Abstract
Insulin-like growth factor-I (IGF-I), is present in both the developing and adult CNS, and specific receptors for this peptide are widely distributed in the brain. IGF-I possesses important neurotrophic actions and its synthesis as well as its type 1 brain receptor numbers are known to decline during aging. Interestingly, replacement therapy with IGF-I in aged rats ameliorate certain memory capacities, possibly through a restorative effect of IGF-I on the dopaminergic D2 receptor levels in the brain. As an initial step to implement IGF-I gene therapy in central DA neurons of the senile rat brain, we constructed a recombinant adenoviral vector (RAd-IGF1) harboring the gene for IGF-I. This replication-defective vector was constructed by the two-plasmid method using the FLP recombinase for efficient vector rescue. The IGF-I transgene was placed under the control of a potent mouse cytomegalovirus promoter and its expression in transduced cells or brain tissue was assessed by radioimmunoassay. To reach the arcuate nucleus (ARC) and the substantia nigra (SN), the vector was stereotaxically injected at 1012 plaque forming units (pfu)/ml in a volume of 10 :l saline per side. Two days after surgery the rats were sacrificed and the target areas were dissected by punching out cylindrical specimens that were homogenized and measured. In ARC, control (saline injected) and experimental (vector injected) tissue IGF-I levels were (pg/sample + SE) 3.77 +0.96 and 6.70 +0.79, P=0.045,whereas the corresponding values for SN were 2.60 + 0.79 and 6.64 + 0.79, P=0.011.The present results demonstrate that RAd-IGF-I administration can significantly increase IGF-I tissue levels in two important DA brain areas, thus constituting a suitably tool for experimental gene therapy in the aging CNS. Con el Apoyo de ANPCYT y CONICET
