Objective: To assess the effect of the metabotropic glutamate 2 (mGlu2) receptor positive allosteric modulator (PAM) AZD8529 on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD).
Background: AZD8529 is a selective mGlu2 PAM that has undergone clinical trials for schizophrenia and tobacco use disorder. In previous studies, we demonstrated that the selective mGlu2 PAMs LY-487,379 and CBiPES alleviated L-DOPA-induced dyskinesia and PLBs in the MPTP-lesioned marmoset. However, neither has clinically relevant pharmacological properties, contrary to AZD8529, which could be repurposed for PD if efficacious in pre-clinical studies.
Method: Parkinsonism was induced by MPTP injections followed by a recovery period ensuring development of a stable phenotype. Dyskinesia and PLBs were induced by daily oral administration of L-DOPA/benserazide (L-DOPA) for at least 30 days. On experimental days, marmosets were injected with L-DOPA (15/3.75 mg/kg s.c.) along with vehicle or AZD8529 (0.1, 0.3, 1, and 10 mg/kg s.c.). These doses were selected based on the pharmacokinetic profile of AZD8529 in the marmoset, which will be reported separately. After treatment, marmosets were individually recorded in observation cages for 6h. Thus, footage was analysed for dyskinesia, PLBs, and parkinsonism by an experienced blinded rater.
Results: Administration of AZD8529 (0.1, 0.3, 1, and 10 mg/kg) along with L-DOPA resulted in a significant reduction of global dyskinesia severity (by up to 70%, P<0.001), and of on-time with disabling dyskinesia (by up to 97%, P<0.001) when compared to L-DOPA/vehicle. Similarly, there was a significant reduction in global PLB severity (by up to 64%, P<0.001), and of on-time with disabling PLBs (by up to 94%, P<0.001) when compared to L-DOPA/vehicle. Additionally, AZD8529 significantly increased the duration of the anti-parkinsonian action of L-DOPA at doses of 0.3 mg/kg and above (by up to 29%, P<0.05).
Conclusion: Our results demonstrate the potential of mGlu2 positive allosteric modulation for alleviating L-DOPA-induced dyskinesia and PLBs and amplifying L-DOPA anti-parkinsonian effects. Given the previous clinical experience with AZD8529, it could be repurposed for endpoints pertaining to treatment of PD.
To cite this abstract in AMA style:
J. Shaqfah, I. Frouni, C. Kwan, D. Bédard, S. Nuara, J. Gourdon, A. Hamadjida, P. Huot. The mGlu2 positive allosteric modulator AZD8529 alleviates L-DOPA-induced dyskinesia and psychosis-like behaviours in the parkinsonian marmoset [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/the-mglu2-positive-allosteric-modulator-azd8529-alleviates-l-dopa-induced-dyskinesia-and-psychosis-like-behaviours-in-the-parkinsonian-marmoset/. Accessed June 15, 2025.« Back to 2023 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-mglu2-positive-allosteric-modulator-azd8529-alleviates-l-dopa-induced-dyskinesia-and-psychosis-like-behaviours-in-the-parkinsonian-marmoset/