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DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives
- Source :
- 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⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Database :
- OpenAIRE
- Journal :
- 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⟩
- Accession number :
- edsair.pmid.dedup....1567651c2ba665159ee0e253160c218d