Objective: This study investigated the antidyskinetic activity of 4-chlorokynurenine (AV-101) in parkinsonian monkeys with L-Dopa-induced dyskinesias.

Background: The common treatment for Parkinson’s disease (PD) is L-Dopa but dyskinesias develop with time. Glutamate neurotransmission is increased in  PD and L-Dopa-induced dyskinesias (LID). Antagonists of glutamate NMDA receptors reduce dyskinesias but direct acting NMDA antagonists have side effects limiting their therapeutic utility. Inhibiting NMDA receptors by blocking the glycine (Gly_B) co-agonist site historically affords a better safety profile. Increasing kynurenic acid (KYNA) levels, an endogenous Gly_B inhibitor, by blocking kynurenine 3-hydroxylase, reduces LID in MPTP monkeys. L-4‑chlorokynurenine (AV-101) developed by VistaGen is a pro-drug of 7-chlorokynurenic acid (7‑Cl‑KYNA), a potent and selective Gly_B antagonist. AV-101, but not 7‑Cl‑KYNA, crosses the blood-brain barrier barrier and is converted into 7-Cl-KYNA by astrocytes. In non-PD clinical studies, AV-101 was shown to have an excellent safety profile.

Method: Motor behaviour was investigated in MPTP monkeys with LID administered  AV-101 with L-Dopa compared to L-Dopa and vehicle.  Locomotion was measured using the electronic monitoring system Vigie Primate, Viewpoint. The antiparkinsonian score (using the Laval University Parkinson disability scale) and dyskinesia score (using the Laval University dyskinesia scale) were measured from video recordings by an experienced observer blind to the treatments.

Results: A first study using 3 dyskinetic MPTP monkeys showed that AV-101 reduced LID and maintained the antiparkinsonian activity of L-Dopa. A second study using 6 other dyskinetic MPTP monkeys showed that AV-101 (250 and 450 mg/kg) maintained their L-Dopa antiparkinsonian response as measured with their locomotion and their antiparkinsonian score. AV-101 maintained the duration of the L-Dopa motor effect and did not delay its motor effect onset. AV-101 alone or with L-Dopa had no non-motor adverse effects in MPTP monkeys. AV-101 consistently reduced LID.

Conclusion: Our study showed an antidyskinetic activity of AV-101 in 9 MPTP monkeys comparable favorably with fewer adverse effects to amantadine 5 mg/kg (equivalent to the therapeutic dose of 100 mg in human) tested previously in our laboratory in MPTP monkeys. Presented at the 7th Int. Conf. on Parkinson’s and Movement Disorders, Nov. 11, 2019.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/4-chlorokynurenine-inhibits-l-dopa-induced-dyskinesias-in-non-human-parkinsonian-primates/