A neuroprotective agent that inactivates prodegenerative TrkA and preserves mitochondria.
J Cell Biol
; 216(11): 3655-3675, 2017 11 06.
Article
em En
| MEDLINE
| ID: mdl-28877995
Axon degeneration is an early event and pathological in neurodegenerative conditions and nerve injuries. To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor wt and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting. Foretinib delayed chemotherapy-induced and Wallerian axonal degeneration in culture by preventing axotomy-induced local energy deficit and preserving mitochondria, and peripheral Wallerian degeneration in vivo. These findings identify a new axon degeneration pathway and a potentially clinically useful therapeutic drug.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
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Nervo Isquiático
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Degeneração Walleriana
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Fármacos Neuroprotetores
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Neuropatia Ciática
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Receptor trkA
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Inibidores de Proteínas Quinases
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Lesões por Esmagamento
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Anilidas
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Mitocôndrias
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Cell Biol
Ano de publicação:
2017
Tipo de documento:
Article