1999 Fiscal Year Final Research Report Summary
EXPLORATORY STUDY FOR ESTABLISHING A NEW THERAPY WITH ENDOGENOUS D-AMINO ACIDS IN MOTOR ATAXIA
| Project/Area Number |
09558100
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | National Institute of Neuroscience, National Center of Neurology and Psychiatry |
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Principal Investigator |
WADA Keiji National Institute of Neuroscience, Department of Degenerative Neurological Diseases, Director, 神経研究所・疾病研究第4部, 部長 (70250222)
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| Co-Investigator(Kenkyū-buntansha) |
MORITA Takuma Yamanouchi Pharmaceutical Co., Pharmacology Institute, Senior Researcher, 薬理研究所, 研究員
NISHIKAWA Toru National Institute of Neuroscience, Department of Mental Disorder Research, Director, 神経研究所・疾病研究第3部, 部長 (00198441)
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| Project Period (FY) |
1997 – 1999
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| Keywords | animal model / spinocerebellar degeneration / motor ataxia / amino acid / D-serine / glutamate receptor / NMDA receptor / medicine |
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| Research Abstract |
In this study, we aimed to develop a new medicine to treat spinocerebellar ataxia, which is one of the most common neurological disorders. To our knowledge, 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 streospecific modulate N-methyl-d-aspartate (NMDA) type glutamate receptors, and impaired glutamate-mediated signaling has been implicated in spinocerebellar ataxia. Using a microdialysis method, we first found that intraperitoneal administration of D-serine ethylester increases the extracellular content of endogenous D-serine in the mouse cerebellum for at leas 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 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 in human.
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