Bcl-2 and GDNF delivered by HSV-mediated gene transfer act additively to protect dopaminergic neurons from 6-OHDA-induced degeneration.
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.
Natsume
A
A
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Mata
M
M
Goss
J
J
Huang
S
S
Wolfe
D
D
Oligino
T
T
Glorioso
J
J
Fink
D J
DJ
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D005260:Female; D007839:Functional Laterality; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D019254:Genes, bcl-2; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000235:genetics / Q000517:prevention & control; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D018139:Simplexvirus; D013378:Substantia Nigra / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis*; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001616:beta-Galactosidase; D003913:Dextroamphetamine; D004298:Dopamine