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Effect of the glycine transporter 1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset.
- Source :
-
European Journal of Pharmacology . Nov2021, Vol. 910, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
-
Abstract
- Dyskinesia and psychosis are complications encountered in advanced Parkinson's disease (PD) following long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA). Disturbances in the glutamatergic system have been associated with both dyskinesia and psychosis, making glutamatergic modulation a potential therapeutic approach for these. Treatments thus far have sought to dampen glutamatergic transmission, for example through blockade of N -methyl-D-aspartate (NMDA) receptors or modulation of metabotropic glutamate receptors 5. In contrast, activation of the glycine-binding site on NMDA receptors is required for their physiological response. Here, we investigated whether indirectly enhancing glutamatergic transmission through inhibition of glycine re-uptake would be efficacious in diminishing both dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned common marmoset. Six marmosets were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA to induce dyskinesia and PLBs, they underwent acute challenges of the glycine transporter 1 (GlyT 1) inhibitor ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of dyskinesia, PLBs and parkinsonian disability was evaluated. In combination with L-DOPA, ALX-5407 0.1 and 1 mg/kg significantly reduced the severity of dyskinesia, by 51% and 41% (both P < 0.001), when compared to vehicle. ALX-5407 0.01, 0.1 and 1 mg/kg also decreased the severity of global PLBs, by 25%, 51% and 38% (all P < 0.001), when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism. Our results suggest that GlyT 1 inhibition may be a novel strategy to attenuate dyskinesia and PLBs in PD, without interfering with L-DOPA anti-parkinsonian action. Inhibition of glycine transporter 1 reduces the expression of established dyskinesia and psychosis in MPTP-lesioned marmosets. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00142999
- Volume :
- 910
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 152739600
- Full Text :
- https://doi.org/10.1016/j.ejphar.2021.174452