Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis

Mitochondria are particularly vulnerable to oxidative stress, and mitochond rial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations(1,2). Mice with the G93A human SOD1 mutation have alte red electron transport enzymes, and expression of the mutant enzyme in vitr o results in a loss of mitochondrial membrane potential and elevated cytoso lic calcium concentration(3). Mitochondrial dysfunction may lead to ATP dep letion, which may contribute to cell death. If this is true, then buffering intracellular energy levels could exert neuroprotective effects. Creatine kinase and its substrates creatine and phosphocreatine constitute an intric ate cellular energy buffering and transport system connecting sites of ener gy production (mitochondria) with sites of energy consumption(4) and creati ne administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore(5). We found that oral admini stration of creatine produced a dose-dependent improvement in motor perform ance and extended survival in G93A transgenic mice, and it protected mice f rom loss of both motor neurons and substantia nigra neurons at 120 days of age. Creatine administration protected G93A transgenic mice from increases in biochemical indices of oxidative damage. Therefore, creatine administrat ion may be a new therapeutic strategy for ALS.