The major hypothesis of this proposal is that (1) topiramate protects motor neurons from excitotoxicity. The primary objective of the study is to determine whether chronic oral treatment with Topiramate (maximum of 800 mg/day) slows disease progression in subjects with ALS. The secondary objectives of this study are to assess the long-term safety profile of topiramate in subjects with ALS and to investigate the efficacy of 12 months treatment with topiramate in terms of its effects on respiratory function, activities of daily living, and survival. Amyotrophic lateral sclerosis is a progressive, neurodegenerative disorder for which there currently is no cure. Recent genetic and biochemical studies implicate glutamate excitotoxicity, free radical toxicity, and mitochondrial dysfunction as possible causes of ALS. These three mechanisms may occur in concert. Abnormalities in glutamate levels and glutamate uptake have been found in tissues from subjects with ALS. Based on these abnormalities, Rothestein and colleagues tested topiramate in a cell culture model of motor neuron death. They found a dose dependent significant protection of motor neurons from death by topiramate. Topiramate is an FDA approved drug for epilepsy. Despite recent critical advances in understanding the pathogenesis of ALS, this remains an untreatable disease. Any compound proven to slow the course of illness will be of immediate importance both clinically and from the perspective of understanding the underlying biology of motor neuron disease.
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