Glial cell line-derived neurotrophic factor gene therapy ameliorates chronic hyperprolactinemia in senile rats

Abstract

Progressive dysfunction of hypothalamic tu-beroinfundibular dopaminergic (TIDA) neurons during nor-mal aging is associated in the female rat with chronic hyper-prolactinemia. We assessed the effectiveness of glial cellline-derived neurotrophic factor (GDNF) gene therapy to re-store TIDA neuron function in senile female rats and reversetheir chronic hyperprolactinemia. Young (2.5 months) andsenile (29 months) rats received a bilateral intrahypothalamicinjection (1010pfu) of either an adenoviral vector expressingthe gene for β-galactosidase; (Y-βgal and S-βgal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF,respectively). Transgenic GDNF levels in supernatants ofGDNF adenovector-transduced N2a neuronal cell cultureswere 25±4 ng/ml, as determined by bioassay. In the rats,serum prolactin (PRL) was measured at regular intervals. Onday 17 animals were sacrificed and neuronal nuclear antigen(NeuN) and tyrosine hydroxylase (TH) immunoreactive cellscounted in the arcuate–periventricular hypothalamic region.The S-GDNF but not the S-βgal rats, showed a significantreduction in body weight. The chronic hyperprolactinemia ofthe senile females was significantly ameliorated in the S-GDNF rats (P<0.05) but not in the S-βgal rats. Neither age norGDNF induced significant changes in the number of NeuNand TH neurons. We conclude that transgenic GDNF amelio-rates chronic hyperprolactinemia in aging female rats, prob-ably by restoring TIDA neuron function.