Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer

Alexis-Pierre Bemelmans (1) , Philippe Horellou (1) , Laurent Pradier (2) , Isabelle Brunet (1) , Philippe Colin (1) , Jacques Mallet (1)

1 LGN - Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs [APHP Pitié-Salpêtrière]
2 Rhône-Poulenc Rorer Gencell

Huntington's disease (HD) is a genetic disorder leading to the degeneration of striatal GABAergic output neurons. No treatment is currently available for this devastating disorder, although several neurotrophic factors, including brain-derived neurotrophic factor (BDNF), have been shown to be beneficial for striatal neuron survival. We analyzed the effect of adenovirusmediated transfer of the BDNF gene in a model of HD. Using a stereological procedure, three groups of rats were given an intrastriatal injection of adenovirus encoding BDNF, ß-galactosidase or sham surgery. Two weeks after treatment, the animals were lesioned with quinolinic acid (QUIN), a toxin which induces striatal neuron death by an excitotoxic process. One month after the lesion, histological study revealed that striatal neurons were protected only in rats treated with the BDNF adenovirus. Volume measurements showed that the QUIN-induced lesions were 55% smaller in the BDNF adenovirus-treated group than in the ßgalactosidase adenovirus-treated group (p<0.05), and the sham-treated group (p<0.05). To determine the survival of striatal GABAergic output neurons after the QUINinduced lesion, we immunostained brain sections with DARPP-32, an antibody specific for striatal output neurons. Prior treatment with the BDNF adenovirus resulted in a cell survival of 64%, whereas that after ßgalactosidase treament was 46% (p<0.05), showing that the BDNF adenovirus protected the striatal neurons. These results indicate that transfer of the BDNF gene is of therapeutic value for Huntington's disease.

Domaines: Neurobiologie

Alexis-Pierre Bemelmans, Philippe Horellou, Laurent Pradier, Isabelle Brunet, Philippe Colin, et al.. Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer. Human Gene Therapy, 1999, 10 (18), pp.2987-2997. ⟨10.1089/10430349950016393⟩. ⟨cea-03650710⟩