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

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 appli...

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Autores principales: Antonioli, Luca, Pellegrini, Carolina, Fornai, Matteo, Benvenuti, Laura, D’Antongiovanni, Vanessa, Colucci, Rocchina, Bertani, Lorenzo, Di Salvo, Clelia, Semeghini, Giorgia, La Motta, Concettina, Giusti, Laura, Zallocco, Lorenzo, Ronci, Maurizio, Quattrini, Luca, Angelucci, Francesco, Coviello, Vito, Oh, Won-Keun, Ha, Quy Thi Kim, Németh, Zoltan H., Haskó, Gyorgy, Blandizzi, Corrado
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231528/
https://www.ncbi.nlm.nih.gov/pubmed/34199160
http://dx.doi.org/10.3390/ijms22126325
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author Antonioli, Luca
Pellegrini, Carolina
Fornai, Matteo
Benvenuti, Laura
D’Antongiovanni, Vanessa
Colucci, Rocchina
Bertani, Lorenzo
Di Salvo, Clelia
Semeghini, Giorgia
La Motta, Concettina
Giusti, Laura
Zallocco, Lorenzo
Ronci, Maurizio
Quattrini, Luca
Angelucci, Francesco
Coviello, Vito
Oh, Won-Keun
Ha, Quy Thi Kim
Németh, Zoltan H.
Haskó, Gyorgy
Blandizzi, Corrado
author_facet Antonioli, Luca
Pellegrini, Carolina
Fornai, Matteo
Benvenuti, Laura
D’Antongiovanni, Vanessa
Colucci, Rocchina
Bertani, Lorenzo
Di Salvo, Clelia
Semeghini, Giorgia
La Motta, Concettina
Giusti, Laura
Zallocco, Lorenzo
Ronci, Maurizio
Quattrini, Luca
Angelucci, Francesco
Coviello, Vito
Oh, Won-Keun
Ha, Quy Thi Kim
Németh, Zoltan H.
Haskó, Gyorgy
Blandizzi, Corrado
author_sort Antonioli, Luca
collection PubMed
description 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.
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spelling pubmed-82315282021-06-26 Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation Antonioli, Luca Pellegrini, Carolina Fornai, Matteo Benvenuti, Laura D’Antongiovanni, Vanessa Colucci, Rocchina Bertani, Lorenzo Di Salvo, Clelia Semeghini, Giorgia La Motta, Concettina Giusti, Laura Zallocco, Lorenzo Ronci, Maurizio Quattrini, Luca Angelucci, Francesco Coviello, Vito Oh, Won-Keun Ha, Quy Thi Kim Németh, Zoltan H. Haskó, Gyorgy Blandizzi, Corrado Int J Mol Sci Article 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. MDPI 2021-06-13 /pmc/articles/PMC8231528/ /pubmed/34199160 http://dx.doi.org/10.3390/ijms22126325 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Antonioli, Luca
Pellegrini, Carolina
Fornai, Matteo
Benvenuti, Laura
D’Antongiovanni, Vanessa
Colucci, Rocchina
Bertani, Lorenzo
Di Salvo, Clelia
Semeghini, Giorgia
La Motta, Concettina
Giusti, Laura
Zallocco, Lorenzo
Ronci, Maurizio
Quattrini, Luca
Angelucci, Francesco
Coviello, Vito
Oh, Won-Keun
Ha, Quy Thi Kim
Németh, Zoltan H.
Haskó, Gyorgy
Blandizzi, Corrado
Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation
title Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation
title_full Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation
title_fullStr Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation
title_full_unstemmed Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation
title_short Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation
title_sort preclinical development of fa5, a novel amp-activated protein kinase (ampk) activator as an innovative drug for the management of bowel inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231528/
https://www.ncbi.nlm.nih.gov/pubmed/34199160
http://dx.doi.org/10.3390/ijms22126325
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