REDUCTION OF LOWER MOTOR-NEURON DEGENERATION IN WOBBLER MICE BY N-ACETYL-L-CYSTEINE

The murine mutant wobbler is a model of lower motoneuron degeneration with associated skeletal muscle atrophy. This mutation most closely re sembles Werdnig-Hofmann disease in humans and shares some of the clini cal features of amyotrophic lateral sclerosis (ALS). It has been sugge sted that reactive oxygen species (ROS) may play a role in the pathoge nesis of disorders such as ALS. To examine the relationship between RO S and neural degeneration, we have studied the effects of agents such as N-acetyl-c-cysteine (NAG), which reduce free radical damage. Litter s of wobbler mice were given a 1% solution of the glutathione precurso r NAC in their drinking water for a period of 9 weeks. Functional and neuroanatomical examination of these animals revealed that wobbler mic e treated with NAC exhibited (1) a significant reduction in motor neur on loss and elevated glutathione peroxidase levels within the cervical spinal cord, (2) increased axon caliber in the medial facial nerve, ( 3) increased muscle mass and muscle fiber area in the triceps and flex or carpi ulnaris muscles, and (4) increased functional efficiency of t he forelimbs, as compared with untreated wobbler littermates. These da ta suggest that reactive oxygen species may be involved in the degener ation of motor neurons in wobbler mice and demonstrate that oral admin istration of NAC effectively reduces the degree of motor degeneration in wobbler mice. This treatment thus may be applicable in the treatmen t of other lower motor neuropathies.