[Gene therapy and neurotrophic factor treatment for amyotrophic lateral sclerosis].
Although excitotoxic and oxidative stress play important roles in spinal neuron death, the exact mechanisms are not fully understood. We examined cell damage of primary culture of 11-day-old rat spinal cord by addition of glutamate, nitric oxide (NO) or peroxynitrite (PN) with detection of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL). With addition of glutamate, NOC18 (a slow NO releaser) or PN, TUNEL positive nuclei were found in spinal large motor neurons from 24 h, and the positive cell proportion greatly increased at 48 h in contrast to the vehicle. The present results suggest that both excitotoxic and oxidative stress play important role in the apoptotic pathway in cultured rat spinal neurons. To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression in transgenic (Tg) mice carrying a Gly 93Ala (G93A) mutant SOD1 gene found in human familial ALS, a replication defective adenoviral vector containing GDNF gene was directly injected unilaterally into leg muscles. There were significantly more large motoneurons in GDNF-treated Tg mice than in untreated and Ad-Laz-treated group. The number of large motoneurons in GDNF-treated side of Tg mice were significantly more than that in untreated side. These observations demonstrate that GDNF gene therapy in a mouse model of FALS promotes the survival of motoneurons, suggesting that a similar approach might delay the progression of neurodegeneration of ALS.
Abe
K
K
Department of Neurology, Graduate School of Medicine and Dentistry, Okayama University.
Manabe
Y
Y
Murakami
T
T
D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000628:therapy*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005609:Free Radicals / Q000009:adverse effects; D015316:Genetic Therapy / Q000379:methods*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018698:Glutamic Acid / Q000009:adverse effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology
D005609:Free Radicals; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018698:Glutamic Acid