Objective: To assess the effect of LY-404,039 on dyskinesia and parkinsonism in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD).
Background: LY-404,039 is an orthosteric agonist of metabotropic type 2 and 3 (mGlu2/3) receptors with possible agonist effect at dopamine D2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously entered clinical trials for psychiatric endpoints and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-OHDA-lesioned rat, without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to confirm these results with the mGlu2/3 orthosteric agonist LY-404,039.
Method: Rats were rendered hemi-parkinsonian with injection of 6-OHDA in the right medial forebrain bundle. After 3 weeks of post-surgical recovery, degree of parkinsonism was assessed via the cylinder test; animals displaying > 70% rearing asymmetry were then primed with L-DOPA/benserazide once daily for 2 weeks, to establish severe and reproducible AIMs. On experimental days, rats received L-DOPA in combination with LY-404,039 (0.1, 1 and 10 mg/kg) or vehicle, after which the severity of AIMs was assessed by a blinded rater. These doses of LY-404,039 were selected based upon its pharmacokinetic profile in the rat, to achieve plasma exposure similar to that encountered in the clinic.
Results: The addition of 10 mg/kg LY-404,039 to L-DOPA resulted in a significant reduction of peak dose ALO AIMs (by 45%, P < 0.05). LY-404,039 did not interfere with, nor enhance, the anti-parkinsonian effect of L-DOPA.
Conclusion: These results provide further evidence that mGlu2/3 orthosteric stimulation may alleviate dyskinesia in PD and, because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase II trials rapidly. Of note, as LY-404,039 did not improve the anti-parkinsonian efficacy of L-DOPA, it remains unclear if it activates D2 receptors in vivo.
To cite this abstract in AMA style:
W. Kang, I. Frouni, C. Kwan, L. Desbiens, D. Bédard, A. Hamadjida, P. Huot. Effect of the mGlu2/3 orthosteric agonist LY-404,039 on abnormal involuntary movements and parkinsonism in the 6-OHDA-lesioned rat [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/effect-of-the-mglu2-3-orthosteric-agonist-ly-404039-on-abnormal-involuntary-movements-and-parkinsonism-in-the-6-ohda-lesioned-rat/. Accessed May 15, 2025.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-the-mglu2-3-orthosteric-agonist-ly-404039-on-abnormal-involuntary-movements-and-parkinsonism-in-the-6-ohda-lesioned-rat/