Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia.
J Parkinsons Dis
; 14(2): 245-259, 2024.
Article
in En
| MEDLINE
| ID: mdl-38427500
ABSTRACT
Background:
Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release.Objective:
We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1âS,2âR)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia.Methods:
The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats.Results:
Neither Lu AF21934 (10 or 30âmg/kg p.o.) nor ADX88178 (10 or 30âmg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10âmg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats.Conclusions:
This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Parkinson Disease
/
Pyrimidines
/
Thiazoles
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Receptors, Metabotropic Glutamate
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Cyclohexanecarboxylic Acids
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Dyskinesia, Drug-Induced
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Anilides
Limits:
Animals
Language:
En
Journal:
J Parkinsons Dis
Year:
2024
Document type:
Article
Affiliation country: