title: The stereo-specific effect of D-serine ethylester and the D-cycloserine in ataxic mutant mice.
abstract: Spinocerebellar ataxia is one of the most common neurological disorders. However, few therapeutics are effective for the treatment of this disorder. In the present study, we investigated the efficacy of d-serine ethylester and a related substance, d-cycloserine, as therapeutic agents for ataxia in a murine model. Both compounds are known to stereospecific modulate N-methyl-d-aspartate type glutamate receptors, and impaired glutamate-mediated signaling has been implicated in spinocerebellar ataxia. Using a microdialysis method, we found that intraperitoneal administration of d-serine ethylester increases the extracellular content of endogenous d-serine in the mouse cerebellum for at least 3 h. Maximum elevation of the extracellular d-serine was observed at 40 min after injection. An open-field study was used to assay the effect of the d-serine derivatives on movement and ataxia. In mice exhibiting cytosine arabinoside-induced ataxia, d-serine ethylester reduced the falling index in a dose-dependent manner. The effect of d-serine ethylester was stereo-specific in that l-serine ethylester had no effect on the falling index at the maximum doses tested, and was partially inhibited by 5,7-dichlorokynurenate, an antagonist that binds to the glycine-binding site. Locomotor activity was not changed by the d-serine ethylester treatment. d-cycloserine also significantly reduced the falling index of the mice. Both d-serine ethylester and d-cycloserine had longer lasting effects than other potential therapeutic reagents for ataxia. Growing evidence suggests the essential involvement of endogenous d-serine in mammalian brain function, and our results suggest that d-serine derivatives may represent an effective new therapeutic for the treatment of spinocerebellar ataxia.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Saigoh
authors.forename: K
authors.initials: K
authors.lastname: Matsui
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Nishikawa
authors.forename: K
authors.initials: K
authors.lastname: Wada
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003523:Cycloserine / Q000627:therapeutic use*; D003561:Cytarabine; D005110:Extracellular Space; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008818:Mice, Neurologic Mutants; D017551:Microdialysis; D012694:Serine / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D013237:Stereoisomerism
chemical_list: D003561:Cytarabine; D012694:Serine; D003523:Cycloserine