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

GOYA R; MOREL G; SOSA Y; BELLINI M,; HEREÑU; BOHN M.

Washington

Congreso; Society for Neuroscience 2008. Annual Meeting-.; 2008

In humans, ParkinsonLs disease, a degeneration of nigro-striatal dopaminergic (DA) neurons is the mostconspicuous reflection of the vulnerability of DA neurons to aging. In rats, aging brings about a progressivedegeneration and loss of another group of central DA neurons namely, the hypothalamic tuberoinfundibulardopaminergic (TIDA) neurons, which are involved in the tonic inhibitory control of prolactin (PRL) secretionand lactotropic cell proliferation in the adenohypophysis. Progressive dysfunction and loss of TIDA neuronsduring normal aging is associated, in the female rat, with chronic hyperprolactinemia and the development ofpituitary prolactinomas. Glial cell line-derived neurotrophic factor (GDNF) has been shown to strongly promotethe survival and differentiation of DA neurons. In young rats and non human primates GDNF gene therapywas able to protect nigral DA neurons from the toxic action of dopaminergic toxins. In the present study weassessed the effectiveness of GDNF gene therapy to restore TIDA neuron function in senile female rats andreverse 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-ƒÀgal (an adenoviral vector expressing the reporter gene for E. coli ƒÀ-galactosidase; the groups were namedY-ƒÀgal and S-ƒÀgal, respectively) or RAd-GDNF (a vector expressing the gene for rat GDNF; the groups werenamed Y-gdnf and S-gdnf, respectively). Animals were weighed and blood samples taken on experimentaldays -3, +5, +10 and +17 and serum PRL was measured by radioimmunoassay. On experimental day 17animals were sacrificed and tyrosine hydroxylase (TH) immunoreactive neurons counted in the differenthypothalamic nuclei. The S-gdnf but not the S-ƒÀgal rats, showed a significant reduction in body weight (BW)(ƒ¢BW S-gdnf= -25}10 g, p< 0.05; ƒ¢BW S-ƒÀgal= 1}3 g, NS). The chronic hyperprolactinemia of the senilefemales 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-ƒÀgal animals (Exptl day -3 vs. 17: 58}5 vs. 59}4 ng PRL/ml; p: NS). In the control rats thenumber of hypothalamic TH+ neurons was not significantly reduced with age, nor was it affected by GDNFgene therapy. We conclude that transgenic GDNF exerts a restorative action (direct or indirect) on TIDAneuron function in aging female rats which is reflected by the reversal of their chronic hyperprolactinemia