Objective: To evaluate the effect of the metabotropic glutamate 2/3 (mGlu_2/3) orthosteric activators (OAs) LY-354,740 and LY-404,039, as well as the effects of the metabotropic glutamate 2 (mGlu₂) positive allosteric modulators (PAMs) LY-487,379 and CBiPES on various parameters used to quantify the severity of parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.

Background: We have previously shown that selective activation of mGlu₂ receptors and concurrent activation of mGlu_2/3 receptors enhances the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Thus, when administered in combination with L-DOPA, each of LY-354,740, LY-404,039, LY-487,379 and CBiPES conferred additional anti-parkinsoinan benefit. In the scale used to rate parkinsonian disability, 4 parameters are evaluated: range of movement, bradykinesia, posture and alertness. In this study, we examined the effect of each molecule on these individual parameters.

Method: Ten MPTP-lesioned marmosets were administered L-DOPA/benserazide (15/3.75 mg/kg) in combination with LY-354,740 (vehicle, 0.1, 0.3, 1 mg/kg), LY-404,039 (vehicle, 0.1, 1, 10 mg/kg), LY-487,379 (vehicle, 0.1, 1, 10 mg/kg) and CBiPES (vehicle, 0.1, 1, 10 mg/kg). Following treatment administration, marmosets were recorded in individual observation cages and their behaviour was analysed post hoc, by a blinded rater. For each molecule, doses were administered according to a randomised Latin square design and a washout of at least 2 weeks was left before another compound would be tested.

Results: When added to L-DOPA and in comparison to L-DOPA/vehicle, LY-354,740 1 mg/kg improved posture by 35% (P < 0.05); LY-404,039 10 mg/kg alleviated bradykinesia by 46% (P < 0.05), improved posture by 44% (P < 0.05) and enhanced alertness by 52% (P < 0.05); CBiPES 10 mg/kg diminished bradykinesia by 45% (P < 0.05), improved posture by 39% (P < 0.05) and increased alertness by 78% (P < 0.01). LY-487,379 did not have any effect on the individual parameters. None of the compounds significantly altered the range of movement parameter.

Conclusion: These results suggest that mGlu_2/3 OAs and mGlu₂ PAMs may improve each of bradykinesia, posture and alertness, when added to L-DOPA. These benefits on individual parameters might be informative in the design of future clinical trials with mGlu₂ and mGlu_2/3 activators.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-various-mglu2-and-mglu2-3-activators-on-parkinsonism-a-sub-analysis-in-the-mptp-lesioned-primate/