Neuroprotective Effect of IND1316, an Indole-Based AMPK Activator, in Animal Models of Huntington Disease
| Autor: | Marta Vela, María Adelaida García-Gimeno, Ana Sanchis, José Bono-Yagüe, José Cumella, Laura Lagartera, Concepción Pérez, Eva-María Priego, Angela Campos, Pascual Sanz, Rafael P. Vázquez-Manrique, Ana Castro |
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| Přispěvatelé: | National Institutes of Health (US), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Fundació La Marató de TV3, European Commission, Fundación Ramón Areces, Generalitat Valenciana, Real e Ilustre Colegio de Farmacéuticos de Sevilla, Fundación Cajasol, Asociación Valenciana de Enfermedad de Huntington, Sanz, Pascual, Sanz, Pascual [0000-0002-2399-4103] |
| Rok vydání: | 2021 |
| Předmět: |
AMPK
Huntingtin Protein Huntington disease mouse models Indoles Physiology Cognitive Neuroscience C. elegans models Cell Biology General Medicine AMP-Activated Protein Kinases Biochemistry polyQ toxicity Neuroprotection Article Disease Models Animal Mice Huntington Disease Neuroprotective Agents Animals Indole derivatives ADME in silico |
| Zdroj: | ACS Chem Neurosci Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1948-7193 |
| Popis: | 49 páginas, 8 figuras, 2 tablas, 1 esquema. Contiene material suplementario Aggregation of mutant huntingtin, because of an expanded polyglutamine track, underlies the cause of neurodegeneration in Huntington disease (HD). However, it remains unclear how some alterations at the cellular level lead to specific structural changes in HD brains. In this context, the neuroprotective effect of the activation of AMP-activated protein kinase (AMPK) appears to be a determinant factor in several neurodegenerative diseases, including HD. In the present work, we describe a series of indole-derived compounds able to activate AMPK at the cellular level. By using animal models of HD (both worms and mice), we demonstrate the in vivo efficacy of one of these compounds (IND1316), confirming that it can reduce the neuropathological symptoms of this disease. Taken together, in vivo results and in silico studies of druggability, allow us to suggest that IND1316 could be considered as a promising new lead compound for the treatment of HD and other central nervous system diseases in which the activation of AMPK results in neuroprotection We thank the CGC, which is funded by the NIH Office ofResearch Infrastructure Programs (P40 OD010440), forproviding worm strains. RPVM is a Miguel Servet type IIresearcher (CPII16/00004) funded by Instituto de SaludCarlos III (ISCIII, Madrid, Spain). Grants from the ISCIII(PI17/00011 and PI20/00114), the Spanish Ministerio deCiencia Innovación y Universidades (RTI2018-095544-B-I00)and the Fundació Marató de TV3 (Ref.: 559) were used toperform this work. All grants from ISCIII are co-financed bythe European Development Regional Fund“A way to achieveEurope”(ERDF). Funds from the Fundación Ramón Areceswere also used (CIVP19S8119). J.B.Y. holds a grant by theGeneralitat Valenciana and the European Social Fund (ACIF/2019/249). R.V.M. received an Ayuda Miguel Gil grant toRPVM (VII Convocatoria Ayudas a la Investigación MHER,2019, cofinanced by Colegio Oficial de Farmacéuticos deSevilla and Fundación Cajasol). R.V.M. has also received fundsfrom the Asociación Valenciana de Enfermedad de Huntington(AVAEH). This work was also supported by an intramuralACCI2016 grant from the CIBERER-ISCiii to A.C., P.S., andR.V.M |
| Databáze: | OpenAIRE |
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