Objective: To assess the effect of LY-404,039 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson’s disease (PD).

Background: LY-404,039, an orthosteric agonist of metabotropic glutamate 2 and 3 (mGlu_2/3) receptors that may harbour additional agonist effect at dopamine D₂ receptor. LY-404,039 and its pro-drug, LY-2140023, have previously entered clinical trials as treatment option for schizophrenia. They could therefore be repurposed, if proven potent for other conditions, notably PD. We have recently shown that the mGlu_2/3 orthosteric agonist LY-354,740 alleviated dyskinesia and PLBs in the MPTP-lesioned marmoset. Unlike LY-404,039, LY-354,740 does not stimulate D₂ receptors, suggesting that LY-404,039 may elicit broader therapeutic effects in PD.

Method: Marmosets were rendered parkinsonian by repeated MPTP injection. Following a recovery period to allow for the development of a parkinsonian phenotype, dyskinesia and PLBs were elicited by daily treatment with oral L-DOPA for minimum of 30 days. On experiment days, marmosets were injected L-DOPA with either vehicle or LY-404,039 (0.1, 0.3, 1, and 10 mg/kg). The doses of LY-404,039 were based on its pharmacokinetic profile in the marmoset (to be reported separately). Each marmoset was then place individually into an observation cage and recorded via webcam. Footage was analysed post hoc for parkinsonism, dyskinesia and PLBs.

Results: The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of global dyskinesia (by 55%, P < 0.01) and PLBs (by 50%, P < 0.05), as well a significant enhancement of the anti-parkinsonian action of L-DOPA (by 47%, P < 0.05).

Conclusion: The results of the present study further reinforce the paradigm of mGlu_2/3 orthosteric stimulation at alleviating dyskinesia and PLBs in PD. Moreover, the possible agonistic effect of LY-404,039 at D₂ receptors might represent an additional therapeutic asset; indeed, in previous experiments, with LY-354,740 in the MPTP-lesioned marmoset, the extra anti-parkinsonian effect obtained was 17%, when LY-354,740 was added to L-DOPA. Because LY-404,039 has already been tested in clinical trials, it could be repurposed for indications related to PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-the-mglu2-3-orthosteric-agonist-ly-404039-on-dyskinesia-psychosis-like-behaviours-and-parkinsonism-in-the-mptp-lesioned-marmoset/