Abstract
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.
© 2017 Feinberg et al.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic Fibers / drug effects
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Adrenergic Fibers / enzymology
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Adrenergic Fibers / pathology
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Anilides / pharmacology*
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Animals
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Axons / drug effects
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Axons / enzymology
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Axons / pathology
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Cells, Cultured
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Crush Injuries / drug therapy*
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Crush Injuries / enzymology
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Crush Injuries / genetics
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Crush Injuries / pathology
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Cytoprotection
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Genotype
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitochondria / drug effects*
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Mitochondria / enzymology
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Mitochondria / pathology
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Motor Neurons / drug effects
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Motor Neurons / enzymology
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Motor Neurons / pathology
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Mutation
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Neurons / drug effects*
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Neurons / enzymology
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Neurons / pathology
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Neuroprotective Agents / pharmacology*
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Phenotype
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology*
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Quinolines / pharmacology*
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Rats, Sprague-Dawley
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Receptor, trkA / antagonists & inhibitors*
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Receptor, trkA / genetics
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Receptor, trkA / metabolism
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Sciatic Nerve / drug effects*
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Sciatic Nerve / enzymology
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Sciatic Nerve / injuries
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Sciatic Nerve / pathology
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Sciatic Neuropathy / drug therapy*
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Sciatic Neuropathy / enzymology
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Sciatic Neuropathy / genetics
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Sciatic Neuropathy / pathology
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Sensory Receptor Cells / drug effects
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Sensory Receptor Cells / enzymology
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Sensory Receptor Cells / pathology
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Signal Transduction
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Superoxide Dismutase-1 / genetics
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Superoxide Dismutase-1 / metabolism
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Time Factors
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Transcription, Genetic
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Wallerian Degeneration*
Substances
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Anilides
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Apoptosis Regulatory Proteins
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GSK 1363089
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Neuroprotective Agents
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Protein Kinase Inhibitors
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Quinolines
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Sod1 protein, mouse
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Superoxide Dismutase-1
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Receptor, trkA