Introduction. The identification of novel drugs for treatment of inflammatory bowel diseases (IBDs) represents an area of active investigation. A promising beneficial effect of acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), has been observed in a mouse model of acute and relapsing TNBS-induced colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications.
Aims: to evaluate the effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories and endowed with an improved pharmacodynamic profile) in an experimental model of colitis in rats.
Methods. The effects of FA-5, ACA (standard AMPK activator) or dexamethasone (DEX, standard anti-inflammatory comparator) were tested in male rats (n=6 for each group) with colitis induced by intrarectal administration of 2,4-dinitrobenzenesulfonic acid (DNBS, 15 mg/rat), to assess systemic [body and spleen weight] and tissue inflammatory parameters [colon length, macroscopic damage, tumor necrosis factor (TNF) and malondialdehyde (MDA) levels]. Animals received FA-5 (1, 3, 10 or 30 mg/kg/day), ACA (1, 3, 10 or 30 mg/kg/day), DEX (0.1 mg/kg/day) or vehicle intraperitoneally for 6 days, starting 1 day before DNBS administration. Animals underwent subsequent experimental procedures 6 days after DNBS injection
Results. Colitis was associated with a decreased body weight (-40.6% vs vehicle) and increased spleen weight (+38.6% vs vehicle). Macroscopic damage score, tissue TNF and MDA levels were also increased, while the colon length was markedly reduced. FA-5, ACA, but not DEX, improved body weight. All test drugs counteracted the increase in spleen weight, improved the colon length, and ameliorated macroscopic damage score. A reduction of TNF and MDA tissue levels were also recorded in rats treated with test drugs. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. Data regarding the effects of FA-5, ACA and DEX on the main tissue inflammatory parameters are summarized in the table.
Conclusions. Pharmacological activation of AMPK exerts beneficial effects on bowel inflammation. In this context, the novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy, as compared to ACA, thus representing a promising pharmacological tool against bowel inflammatory disorders.
