Glycine transporter blockade ameliorates motor ataxia in a mouse model of spinocerebellar atrophy.
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 beta-D-arabinofuranoside. Intracerebroventricular (i.c.v.) injection of sarcosine (3, 10, and 30 microg) and NFPS (0.01 and 0.03 microg) reduced the number of falls without affecting spontaneous motor activity, and therefore the falling index [(number of falls / spontaneous motor activity) x 100], and dose-dependently ameliorated ataxic movements. Similar effects were observed upon i.c.v. injection of D-serine (1 and 10 microg), an agonist of the glycine-recognition site of the N-methyl-D-aspartate (NMDA) receptor. However, exogenously injected glycine (1, 3, and 10 microg, i.c.v.) only weakly ameliorated the ataxic movements at 3 microg. 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.
Tanabe
Mitsuo
M
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan. mitana@phar.nagoya-cu.ac.jp
Nakano
Tomoharu
T
Honda
Motoko
M
Ono
Hideki
H
D000818:Animals; D001665:Binding Sites; D003561:Cytarabine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000008:administration & dosage / Q000494:pharmacology; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012521:Sarcosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012694:Serine / Q000008:administration & dosage / Q000494:pharmacology; D020754:Spinocerebellar Ataxias / Q000188:drug therapy* / Q000503:physiopathology
D050487:Glycine Plasma Membrane Transport Proteins; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; D016194:Receptors, N-Methyl-D-Aspartate; D003561:Cytarabine; D012694:Serine; D005998:Glycine; D012521:Sarcosine