| Mitochondria are particularly vulnerable to oxidative stress, and
mitochondrial swelling and vacuolization are among the earliest
pathologic features found in two strains of transgenic amyotrophic
lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A
human SOD1 mutation have altered electron transport enzymes, and
expression of the mutant enzyme in vitro results in a loss of
mitochondrial membrane potential and elevated cytosolic calcium
concentration. Mitochondrial dysfunction may lead to ATP depletion,
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 intricate cellular energy buffering and transport
system connecting sites of energy production (mitochondria) with
sites of energy consumption, and creatine administration stabilizes
the mitochondrial creatine kinase and inhibits opening of the
mitochondrial transition pore. We found that oral administration of
creatine produced a dose-dependent improvement in motor performance
and extended survival in G93A transgenic mice, and it protected mice
from 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 administration may be a new therapeutic strategy for ALS.
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