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DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluo...

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Autores principales: Neumann, Fernanda, Gourdain, Stéphanie, Albac, Christelle, Dekker, Alain D., Bui, Linh Chi, Dairou, Julien, Schmitz-Afonso, Isabelle, Hue, Nathalie, Rodrigues-Lima, Fernando, Delabar, Jean M., Potier, Marie-Claude, Le Caër, Jean-Pierre, Touboul, David, Delatour, Benoît, Cariou, Kevin, Dodd, Robert H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809559/
https://www.ncbi.nlm.nih.gov/pubmed/29434250
http://dx.doi.org/10.1038/s41598-018-20984-z
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author Neumann, Fernanda
Gourdain, Stéphanie
Albac, Christelle
Dekker, Alain D.
Bui, Linh Chi
Dairou, Julien
Schmitz-Afonso, Isabelle
Hue, Nathalie
Rodrigues-Lima, Fernando
Delabar, Jean M.
Potier, Marie-Claude
Le Caër, Jean-Pierre
Touboul, David
Delatour, Benoît
Cariou, Kevin
Dodd, Robert H.
author_facet Neumann, Fernanda
Gourdain, Stéphanie
Albac, Christelle
Dekker, Alain D.
Bui, Linh Chi
Dairou, Julien
Schmitz-Afonso, Isabelle
Hue, Nathalie
Rodrigues-Lima, Fernando
Delabar, Jean M.
Potier, Marie-Claude
Le Caër, Jean-Pierre
Touboul, David
Delatour, Benoît
Cariou, Kevin
Dodd, Robert H.
author_sort Neumann, Fernanda
collection PubMed
description Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.
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spelling pubmed-58095592018-02-15 DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives Neumann, Fernanda Gourdain, Stéphanie Albac, Christelle Dekker, Alain D. Bui, Linh Chi Dairou, Julien Schmitz-Afonso, Isabelle Hue, Nathalie Rodrigues-Lima, Fernando Delabar, Jean M. Potier, Marie-Claude Le Caër, Jean-Pierre Touboul, David Delatour, Benoît Cariou, Kevin Dodd, Robert H. Sci Rep Article Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS. Nature Publishing Group UK 2018-02-12 /pmc/articles/PMC5809559/ /pubmed/29434250 http://dx.doi.org/10.1038/s41598-018-20984-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Neumann, Fernanda
Gourdain, Stéphanie
Albac, Christelle
Dekker, Alain D.
Bui, Linh Chi
Dairou, Julien
Schmitz-Afonso, Isabelle
Hue, Nathalie
Rodrigues-Lima, Fernando
Delabar, Jean M.
Potier, Marie-Claude
Le Caër, Jean-Pierre
Touboul, David
Delatour, Benoît
Cariou, Kevin
Dodd, Robert H.
DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
title DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
title_full DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
title_fullStr DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
title_full_unstemmed DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
title_short DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
title_sort dyrk1a inhibition and cognitive rescue in a down syndrome mouse model are induced by new fluoro-dandy derivatives
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809559/
https://www.ncbi.nlm.nih.gov/pubmed/29434250
http://dx.doi.org/10.1038/s41598-018-20984-z
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