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-deriv ed neurotrophic factor (GDNF) or the antiapoptotic peptide Bcl-2 delivered into striatum by a viral vector protects dopaminergic neurons of the substa ntia nigra in vivo from degeneration induced by the administration of the n eurotoxin g-hydroxydopamine (6-OHDA), In this study we used recombinant, re plication-incompetent, genomic herpes simplex virus-based vectors to delive r 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 com pared to the unlesioned side. Gene transfer of Bcl-2 and GDNF were equivale nt in this effect. Coadministration of the Bcl-2-expressing vector with the GDNF-expressing vector improved the survival of lesioned SN neurons as mea sured by FG labeling by 33% and by the expression of TH-IR by 15%. These re sults suggest that the two factors delivered together act in an additive fa shion to improve DA cell survival in the face of 6-OHDA toxicity. (C) 2001 Academic Press.