Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
1.
Sci Transl Med ; 11(503)2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366578

RESUMO

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. There are currently no approved treatments for RTT. The expression of K+/Cl- cotransporter 2 (KCC2), a neuron-specific protein, has been found to be reduced in human RTT neurons and in RTT mouse models, suggesting that KCC2 might play a role in the pathophysiology of RTT. To develop neuron-based high-throughput screening (HTS) assays to identify chemical compounds that enhance the expression of the KCC2 gene, we report the generation of a robust high-throughput drug screening platform that allows for the rapid assessment of KCC2 gene expression in genome-edited human reporter neurons. From an unbiased screen of more than 900 small-molecule chemicals, we have identified a group of compounds that enhance KCC2 expression termed KCC2 expression-enhancing compounds (KEECs). The identified KEECs include U.S. Food and Drug Administration-approved drugs that are inhibitors of the fms-like tyrosine kinase 3 (FLT3) or glycogen synthase kinase 3ß (GSK3ß) pathways and activators of the sirtuin 1 (SIRT1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) pathways. Treatment with hit compounds increased KCC2 expression in human wild-type (WT) and isogenic MECP2 mutant RTT neurons, and rescued electrophysiological and morphological abnormalities of RTT neurons. Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2.


Assuntos
Proteína 2 de Ligação a Metil-CpG/metabolismo , Neurônios/citologia , Síndrome de Rett/metabolismo , Simportadores/metabolismo , Anilidas/farmacologia , Animais , Benzimidazóis/farmacologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Eletrorretinografia , Inibidores Enzimáticos/farmacologia , Feminino , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Indazóis/farmacologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Neurônios/efeitos dos fármacos , Piperazinas/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sirtuína 1/metabolismo , Sunitinibe/farmacologia , Simportadores/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Cotransportadores de K e Cl-
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA