TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo

J Neurosci. 2002 May 15;22(10):3977-86. doi: 10.1523/JNEUROSCI.22-10-03977.2002.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axotomy
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Survival / physiology
  • Cytoprotection / drug effects
  • Cytoprotection / physiology
  • Dependovirus / genetics
  • Down-Regulation / physiology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Transfer, Horizontal
  • Genetic Vectors
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism*
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Up-Regulation / physiology

Substances

  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptor, trkB
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases