Jeffrey T. Henderson, Mohammed Javaheri, SusanKopko and John C. Roder

Samuel Lunenfeld Research Institute, Mount SinaiHospital,
Program in Development and Fetal Health, 600University Ave., Toronto, Ontario M5G-1X5

Journal of Neuroscience, 16(23),pp. 7574-7582, 1996

Abstract

The murine mutant wobbler is a model of lower motor neuron degeneration with associated skeletal muscle atrophy.This mutation most closely resembles Werdnig-Hofmann disease in humans and shares some of the clinical features of amyotrophic lateral sclerosis(ALS). It has been suggested that reactive oxygen species (ROS) may playa role in the pathogenesis of disorders such as ALS. In order to examine the relationship between ROS and neural degeneration, we have studied the effects of agents such as N-acetylcysteine (NAC), which reduce free radical damage. Litters of wobbler mice were given a solution of one percent solution of the glutathione precursor NAC in their drinking water for a period of nine weeks. Functional and neuro-anatomical examination of these animals revealed that wobbler mice treated with NAC exhibited: (1) a significant reduction in motor neuron 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 flexor carpi ulnaris muscles and; (4) increased functional efficiency of the forelimbs compared to untreated wobbler littermates. These data suggest that reactive oxygen species may be involved in the degeneration of motor neurons in wobbler mice, and demonstrate that oral administration of NAC effectively reduces the degree of motor degeneration in wobbler mice. This treatment may thus be applicable in the treatment of other lower motor neuropathies.

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