Glial cell line derived neurotrophic factor (GDNF) gene therapy restores dopsminergic neuron function in the hypothalamus of senile female rats.

GOYA RG; MOREL GR; SOSA Y. E.; BELLINI MJ; HEREÑU CB; BOHN MC

WASHINGTON DC, USA

Congreso; Neuroscience Meeting; 2008

In humans, Parkinson's disease, a degeneration of nigro-striatal dopaminergic (DA) neurons is the most conspicuous reflection of the vulnerability of DA neurons to aging. In rats, aging brings about a progressive degeneration and loss of another group of central DA neurons namely, the hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons, which are involved in the tonic inhibitory control of prolactin (PRL) secretion and lactotropic cell proliferation in the adenohypophysis. Progressive dysfunction and loss of TIDA neurons during normal aging is associated, in the female rat, with chronic hyperprolactinemia and the development of pituitary prolactinomas. Glial cell line-derived neurotrophic factor (GDNF) has been shown to strongly promote the survival and differentiation of DA neurons. In young rats and non human primates GDNF gene therapy was able to protect nigral DA neurons from the toxic action of dopaminergic toxins. In the present study we assessed the effectiveness of GDNF gene therapy to restore TIDA neuron function in senile female rats and reverse their chronic hyperprolactinemia. On experimental day 0, young (3 months) and senile (29 months) female rats received a bilateral intrahypothalamic injection (1010 plaque forming units per side) of either RAd-βgal (an adenoviral vector expressing the reporter gene for E. coli β-galactosidase; the groups were named Y-βgal and S-βgal, respectively) or RAd-GDNF (a vector expressing the gene for rat GDNF; the groups were named Y-gdnf and S-gdnf, respectively). Animals were weighed and blood samples taken on experimental days -3, +5, +10 and +17 and serum PRL was measured by radioimmunoassay. On experimental day 17 animals were sacrificed and tyrosine hydroxylase (TH) immunoreactive neurons counted in the different hypothalamic nuclei. The S-gdnf but not the S-βgal rats, showed a significant reduction in body weight (BW) (ΔBW S-gdnf= -25±10 g, p< 0.05; ΔBW S-βgal= 1±3 g, NS). The chronic hyperprolactinemia of the senile females was significantly reversed in the S-gdnf rats (Exptl day -3 vs. 17: 56±6 vs. 38±5 ng PRL/ml; p< 0.05) but not in the S-βgal animals (Exptl day -3 vs. 17: 58±5 vs. 59±4 ng PRL/ml; p: NS). In the control rats the number of hypothalamic TH+ neurons was not significantly reduced with age, nor was it affected by GDNF gene therapy. We conclude that transgenic GDNF exerts a restorative action (direct or indirect) on TIDA neuron function in aging female rats which is reflected by the reversal of their chronic hyperprolactinemia.