1077 AMP-Activated Protein Kinase as a Novel Target for the Pharmacological Treatment of Inflammatory Bowel Diseases

AMP-Activated Protein Kinase as a Novel Target for the Pharmacological Treatment of Inflammatory Bowel Diseases Luca Antonioli, Matteo Fornai, Rocchina Colucci, Narcisa Ghisu, Marco Tuccori, Oriana Awwad, Gianfranco Natale, Federica Fulceri, Ilaria Rugani, Emiliano Duranti, Agostino Virdis, Corrado Blandizzi, Mario Del Tacca Introduction. Acadesine (ACA), an activator of AMP-activated protein kinase (AMPK), has been shown to act in a site- and event-specific manner against inflammation, through local increments of endogenous adenosine levels. However, the effects of ACA on intestinal inflammation have not been investigated. This study examined the effects of ACA in an experimental model of colitis and evaluated the underlying anti-inflammatory mechanisms. Methods. The effects of ACA and dexamethasone (DEX, used as a standard comparator) 2,4-dinitrobenzenesulfonic acid (DNBS, 15 mg/rat), to assess systemic [body and spleen weight] and tissue inflammatory parameters [macroscopic and microscopic damage, tumour necrosis factor-α (TNF-α), interleukin-10 (IL-10), superoxide anion production (dihydroethidium fluorescence) and malondialdehyde (MDA) levels]. Animals received 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. Results. Colitis was associated with a decreased body weight (-10±5 g vs vehicle; P<0.05) and increased spleen weight (+22±3% vs vehicle; P<0.05). Microscopic damage score, tissue TNF-α and oxidative stress were also enhanced, while tissue IL-10 levels were markedly reduced. Treatment with ACA, but not DEX, improved body weight. Both drugs counteracted the increase in spleen weight and ameliorated the histological damage (DNBS: 4.8±0.9; ACA 10 mg/kg/day: 3.1±0.7; DEX: 2±0.4; P<0.05 vs DNBS; ANOVA). A reduction of TNF-α and increase in IL-10 tissue levels were also recorded in rats treated with test drugs. Moreover, ACA or DEX ameliorated colonic oxidative damage. Data regarding the effects of ACA and DEX on inflammatory parameters are summarized in table (*P<0.05 vs vehicle; aP<0.05 vs DNBS). Conclusions. The AMPK activator ACA exerts beneficial effects on bowel inflammation, acting through a rearrangement of pro-inflammatory/anti-inflammatory cytokine balance and a reduction of oxidative stress. These findings suggest that the pharmacological modulation of AMPK function could represent a promising strategy to develop novel classes of drugs effective against intestinal inflammation.