RESUMO

Progressive dysfunction of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons during normal aging is associated in the female rat with chronic hyperprolactinemia. We assessed the effectiveness of glial cell line-derived neurotrophic factor (GDNF) gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. Young (2.5 months) and senile (29 months) rats received a bilateral intrahypothalamic injection (10(10) pfu) of either an adenoviral vector expressing the gene for beta-galactosidase; (Y-betagal and S-betagal, respectively) or a vector expressing rat GDNF (Y-GDNF and S-GDNF, respectively). Transgenic GDNF levels in supernatants of GDNF adenovector-transduced N2a neuronal cell cultures were 25+/-4 ng/ml, as determined by bioassay. In the rats, serum prolactin (PRL) was measured at regular intervals. On day 17 animals were sacrificed and neuronal nuclear antigen (NeuN) and tyrosine hydroxylase (TH) immunoreactive cells counted in the arcuate-periventricular hypothalamic region. The S-GDNF but not the S-betagal rats, showed a significant reduction in body weight. The chronic hyperprolactinemia of the senile females was significantly ameliorated in the S-GDNF rats (P<0.05) but not in the S-betagal rats. Neither age nor GDNF induced significant changes in the number of NeuN and TH neurons. We conclude that transgenic GDNF ameliorates chronic hyperprolactinemia in aging female rats, probably by restoring TIDA neuron function.

Assuntos

Envelhecimento/metabolismo , Terapia Genética/métodos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Hiperprolactinemia/genética , Hiperprolactinemia/terapia , Adenoviridae/genética , Animais , Antígenos Nucleares/metabolismo , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Contagem de Células , Células Cultivadas , Doença Crônica/terapia , Feminino , Genes Reporter/genética , Vetores Genéticos/genética , Vetores Genéticos/farmacologia , Hiperprolactinemia/metabolismo , Lactotrofos/metabolismo , Microinjeções/métodos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Prolactina/análise , Prolactina/sangue , Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/genética , Resultado do Tratamento , Túber Cinéreo/metabolismo , Túber Cinéreo/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo , beta-Galactosidase/genética