Abstract
Gene mutations of superoxide dismutase (SOD) have been discovered in familial amyotrophic
lateral sclerosis (ALS). Neuronal nitric oxide synthase (NOS), endothelial NOS and
3-nitrotyrosine immunoreactivities are selectively increased in the spinal motoneurons
of sporadic ALS. Other study suggests that 3-nitrotyrosine immunoreactivity is enhanced
in the spinal motoneurons of sporadic and familial ALS patients. The hypothesis is
postulated that increased production of radical species, such as superoxide and peroxynitrite,
may cause motoneuron degeneration in ALS. There are increased amounts of nitric oxide
and SOD hypoactivities in the brain and spinal cord of wobbler mice. NOS is also induced
in the vacuolated spinal motoneurons or axons in this animal. Free radicals might
contribute to the pathogenesis of wobbler mouse motoneuron disease. Lecithinized SOD
treatment has retarded the progression of this disease. This evidence allowed us to
determine whether NOS inhibitors delay progression of wobbler mouse motoneuron disease.
After clinical diagnosis at age 3–4 weeks, wobbler mice were injected with intraperitoneal
non-selective NOS inhibitor, NG-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg), two doses of neuronal NOS inhibitor, 7-nitroindazole (5 or 50 mg/kg)
or a vehicle solution, daily for 4 weeks in a blind fashion. In comparison with vehicle,
7-nitroindazole-treated mice potentiated grip strength and attenuated deformities
in the forelimbs. 7-Nitroindazole treatment increased the biceps muscle weight, reduced
denervation muscle atrophy, and suppressed degeneration of spinal motoneurons. To
a lesser degree, l-NAME-treated mice displayed slowed progression of disease. The present studies indicate
that neuronal NOS inhibitor may be a candidate for promising therapy in lower motoneuron
disease or motor neuropathy.
Keywords
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Article info
Publication history
Accepted:
May 22,
1998
Received in revised form:
May 21,
1998
Received:
December 8,
1997
Identification
Copyright
© 1998 Elsevier Science B.V. Published by Elsevier Inc. All rights reserved.
