Glycine Transporter Blockade Ameliorates Motor Ataxia in a Mouse Model of Spinocerebellar Atrophy
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概要
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Ataxic movement, the common major symptom of spinocerebellar atrophy, has been considered to involve impaired glutamatergic excitatory neurotransmission in the cerebellum. Considering the therapeutic importance of ataxia control, we assessed the effectiveness of increasing the extracellular concentration of glycine by administering it exogenously or via blockade of glycine transporter 1, using its selective inhibitors sarcosine and N-[3-(4-fluorophenyl)-3-(4-phenylphenoxy)propyl]sarcosine (NFPS), for amelioration of motor ataxia in a mouse model of spinocerebellar atrophy developing after neonatal treatment with cytosine β-<sc>D</sc>-arabinofuranoside. Intracerebroventricular (i.c.v.) injection of sarcosine (3, 10, and 30 μg) and NFPS (0.01 and 0.03 μg) reduced the number of falls without affecting spontaneous motor activity, and therefore the falling index [(number of falls / spontaneous motor activity) × 100], and dose-dependently ameliorated ataxic movements. Similar effects were observed upon i.c.v. injection of <sc>D</sc>-serine (1 and 10 μg), an agonist of the glycine-recognition site of the N-methyl-<sc>D</sc>-aspartate (NMDA) receptor. However, exogenously injected glycine (1, 3, and 10 μg, i.c.v.) only weakly ameliorated the ataxic movements at 3 μg. These results suggest the therapeutic relevance of GlyT1 inhibitors for amelioration of motor ataxia in spinocerebellar atrophy by increasing the endogenous concentration of glycine near the glycine-recognition site of the NMDA receptor.
- 社団法人 日本薬理学会の論文
- 2009-03-20
著者
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HONDA Motoko
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University
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TANABE Mitsuo
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University
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ONO Hideki
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University
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Ono Hideki
Laboratory Of Cns Pharmacology Graduate School Of Pharmaceutical Sciences Nagoya City University
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Honda Motoko
Laboratory Of Cns Pharmacology Graduate School Of Pharmaceutical Sciences Nagoya City University
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Tanabe Mitsuo
名古屋大学 薬学研究科中枢神経機能薬理学
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Tanabe Mitsuo
Laboratory Of Cns Pharmacology Graduate School Of Pharmaceutical Sciences Nagoya City University
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Nakamura Tomoka
Laboratory Of Cns Pharmacology Graduate School Of Pharmaceutical Sciences Nagoya City University
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NAKANO Tomoharu
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University
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Ono Hideki
Laboratory Of Cns Pharmacology Graduate School Of Pharmaceutical Sciences
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Tanabe Mitsuo
Laboratory Of Pharmacology School Of Pharmacy Kitasato University
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