Objective: To investigate the effect of the metabotropic glutamate 4 (mGlu₄) positive allosteric modulator (PAM) ADX-88178 on parkinsonism, dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.

Background: Positive allosteric modulation of mGlu₄ receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Recently, the development of the mGlu₄ PAM foliglurax was discontinued, after it failed to meet endpoints pertaining to off time and dyskinesia in a clinical trial. Despite this setback, there is abundant evidence in experimental models supporting the use of mGlu₄ PAMs in the treatment of advanced Parkinson’s disease (PD). ADX-88178 is a highly-selective mGlu₄ PAM that previously reversed catalepsy induced by haloperidol in the rat and enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat. Here, we sought to explore the effects of ADX-88178 in the parkinsonian non-human primate.

Method: Six common marmosets were rendered parkinsonian by injection of MPTP. After induction of stable dyskinesias and PLBs, they were administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, sub-cutaneously, in combination with L-DOPA/benserazide (15/3.75 mg/kg), in a randomised fashion. Parkinsonism, dyskinesia and PLBs were then evaluated by a blinded experienced rater.

Results: L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 180 min (13% increase, P<0.05) and 211 min (33% increase, P<0.01), after adding ADX-88178 0.1 and 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P<0.01). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 36% (P<0.05), but did not produce a significant effect on global dyskinesia severity. Whereas ADX-88178 did not have any significant effect on the severity of peak dose PLBs, it mildly worsened global PLBs, by 12% (P<0.05).

Conclusion: These results provide additional evidence of the anti-parkinsonian effect of ADX-88178 as an adjunct to L-DOPA and also indicate that ADX-88178 may alleviate L-DOPA-induced dyskinesia. However, they also suggest that ADX-88178 may not be suitable for PD patients with psychotic manifestations; whether it is a drug-specific or a class effect warrants further investigation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-adx-88178-a-highly-selective-mglu4-pam-on-parkinsonism-dyskinesia-and-psychosis-like-behaviours-in-the-mptp-lesioned-marmoset/