Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency
Yuko Kurosawa, … , Stephen C. Benoit, Joseph F. Clark
Yuko Kurosawa, … , Stephen C. Benoit, Joseph F. Clark
Published July 2, 2012
Citation Information: J Clin Invest. 2012;122(8):2837-2846. https://doi.org/10.1172/JCI59373.
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Research Article Neuroscience

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

Abstract

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8–/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8–/y mouse was comparable to that of human patients. We successfully treated the Slc6a8–/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8–/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8–/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.

Authors

Yuko Kurosawa, Ton J. DeGrauw, Diana M. Lindquist, Victor M. Blanco, Gail J. Pyne-Geithman, Takiko Daikoku, James B. Chambers, Stephen C. Benoit, Joseph F. Clark

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Figure 4

Phosphorylated metabolites in the brain, measured by 31P-MRS.

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Phosphorylated metabolites in the brain, measured by 31P-MRS. An indir...
An indirect measure of the phosphate metabolites was determined by taking the peak height of the metabolite of interest and dividing by the sum of all the other phosphate metabolites. (A) Baseline measurements (n = 3 per group) of inorganic phosphate (Pi), phosphocreatine (PCr), and β-adenosine triphosphate (β-ATP). (B) Ratio of phosphocreatine plus phosphorylated cyclocreatine (PcCr) to total phosphorylated metabolites after 9 weeks of treatment (n = 3 per group). Data are mean ± SEM. *P ≤ 0.05, **P ≤ 0.01 vs. Slc6a8fl/y.