Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation.

Luca Antonioli,Vanessa D’Antongiovanni,Carolina Pellegrini,Rocchina Colucci,Lorenzo Zallocco,Concettina La Motta,Clelia Di Salvo,Laura Giusti,Giorgia Semeghini,Corrado Blandizzi,Matteo Fornai,Quy Thi Kim Ha,Francesco Angelucci,Vito Coviello,Lorenzo Bertani,Laura Benvenuti,Luca Quattrini,Maurizio Ronci,György Haskó ,Zoltán Németh ,Won Keun Oh

doi:10.3390/ijms22126325

Abstract

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.

Highlights

Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), are severe chronic pathologies characterized by a wide range of gastrointestinal and extra-digestive symptoms with a substantial negative impact on patient well-being [1]
Based on these premises, increasing efforts have been addressed toward the characterization of such pro-resolving mechanisms allowing to identify novel molecular targets useful to design resolution-based therapies for IBDs [23]
The AMP-activated protein kinase (AMPK) represents a critical molecular target involved in reprogramming the immune cell populations from a pro-inflammatory glycolytic metabolism towards a more oxidative phosphorylation which characterize the pro-resolutive phenotype of immune cells [24]

Summary

Introduction

Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), are severe chronic pathologies characterized by a wide range of gastrointestinal and extra-digestive symptoms with a substantial negative impact on patient well-being [1]. A large body of evidence highlighted that such alteration in tissue metabolism results from a combination of marked inflammatory cell recruitment (neutrophils and monocytes) in parallel with a high proliferation rate among lymphocyte populations [3]. This increased recruitment of immune cells coincides with a massive release of Th1/Th17- or Th2/Th9-related pro-inflammatory cytokines in Crohn’s disease or ulcerative colitis, respectively [4,5]. Increased reactive oxygen species (ROS) production and a defective pro-resolutive cytokine generation (i.e., transforming growth factor (TGF)-β and IL-10) are prominent features [6]

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