Adenoviral gene transfer of glial cell line-derived neurotrophic factor to injured adult motoneurons.
Glial cell line-derived neurotrophic factor (GDNF) strongly supports the survival of injured neonatal motoneurons, suggesting its potential uses in the treatment of motoneuron injury and motor neuron diseases. We examined neuroprotective effects of an adenoviral vector encoding GDNF (AxCAhGDNF) on the survival of lesioned adult rat facial and spinal motoneurons. The facial nerve or the seventh cervical segment (C7) ventral and dorsal roots of 3 month-old Fischer 344 male rats were avulsed and removed from the stylomastoid or vertebral foramen, respectively, and AxCALacZ (adenovirus containing beta-galactosidase gene), AxCAhGDNF, or PBS was inoculated in the lesioned foramen. One week after the avulsion and treatment with AxCALacZ, the animal showed expression of beta-galactosidase activity in lesioned facial and spinal motoneurons. Animals avulsed and treated with AxCAhGDNF showed intense immunolabeling for GDNF in lesioned facial and spinal motoneurons and expression of virus-induced human GDNF mRNA transcripts in the lesioned brain stem and spinal cord tissues. The treatment with AxCAhGDNF after avulsion significantly prevented the loss of lesioned facial and C7 spinal motoneurons, ameliorated choline acetyltransferase immunoreactivity, and suppressed the activity of nitric oxide synthase in these neurons. These results indicate that the adenovirus-mediated gene transfer of GDNF may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.
Watabe
K
K
Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience. kazwtb@tmin.ac.jp
Sakamoto
T
T
Ohashi
T
T
Kawazoe
Y
Y
Oyanagi
K
K
Takeshima
T
T
Inoue
K
K
Eto
Y
Y
Kim
S U
SU
D000256:Adenoviridae; D000690:Amyotrophic Lateral Sclerosis / Q000628:therapy; D000818:Animals; D020220:Facial Nerve Injuries / Q000628:therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D009046:Motor Neurons; D009410:Nerve Degeneration / Q000517:prevention & control; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051381:Rats
C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins