DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
| Autor: | 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. |
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| Přispěvatelé: | Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center Groningen [Groningen] (UMCG), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Gestionnaire, Hal Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
DUAL-SPECIFICITY
Pyridines [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology lcsh:Medicine Protein Serine-Threonine Kinases Article Mice Cognition DEFICITS Animals Humans BRAIN Maze Learning lcsh:Science Protein Kinase Inhibitors SYNDROME MICE ALZHEIMER-DISEASE Memory Disorders Molecular Structure Learning Disabilities lcsh:R [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Protein-Tyrosine Kinases FUNCTIONAL-LINK Disease Models Animal ENVIRONMENTAL NEUROTOXIN ANNONACIN UPLC-MS/MS PROTEIN-KINASE INHIBITORS RAT lcsh:Q Down Syndrome Injections Intraperitoneal |
| Zdroj: | Scientific Reports Scientific Reports, 2018, 8, pp.2859. ⟨10.1038/s41598-018-20984-z⟩ Scientific Reports, 8:2859. Nature Publishing Group Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) Scientific Reports, Nature Publishing Group, 2018, 8, pp.2859. ⟨10.1038/s41598-018-20984-z⟩ |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-20984-z⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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