Objective: To assess the effect of selective metabotropic glutamate type 2 (mGlu2) receptor activation on parkinsonism as monotherapy in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset compared to the mainstay treatment of L-3,4-dihydroxyphenylalanine (L-DOPA).

Background: The excessive glutamatergic activity in Parkinson’s disease may be alleviated by mGlu2 receptor activation, where inhibition of glutamate release in overactive cortico-striatal synapses may improve motor features of the disease. We previously demonstrated that mGlu2 receptor activation via the positive allosteric modulator (PAM) LY-487,379 elicits a reversal of parkinsonian deficits when administered as monotherapy. However, the pharmacokinetic properties of LY-487,379 are suboptimal, suggesting that higher efficacy might be achieved with compounds with more optimal properties. Here, we sought to examine the effect of the mGlu2 PAM biphenylindanone A (BINA) because it exhibits superior selectivity, brain penetrance, and longer half-life, features that may be associated with a greater anti-parkinsonian benefit. To this end, we administered BINA as monotherapy to MPTP-lesioned marmosets and assessed its effect on parkinsonism.

Method: Six common marmosets (Callithrix jacchus, 3 of each sex) were rendered parkinsonian by injection of MPTP. Animals were randomised in a within-subjects design and administered one of the following treatments: vehicle/vehicle, vehicle/BINA (0.1, 1 or 10 mg/kg) or L-DOPA/vehicle. Parkinsonism severity was assessed post hoc.

Results: Whereas L-DOPA diminished global parkinsonism severity by 44% (P < 0.0001), BINA 1 and 10 mg/kg led to a reduction of 22% (P < 0.01) and 48% (P < 0.0001). This improvement in parkinsonism was accompanied by a significant increase of on-time from 24 min with vehicle to 112 min with BINA 10 mg/kg (P < 0.0001), albeit on-time was highest (176 min) with L-DOPA (P < 0.0001).

Conclusion: Our results suggest that monotherapy with mGlu2 receptor positive allosteric modulation may improve parkinsonism in the MPTP-lesioned marmoset to a similar extent as L-DOPA. Therefore, mGlu2 positive allosteric modulation might represent an attractive treatment approach in early Parkinson’s disease, in the context of a L-DOPA-sparing strategy, by providing management of symptoms whilst lowering risk of motor complications.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/administration-of-the-mglu2-positive-allosteric-modulator-bina-as-monotherapy-improves-parkinsonism-in-the-mptp-lesioned-marmoset/