Insulin-like growth factor-I (IGF-I), which is present in both the developing and adult CNS, possesses important neurotrophic actions and its synthesis as well as its type 1 brain receptor expression decline during aging. Replacement therapy with IGF-I in aged rats ameliorates certain memory capacities. In the present study we constructed a recombinant adenoviral vector (RAd-IGFI) harboring the gene for IGF-Ib and used it to implement restorative gene therapy in senile hyperprolactinemic female rats displaying severe dopaminergic neurodegeneration in the hypothalamus. RAd-IGFI was constructed by the two-plasmid method and was injected in the arcuate nucleus (ARC) of young and senile rats (controls received vehicle). Serum prolactin (PRL) was monitored every 4 days during the treatment. Seventeen days post injection, all animals were sacrificed, their brains fixed and 30-µm thick sections obtained. Hypothalamic sections were assessed immunohistochemically using antibodies against tyrosine hydroxylase (TH), the NeuN neuronal marker, the CD11 microglial marker, neuronal nitric oxide synthase, and nitrosylated tyrosine. In the control (vehicle injected) and experimental (vector injected) ARC tissue, IGF-I levels were (ng/sample + SE) 3.77 +0.96 and 6.70 +0.79, P=0.045. Serum PRL levels fell sharply in the hyperprolactinemic senile rats treated with RAd-IGFI but not in control senile rats. The expression of the above markers in control and treated animals was quantitated, the most significant finding being a nearly complete restoration in the number of TH+ neurons in the arcuate nucleus of the senile animals injected with RAd-IGFI. The present study demonstrates that IGF-I gene therapy in the aging brain can restore dopaminergic neuron function, thus constituting a promising approach in the treatment of senile dopaminergic neurodegeneration.
