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Effect of glycine transporter 1 inhibition with bitopertin on parkinsonism and L-DOPA induced dyskinesia in the 6-OHDA-lesioned rat.
- Source :
-
European Journal of Pharmacology . Aug2022, Vol. 929, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
-
Abstract
- Dyskinesia remains an unmet need in Parkinson's disease (PD). We have previously demonstrated that glycine transporter 1 (GlyT1) inhibition with ALX-5407 reduces dyskinesia and slightly improves parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine the effect of bitopertin, a clinically-tested GlyT1 inhibitor, on parkinsonism and dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat. To do so, we assessed the effect of bitopertin on parkinsonism as monotherapy and as adjunct to a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA). We then assessed the efficacy of bitopertin on dyskinesia in the context of acute challenge and chronic administration studies. Lastly, we evaluated whether de novo treatment with bitopertin, started concurrently with L-DOPA, would diminish the development of dyskinesia. We discovered that bitopertin (0.3 mg/kg), when administered alone, reduced the severity of parkinsonism by 35% (P < 0.01). As adjunct to a low dose of L-DOPA, bitopertin (3 mg/kg) enhanced the anti-parkinsonian effect of L-DOPA by 36% (P < 0.05). Moreover, the acute addition of bitopertin (0.03 mg/kg) to L-DOPA reduced dyskinesia by 27% (P < 0.001), and there was no tolerance to the anti-dyskinetic benefit after 4 weeks of daily administration. Lastly, bitopertin (0.03 mg/kg) started concurrently with L-DOPA, also attenuated the development of dyskinesia, by 33% (P < 0.01), when compared to L-DOPA alone. Our results suggest that GlyT1 inhibition may simultaneously reduce parkinsonism and L-DOPA-induced dyskinesia and represents a novel approach to treat, possibly prevent, motor complications in PD. [ABSTRACT FROM AUTHOR]
- Subjects :
- *GLYCINE agents
*DYSKINESIAS
*PARKINSONIAN disorders
*DOPA
*PARKINSON'S disease
*RATS
Subjects
Details
- Language :
- English
- ISSN :
- 00142999
- Volume :
- 929
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 158116870
- Full Text :
- https://doi.org/10.1016/j.ejphar.2022.175090