Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency

Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2012; 122(8):2837-46. DOI: 10.1172/JCI59373
Source: PubMed


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.

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Available from: Gail J Pyne-Geithman
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    • "Since in hereditary CRT de¯ciency the Cr/PCr system is altogether absent (Degrauw et al., 2003) there is the possibility that even a small CC/PCC system was e®ective, from a functional point of view, in replacing the missing Cr/PCr system. That this is indeed the case is suggested by recent data showing that treatment with CC is capable to reverse the cognitive impairment of mice lacking the Cr transporter (Kurosawa et al., 2012). Thus, a therapy may ¯nally be in sight for hereditary CRT de¯ciency, a severe disease that has been so far incurable (Degrauw et al., 2003). "
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    ABSTRACT: In in vitro mouse hippocampal slices we investigated whether cyclocreatine is capable of entering brain cells independently of the creatine transporter and if it reproduces the neuroprotective effect of creatine. Our study shows that cyclocreatine does not increase the creatine content, but is taken up as such and then phosphorylated to phosphocyclocreatine. This uptake is largely blocked by inactivation of the creatine transporter, however some cyclocreatine is taken up and posphorylated even after such inactivation. Thus, cyclocreatine sets up a cyclocreatine/phosphocyclocreatine system in the brain independently of the creatine transporter. Cyclocreatine did not delay the disappearance of the evoked synaptic potentials during anoxia in hippocampal slices, unlike creatine which exerts a neuroprotective effect.
    Full-text · Article · Jun 2013 · Journal of Integrative Neuroscience
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    • "lu et al . , 2010 ) . In this context , the availability of a potential effective therapy makes it mandatory to test all females with intellectual dis - ability for CT1 deficiency ( Van de Kamp et al . , 2011 ) . A recent study showed that cognitive deficits in SLC6A8 ) / y mouse can be reversed through nine weeks of treatment with cyclocreatine ( Kurosawa et al . , 2012 ) ."
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