Jérôme Jeanblanc1,2, Erika Bourguet3,4, Diana Sketriené1,2, Céline Gonzalez1,2, Gautier Moroy5, Rémi Legastelois1,2, Mathieu Létévé2,6, Aurélie Trussardi-Régnier2,7, Mickaël Naassila8,9. 1. Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), INSERM U1247, Université de Picardie Jules Verne, C.U.R.S. (Centre Universitaire de Recherche en Santé), Chemin du Thil, 80000, Amiens, France. 2. Structure Fédérative de Recherche-Champagne Ardenne Picardie Santé (SFR-CAP Santé), Amiens, France. 3. Structure Fédérative de Recherche-Champagne Ardenne Picardie Santé (SFR-CAP Santé), Amiens, France. erika.bourguet@univ-reims.fr. 4. Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51096, Reims Cedex, France. erika.bourguet@univ-reims.fr. 5. Molécules Thérapeutiques In Silico (MTi), INSERM UMR-S 973, Université Paris Diderot, Sorbonne Paris Cité, 35 rue Hélène Brion, 75013, Paris, France. 6. Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51096, Reims Cedex, France. 7. Unité Derm-I-C, EA n°7319, Faculté de Médecine de Reims, Université de Reims Champagne-Ardenne, 1 rue du Maréchal Juin, 51096, Reims Cedex, France. 8. Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), INSERM U1247, Université de Picardie Jules Verne, C.U.R.S. (Centre Universitaire de Recherche en Santé), Chemin du Thil, 80000, Amiens, France. mickael.naassila@u-picardie.fr. 9. Structure Fédérative de Recherche-Champagne Ardenne Picardie Santé (SFR-CAP Santé), Amiens, France. mickael.naassila@u-picardie.fr.
Abstract
RATIONALE: Recent preclinical research suggested that histone deacetylase inhibitors (HDACIs) and specifically class I HDAC selective inhibitors might be useful to treat alcohol use disorders (AUDs). OBJECTIVE: The objective of this study was to find a new inhibitor of the HDAC-1 isoenzyme and to test its efficacy in an animal model of AUDs. METHODS: In the present study, we prepared new derivatives bearing sulfonylhydrazide-type zinc-binding group (ZBG) and evaluated these compounds in vitro on HDAC-1 isoenzyme. The most promising compound was tested on ethanol operant self-administration and relapse in rats. RESULTS: We showed that the alkylsulfonylhydrazide-type compound (ASH) reduced by more than 55% the total amount of ethanol consumed after one intracerebroventricular microinjection, while no effect was observed on motivation of the animals to consume ethanol. In addition, one ASH injection in the central amygdala reduced relapse. CONCLUSIONS: Our study demonstrated that a new compound designed to target HDAC-1 is effective in reducing ethanol intake and relapse in rats and further confirm the interest of pursuing research to study the exact mechanism by which such inhibitor may be useful to treat AUDs.
RATIONALE: Recent preclinical research suggested that histone deacetylase inhibitors (HDACIs) and specifically class I HDAC selective inhibitors might be useful to treat alcohol use disorders (AUDs). OBJECTIVE: The objective of this study was to find a new inhibitor of the HDAC-1 isoenzyme and to test its efficacy in an animal model of AUDs. METHODS: In the present study, we prepared new derivatives bearing sulfonylhydrazide-type zinc-binding group (ZBG) and evaluated these compounds in vitro on HDAC-1 isoenzyme. The most promising compound was tested on ethanol operant self-administration and relapse in rats. RESULTS: We showed that the alkylsulfonylhydrazide-type compound (ASH) reduced by more than 55% the total amount of ethanol consumed after one intracerebroventricular microinjection, while no effect was observed on motivation of the animals to consume ethanol. In addition, one ASH injection in the central amygdala reduced relapse. CONCLUSIONS: Our study demonstrated that a new compound designed to target HDAC-1 is effective in reducing ethanol intake and relapse in rats and further confirm the interest of pursuing research to study the exact mechanism by which such inhibitor may be useful to treat AUDs.
Entities:
Keywords:
Alkylsulfonylhydrazide; Ethanol self-administration; Histone deacetylase; Inhibition; Rats; Zinc-binding group
Authors: Annemieke J M de Ruijter; Albert H van Gennip; Huib N Caron; Stephan Kemp; André B P van Kuilenburg Journal: Biochem J Date: 2003-03-15 Impact factor: 3.857
Authors: Jose Antonio López-Moreno; Miguel Marcos; Javier Calleja-Conde; Victor Echeverry-Alzate; Kora M Bühler; Pilar Costa-Alba; Edgar Bernardo; Francisco-Javier Laso; Fernando Rodríguez de Fonseca; Roser Nadal; Maria Paz Viveros; Rafael Maldonado; Elena Giné Journal: Alcohol Clin Exp Res Date: 2015-09-13 Impact factor: 3.455