title: Neuronal nitric oxide synthase inhibitor, 7-nitroindazole, delays motor dysfunction and spinal motoneuron degeneration in the wobbler mouse.
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, N(G)-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.
authors.affiliation: The Fourth Department of Internal Medicine, Toho University Ohashi Hospital, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: Y
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: M
authors.initials: M
authors.lastname: Kinoshita
mesh_terms: D000690:Amyotrophic Lateral Sclerosis; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D018737:Hand Strength; D007191:Indazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008818:Mice, Neurologic Mutants; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009046:Motor Neurons / Q000473:pathology; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D009929:Organ Size / Q000187:drug effects; D014617:Vacuoles / Q000648:ultrastructure
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D009419:Nerve Tissue Proteins; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester