HEREÑÚ CLAUDIA BEATRIZ
Congresos y reuniones científicas
Título:
Glial cell line-derived neurotrophic factor (GDNF) gene therapy restores dopaminergic neuron function in the hypothalamus of senile female rats
Autor/es:
GOYA R; MOREL G; SOSA Y; BELLINI M,; HEREÑU; BOHN M.
Lugar:
Washington
Reunión:
Congreso; Society for Neuroscience 2008. Annual Meeting-.; 2008
Resumen:
In humans, Parkinson�Ls 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-
ƒÀgal (an adenoviral vector expressing the reporter gene for E. coli ƒÀ-galactosidase; the groups were named
Y-ƒÀgal and S-ƒÀgal, 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-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 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-ƒÀgal 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
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-
ƒÀgal (an adenoviral vector expressing the reporter gene for E. coli ƒÀ-galactosidase; the groups were named
Y-ƒÀgal and S-ƒÀgal, 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-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 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-ƒÀgal 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
