Abstract: Insulin-like growth factor I (IGF-I) is emerging as a powerful neuroprotective molecule which is strongly induced in the central nervous system after different insults. We constructed a recombinant adenoviral vector (RAd-IGFI) harboring the gene for rat IGF-I and used it to implement IGF-I gene therapy in the hypothalamus of senile female rats, which display hypothalamic dopaminergic (DA) dysfunction and as a consequence, chronic hyperprolactinemia. Neuronal (N2a) and glial (B92) cell cultures incubated for 3 days with RAd-IGFI overxpressed IGF-I as compared with cells incubated with Ad.RSV$gal, a control adenoviral vector expressing $-galactosidase. Hypothalamic overexpression of IGF-I was observed for up to 50 days after a single bilateral intrahypothalamic injection (1.5 :l per side) of RAd-IGFI but not Ad.RSV$gal, in young female rats. Restorative IGF-I gene therapy was implemented in young (5 mo.) and senile (28 mo.) female rats, which received a single intrahypothalamic injection of 3 X109 plaque forming units (pfu) of Ad.RSV$gal or RAd-IGFI (control and experimental group, respectively) and were sacrificed 17 days post-injection. In the young animals, neither vector modified serum prolactin (PRL) levels but in the RAd-IGFI-injected senile rats a nearly full reversion of their hyperprolactinemic status was recorded. Morphometric analysis revealed a significant increase in the total number of tyrosine hydroxylase (TH) positive cells in the hypothalamus of experimental as compared with control senile animals (5,874 ± 486 and 3,390 ± 498, respectively). Our results indicate that IGF-I gene therapy in senile female rats is highly effective for reversing their hypothalamic DA neurodegeneration.
