The highly selective mGlu 2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease

• Published in: The European journal of neuroscience Vol. 51; no. 12; pp. 2412 - 2422
• Main Authors: Hamadjida, Adjia, Sid-Otmane, Lamia, Kwan, Cynthia, Frouni, Imane, Nafade, Vaidehi, Bédard, Dominique, Gagnon, Dave, Wallman, Marie-Josée, Rouillard, Claude, Parent, André, Parent, Martin, Huot, Philippe
• Format: Journal Article
• Language: English
• Published: France 01.06.2020
• Subjects: LY-487,379; l-DOPA; Parkinson's disease; dyskinesia; positive allosteric modulator; mGlu2 receptor
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14679

l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu ) receptor activation with LY-354,740 alleviates dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to determine the role played by selective mGlu activation in the anti-dyskinetic effect of mGlu stimulation and have investigated the effect of the highly selective mGlu positive allosteric modulator LY-487,379 at alleviating established, and preventing the development of, l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat. First, dyskinetic 6-OHDA-lesioned rats were administered l-DOPA in combination with LY-487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6-OHDA-lesioned rats were administered LY-487,379 (0.1 or 1 mg/kg), started concurrently with l-DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY-487,379 on l-DOPA anti-parkinsonian effect. We found that acute challenges of LY-487,379 0.1 mg/kg in combination with l-DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l-DOPA/LY-487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l-DOPA/vehicle. LY-487,379 did not impair l-DOPA anti-parkinsonian activity. These results suggest that mGlu activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.