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

Abstract

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 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 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-βgal 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 Sβgal 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. Keywordsaging; DA neurodegeneration; TIDA neurons; chronic hyperprolactinemia; GDNF; gene therapyThe dopaminergic (DA) neurons of the rat hypothalamus are grouped into two main areas, A 12 and A 14, (Dahlstrom and Fuxe, 1964;Tillet and Kitahama, 1998) with the DA perikarya of the A 12 area being located in the arcuate (ARC) nucleus and in the periarcuate region (Kawano and Daikoku, 1997). The A 14 DA neurons are mainly located within the paraventricular (PaV) and periventricular (PeV) nuclei, with a few scattered DA neurons in Goudreau et al., 1992). The A 12 area and its corresponding axon terminals constitute the tuberoinfundibular (TIDA) system, whereas the A 14 area and its fibers are known as the periventricular dopaminergic system. Both systems regulate prolactin (PRL) secretion by exerting a tonic inhibitory control on both PRL secretion and lactotroph proliferation (BenJonathan et al., 1989).In female rats, aging brings about a progressive dysfunction and loss of TIDA neurons. Degeneration and loss of TIDA neurons during normal aging is associated, in the female rat, with a progressive hyperprolactinemia (Goya et al., 1990) and the development of pituitary prolactinomas (Console et al., 1997). This neuroendocrine pathology provides a unique animal model to assess the efficacy of therapeutic strategies aimed at protecting central DA neurons. Interestingly, Parkinsonian patients were reported to show functional alterations in the hypothalamo-PRL axis (Cusimano et al., 1991).Glial cell line-derived neurotrophic factor (GDNF), a distant ...

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