INDUCED IN RATS

Ahmad A. Alresheedi, Omnia A. Nour*, Dalia H. El-Kashef, Manar A. Nader

ABSTRACT

Metabolic dysfunction-associated steatohepatitis (MASH) occurs in a progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD), which is characterized by the accumulation of toxic lipids, oxidative stress and activation of immune cells. Chronic exposure to glucocorticoids, especially dexamethasone (DEXA), generates metabolic dysfunction and hepatocellular injury that recapitulates the histopathological features of MASH and thus offers an experimental model for its study. Objective: To explore the effect of Roflumilast, a selective phosphodiesterase-4 inhibitor, on DEXA-induced hepatic injury in Wistar rats Materials and Methods: Seventy-five male Wistar rats were divided randomly into 5 groups (A to E): Group-A served as control group that received normal saline only during fourteen days; Groups B-D serve as DEXA treatement group (DEXA is administered 24 hours before sacrificing) with differnt doses range from 0.05mg/kg/day to 1 mg/kg/day; and Group-E serves as standard drug (silymarin), after two-week-experiment period the samples are taken from all experimental animal brain tissues where provoked liver damage by DEXA in order to create a guiding model for humans Results/Observation: Histopathological analysis revealed significant hepatoprotective activity observed with Roflumilast at32. Thirty male rats were allocated to control, DEXA and Roflumilast + DEXA in a randomised manner. Biochemical analysis showed that DEXA markedly increased serum ALT, AST and GGT activities, raised hepatic malondialdehyde (MDA) levels and caused severe histopathological changes such as hepatocellular ballooning, necrosis and inflammatory infiltration. The associated elevations of serum liver enzymes, hepatic MDA and impaired histological architecture characterized by clear hepatocyte swelling were significantly inhibited with concomitant administration of Roflumilast whereby only mild to moderate hepatocellular swelling occurred. Mechanistically, Roflumilast appears to have exerted its protective effects by increasing intracellular cAMP, activating protein kinase A, inhibiting NF-κB signaling, and modulating NLRP3 inflammasome activation leading to decreased oxidative stress and inflammation. Overall, these findings identify Roflumilast as a new helpful option for mitigating steroid-associated liver injury and suggest its useful role in the treatment of MASH.

Keywords: Metabolic dysfunction-associated steatohepatitis, Dexamethasone-induced hepatotoxicity, Roflumilast, Oxidative stress.