Objective: To investigate the effect of selective metabotropic glutamate type 2 (mGlu2) receptor positive allosteric modulation on the anti-parkinsonian action of a low dose of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.
Background: In previous experiments, we discovered that mGlu2 positive allosteric modulation enhances the anti-parkinsonian action of an optimal dose of L-DOPA. Here, we aimed to further characterise the anti-parkinsonian potential of mGlu2 positive allosteric modulation, by determining if it would also enhance the effects of a low dose of L-DOPA, defined as a dose that would mildly and briefly reverse parkinsonian signs. To do so, we employed the selective mGlu2 positive allosteric modulator (PAM) LY-487,379.
Method: A parkinsonian phenotype was induced in 6 common marmosets (Callithrix jacchus, 3 females and 3 males) by MPTP injection. Marmosets were then administered the following treatments, in a randomised within-subject fashion: L-DOPA/vehicle, L-DOPA/LY-487,379 0.1 mg/kg, L-DOPA/LY-487,379 1 mg/kg and L-DOPA/LY-487,379 10 mg/kg, after which the severity of parkinsonism was assessed by a blinded rater. The doses of LY-487,379 were selected from prior studies we performed in the marmoset.
Results: LY-487,379 1 and 10 mg/kg both provided additional anti-parkinsonian benefit, when added to L-DOPA, the former dose by 27% (P < 0.05) and the latter, by 44% (P < 0.001), when compared to L-DOPA alone. No significant additional benefit was obtained with the lowest dose of LY-487,379.
Conclusion: Our results suggest that mGlu2 positive allosteric modulation may enhance the anti-parkinsonian action of a low dose of L-DOPA. A potential therapeutic application may be in the treatment of early Parkinson’s disease, where mGlu2 PAMs could be employed as DOPA-sparing drugs, to delay and minimise the development of motor complications.
To cite this abstract in AMA style:
C. Kwan, I. Frouni, S. Nuara, S. Belliveau, A. Hamadjida, W. Kang, D. Bédard, J. Gourdon, P. Huot. LY-487,379 enhances the anti-parkinsonian action of a low dose of L-DOPA in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/ly-487379-enhances-the-anti-parkinsonian-action-of-a-low-dose-of-l-dopa-in-the-mptp-lesioned-marmoset/. Accessed May 12, 2025.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/ly-487379-enhances-the-anti-parkinsonian-action-of-a-low-dose-of-l-dopa-in-the-mptp-lesioned-marmoset/