Bcl-2 and GDNF Delivered by HSV-Mediated Gene Transfer Act Additively to Protect Dopaminergic Neurons from 6-OHDA-Induced Degeneration

• Published in: Experimental neurology 2001-06, Vol.169 (2), p.231-238
• Main Authors: Natsume, Atsushi, Mata, Marina, Goss, James, Huang, Shaohua, Wolfe, Darren, Oligino, Thomas, Glorioso, Joseph, Fink, David J.
• Format: Article
• Language: English
• Subjects: 6-hydroxydopamine; Animals; apoptosis; beta-Galactosidase - analysis; beta-Galactosidase - genetics; Biological and medical sciences; Corpus Striatum - drug effects; Corpus Striatum - pathology; Corpus Striatum - physiology; Dextroamphetamine - pharmacology; Dopamine - physiology; Female; Functional Laterality; gene therapy; Gene Transfer Techniques; Genes, bcl-2; Genes, Reporter; Genetic Therapy - methods; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; herpes simplex; Humans; Medical sciences; 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; Neuropharmacology; Neuroprotective agent; Oxidopamine - toxicity; Parkinson; Pharmacology. Drug treatments; 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
• ISSN: 0014-4886; 1090-2430
• 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.