Neuroprotective effects of Creatine in a transgenic mouse model of Huntington's disease RJ Ferrante, OA Andreassen, BG Jenkins, A Dedeoglu, S Kuemmerle, JK Kubilus, R Kaddurah-Daouk, SM Hersch, MF Beal J Neuroscience 2000;20:4389-4397

Dietary supplementation with creatine increases survival, decreases brain atrophy, and improves motor performance in a mouse model of Huntington's disease, according to this report.

Transgenic mice with 151-154 CAG repeats were fed diets supplemented with 1%, 2%, or 3% creatine, beginning at day 21.

Results showed: Survival was 97.7 days in untreated mice, 106.5 days in mice receiving 1% creatine (p<0.0001), 114.6 days in mice receiving 2% creatine (p<0.0001), and 101.9 days in mice receiving 3% creatine (p<0.0002).

Rotarod performance was significantly improved on 2% creatine throughout the lifespan. One percent creatine improved performance less and for a shorter duration, while 3% creatine showed significant improvement of only one time point early on.

All three doses of creatine improved body weight gain, with maximum benefit from the 2% dose.

While unsupplemented mice showed a 20% decrease in brain weight compared to gene-negative litter mates, 2%-supplemented mice had brain weights similar to gene-negative mice up until 90 days. At that point, brain weights in gene-negative, 2%, and untreated mice were 437 g, 407 g, and 348 g, respectively.

Gross brain atrophy was markedly reduced in supplemented mice compared to controls, especially in the neostriatum. “The cytoprotective effect of 2% creatine significantly delayed striatal neuron atrophy. There were no significant differences in neuronal areas in 2% creatine- supplemented mice [compared to gene negative mice] until endstage measurements at 90 days.”

Two percent creatine reduced the number of huntington-positive aggregates in the striatum by 60% - 39% over time compared to controls, but led to only insignificant reductions in the cortex, where aggregates were more prominent.

The authors suggest that creatine administration may improve impaired cellular energetics, noting “there is substantial evidence that energy dysfunction occurs in HD, and that this may play a role in cell death.” Regarding the ineffectiveness of the highest dose of creatine, they suggest that ata very high doses, creatine may be cytotoxic, “similar to observations with cyclocreatine.” They conclude, “The present findings support a role for metabolic dysfunction in a transgenic mouse model of HD and provide further evidence that treatment with creatine might be a novel therapeutic strategy to slow or halt the progression of neurodegeneration in HD.”