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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doaj-4c336995eae3454b93eedb2acc5c7adc2021-07-01T00:04:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-01226325632510.3390/ijms22126325Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel InflammationLuca Antonioli0Carolina Pellegrini1Matteo Fornai2Laura Benvenuti3Vanessa D’Antongiovanni4Rocchina Colucci5Lorenzo Bertani6Clelia Di Salvo7Giorgia Semeghini8Concettina La Motta9Laura Giusti10Lorenzo Zallocco11Maurizio Ronci12Luca Quattrini13Francesco Angelucci14Vito Coviello15Won-Keun Oh16Quy Thi Kim Ha17Zoltan H. Németh18Gyorgy Haskó19Corrado Blandizzi20Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyDepartment of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyDepartment of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, 35122 Padova, ItalyDepartment of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, ItalyDepartment of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyDepartment of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalySchool of Pharmacy, University of Camerino, 62032 Camerino, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, KoreaResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, KoreaDepartment of Anesthesiology, Columbia University, New York City, NY 10027, USADepartment of Anesthesiology, Columbia University, New York City, NY 10027, USADepartment of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyAcadesine (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.https://www.mdpi.com/1422-0067/22/12/6325inflammatory bowel diseasesimmune systemAMPKDNBS colitisoxidative stress |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Luca Antonioli Carolina Pellegrini Matteo Fornai Laura Benvenuti Vanessa D’Antongiovanni Rocchina Colucci Lorenzo Bertani Clelia Di Salvo Giorgia Semeghini Concettina La Motta Laura Giusti Lorenzo Zallocco Maurizio Ronci Luca Quattrini Francesco Angelucci Vito Coviello Won-Keun Oh Quy Thi Kim Ha Zoltan H. Németh Gyorgy Haskó Corrado Blandizzi |
spellingShingle |
Luca Antonioli Carolina Pellegrini Matteo Fornai Laura Benvenuti Vanessa D’Antongiovanni Rocchina Colucci Lorenzo Bertani Clelia Di Salvo Giorgia Semeghini Concettina La Motta Laura Giusti Lorenzo Zallocco Maurizio Ronci Luca Quattrini Francesco Angelucci Vito Coviello Won-Keun Oh Quy Thi Kim Ha Zoltan H. Németh Gyorgy Haskó Corrado Blandizzi Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation International Journal of Molecular Sciences inflammatory bowel diseases immune system AMPK DNBS colitis oxidative stress |
author_facet |
Luca Antonioli Carolina Pellegrini Matteo Fornai Laura Benvenuti Vanessa D’Antongiovanni Rocchina Colucci Lorenzo Bertani Clelia Di Salvo Giorgia Semeghini Concettina La Motta Laura Giusti Lorenzo Zallocco Maurizio Ronci Luca Quattrini Francesco Angelucci Vito Coviello Won-Keun Oh Quy Thi Kim Ha Zoltan H. Németh Gyorgy Haskó Corrado Blandizzi |
author_sort |
Luca Antonioli |
title |
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_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_sort |
preclinical development of fa5, a novel amp-activated protein kinase (ampk) activator as an innovative drug for the management of bowel inflammation |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-06-01 |
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. |
topic |
inflammatory bowel diseases immune system AMPK DNBS colitis oxidative stress |
url |
https://www.mdpi.com/1422-0067/22/12/6325 |
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