DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives - Unité de Biologie Fonctionnelle et Adaptative Accéder directement au contenu
Article Dans Une Revue Scientific Reports Année : 2018

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

David Touboul
Kevin Cariou

Résumé

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.

Domaines

Neurobiologie
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Dates et versions

hal-02292094 , version 1 (19-09-2019)

Identifiants

Citer

Fernanda Neumann, Stéphanie Gourdain, Christelle Albac, Alain D Dekker, Linh Chi Bui, et al.. DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives. Scientific Reports, 2018, 8, pp.2859. ⟨10.1038/s41598-018-20984-z⟩. ⟨hal-02292094⟩
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