Abstract
Injury-induced downregulation of neurotrophin receptors may limit the response of neurons to trophic factors, compromising their ability to survive. We tested this hypothesis in a model of CNS injury: retinal ganglion cell (RGC) death after transection of the adult rat optic nerve. TrkB mRNA rapidly decreased in axotomized RGCs to approximately 50% of the level in intact retinas. TrkB gene transfer into RGCs combined with exogenous BDNF administration markedly increased neuronal survival: 76% of RGCs remained alive at 2 weeks after axotomy, a time when >90% of these neurons are lost without treatment. Activation of mitogen-activated protein kinase, but not phosphatidylinositol-3 kinase, was required for TrkB-induced survival. These data provide proof-of-principle that enhancing the capacity of injured neurons to respond to trophic factors can be an effective neuroprotective strategy in the adult CNS.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Axotomy
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Cell Death / drug effects
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Cell Death / physiology
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Cell Survival / physiology
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Cytoprotection / drug effects
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Cytoprotection / physiology
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Dependovirus / genetics
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Down-Regulation / physiology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Female
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Gene Transfer, Horizontal
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Genetic Vectors
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Mitogen-Activated Protein Kinases / metabolism
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptor, trkB / genetics
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Receptor, trkB / metabolism*
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Retinal Ganglion Cells / cytology
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Up-Regulation / physiology
Substances
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Enzyme Inhibitors
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptor, trkB
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases