title: 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: Department of Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors: Yuko
authors: Y
authors: Kurosawa
authors: Ton J
authors: TJ
authors: Degrauw
authors: Diana M
authors: DM
authors: Lindquist
authors: Victor M
authors: VM
authors: Blanco
authors: Gail J
authors: GJ
authors: Pyne-Geithman
authors: Takiko
authors: T
authors: Daikoku
authors: James B
authors: JB
authors: Chambers
authors: Stephen C
authors: SC
authors: Benoit
authors: Joseph F
authors: JF
authors: Clark
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D003404:Creatinine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D048289:Imidazolidines / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008568:Memory / Q000187:drug effects; D038901:X-Linked Intellectual Disability / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D010725:Phosphocreatine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D017931:DNA Primers; D048289:Imidazolidines; D026901:Membrane Transport Proteins; C080679:creatine transporter; D010725:Phosphocreatine; C012487:phosphocyclocreatine; C012260:cyclocreatine; D003404:Creatinine