Abstract
Sensory axons in the adult spinal cord do not regenerate after injury. This is essentially because of inhibitory components in the damaged CNS, such as myelin-associated inhibitors and the glial scar. However, if the sciatic nerve is axotomized before injury of the dorsal column, injured axons can regenerate a short distance in the spinal cord. Here, we show that sciatic nerve transection results in time-dependent phosphorylation and activation of the transcription factor, signal transducer and activator of transcription 3 (STAT3), in dorsal root ganglion (DRG) neurons. This effect is specific to peripheral injuries and does not occur when the dorsal column is crushed. Sustained perineural infusion of the Janus kinase 2 (JAK2) inhibitor AG490 to the proximal nerve stump can block STAT3 phosphorylation after sciatic nerve transection and results in reduced growth-associated protein 43 upregulation and compromised neurite outgrowth in vitro. Importantly, in vivo perineural infusion of AG490 also significantly attenuates dorsal column axonal regeneration in the adult spinal cord after a preconditioning sciatic nerve transection. We conclude that STAT3 activation is necessary for increased growth ability of DRG neurons and improved axonal regeneration in the spinal cord after a conditioning injury.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / physiology
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Axons / physiology
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Axotomy
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Cells, Cultured / drug effects
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Cells, Cultured / ultrastructure
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Cholera Toxin / administration & dosage
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Cholera Toxin / toxicity
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Cytokine Receptor gp130
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DNA-Binding Proteins / physiology*
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GAP-43 Protein / biosynthesis
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GAP-43 Protein / genetics
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Ganglia, Spinal / physiopathology
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Infusion Pumps, Implantable
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Janus Kinase 2
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Male
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / physiology
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Nerve Crush
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Nerve Regeneration / drug effects
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Nerve Regeneration / physiology*
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Neurites / physiology
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Phosphorylation
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Protein Processing, Post-Translational
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / physiology
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Rats
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Rats, Wistar
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STAT3 Transcription Factor
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Sciatic Nerve / injuries
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Spinal Cord Injuries / physiopathology*
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Trans-Activators / physiology*
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Tyrphostins / administration & dosage
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Tyrphostins / pharmacology
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Tyrphostins / toxicity
Substances
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Antigens, CD
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DNA-Binding Proteins
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GAP-43 Protein
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Il6st protein, rat
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Membrane Glycoproteins
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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Stat3 protein, rat
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Trans-Activators
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Cytokine Receptor gp130
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Cholera Toxin
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Protein-Tyrosine Kinases
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Jak2 protein, rat
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Janus Kinase 2