Bcl-2 and GDNF delivered by HSV-mediated gene transfer act additively to protect dopaminergic neurons from 6-OHDA-induced degeneration

Exp Neurol. 2001 Jun;169(2):231-8. doi: 10.1006/exnr.2001.7671.


Previous studies have demonstrated that either the neurotrophin glial-derived neurotrophic factor (GDNF) or the antiapoptotic peptide Bcl-2 delivered into striatum by a viral vector protects dopaminergic neurons of the substantia nigra in vivo from degeneration induced by the administration of the neurotoxin 6-hydroxydopamine (6-OHDA). In this study we used recombinant, replication-incompetent, genomic herpes simplex virus-based vectors to deliver the genes coding for Bcl-2 and GDNF into rat substantia nigra (SN) 1 week prior to 6-OHDA injection into the striatum. Vector-mediated expression of either Bcl-2 or GDNF alone each resulted in a doubling in cell survival as measured by retrograde labeling with fluorogold (FG) and a 50% increase in tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the lesioned SN compared to the unlesioned side. Gene transfer of Bcl-2 and GDNF were equivalent in this effect. Coadministration of the Bcl-2-expressing vector with the GDNF-expressing vector improved the survival of lesioned SN neurons as measured by FG labeling by 33% and by the expression of TH-IR by 15%. These results suggest that the two factors delivered together act in an additive fashion to improve DA cell survival in the face of 6-OHDA toxicity.

Publication types

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

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / pathology
  • Corpus Striatum / physiology*
  • Dextroamphetamine / pharmacology
  • Dopamine / physiology*
  • Female
  • Functional Laterality
  • Gene Transfer Techniques*
  • Genes, Reporter
  • Genes, bcl-2*
  • Genetic Therapy / methods
  • Genetic Vectors
  • Glial Cell Line-Derived Neurotrophic Factor
  • Humans
  • Motor Activity / drug effects
  • Nerve Degeneration / genetics
  • Nerve Degeneration / prevention & control
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Oxidopamine / toxicity*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Rotation
  • Simplexvirus
  • Substantia Nigra / physiology*
  • Tyrosine 3-Monooxygenase / analysis*
  • beta-Galactosidase / analysis
  • beta-Galactosidase / genetics


  • GDNF protein, human
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Oxidopamine
  • Tyrosine 3-Monooxygenase
  • beta-Galactosidase
  • Dextroamphetamine
  • Dopamine