Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer.
Huntington's disease (HD) is a genetic disorder leading to the degeneration of striatal GABA-ergic 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 adenovirus-mediated 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, beta-galactosidase, or sham surgery. Two weeks after treatment, the animals were lesioned with quinolinic acid (QUIN), a toxin that 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 beta-galactosidase adenovirus-treated group (p < 0.05), and the sham-treated group (p < 0.05). To determine the survival of striatal GABA-ergic output neurons after the QUIN-induced 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 beta-galactosidase treatment 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.
Bemelmans
A P
AP
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, UMR C9923, Centre National de la Recherche Scientifique, Hôpital de la Pitié-Salpêtrière, Bâtiment CERVI, Paris, France.
Horellou
P
P
Pradier
L
L
Brunet
I
I
Colin
P
P
Mallet
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D003342:Corpus Striatum / Q000473:pathology*; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006816:Huntington Disease / Q000473:pathology / Q000628:therapy*; D009474:Neurons / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D017931:DNA Primers; D011994:Recombinant Proteins