Objective: To evaluate the effect of biphenyl-indanone A (BINA), a metabotropic glutamate 2 (mGlu₂) receptor positive allosteric modulator (PAM), on parkinsonian disability in the 6-OHDA-lesioned rat as an adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA).

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterised by typical motor symptoms due to death of neurons in the substantia nigra and secondary changes in dopaminergic and glutamatergic transmission. The motor symptoms of PD are treated by L-DOPA, the most effective therapeutic drug. However, chronic use of L-DOPA is associated with development of complications such as dyskinesia and motor fluctuations, necessitating novel therapeutic strategies for treatment of PD motor symptoms. Recently, mGlu₂ receptors have been garnering attention as a novel therapeutic target because of their glutamatergic modulation properties. MGlu₂ receptors could potentially alleviate motor symptoms, by regulating associated aberrant glutamatergic transmission in the synaptic cleft along the basal ganglia circuitry. In this study, we assessed the anti-parkinsonian effect of the mGlu₂ PAM BINA as an adjunct to L-DOPA in 6-OHDA-lesioned rats.

Method: Fifteen 6-OHDA-lesioned female Sprague-Dawley rats were administered L-DOPA/benserazide (3/15 mg/kg) in combination with either vehicle or BINA (0.1 or 1 mg/kg) sub-cutaneously in a randomised within-subject design. They were placed into transparent glass cylinders 45 min after injections for 10-min recordings, which were assessed for post hoc quantification of forepaw rears on the cylinder wall. Individual rears with the forepaw ipsilateral to the 6-OHDA injection, contralateral to the injection and of both forepaws concurrently were counted.

Results: After administration of BINA 1 mg/kg in combination with L-DOPA, there was a significant reduction of the preferential use of the forepaw ipsilateral to 6-OHDA injection (non-parkinsonian forepaw), by 27%, when compared to the L-DOPA/vehicle treatment (P = 0.01, one-way repeated measures [RM] analysis of variance [ANOVA]; P = 0.0496, Tukey’s test).

Conclusion: These results show that BINA may enhance the anti-parkinsonian effect of L-DOPA. The clinical correlate of our findings might be that BINA, and presumably other mGlu₂ PAMs, might be used as an adjunct to L-DOPA in the treatment of PD patients with motor fluctuations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-the-mglu2-positive-allosteric-modulator-biphenyl-indanone-a-on-parkinsonian-disability-in-the-6-hydroxydopamine-lesioned-rat/