Objective: To determine the effect of glycine transporter 1 (GlyT1) inhibition with ALX-5407 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism severity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.
Background: Advanced Parkinson’s disease (PD) is often complicated by the occurrence of dyskinesia and psychosis after long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA). GlyT1 inhibition could possibly be a target to improve these symptoms by modulating N-methyl-D-aspartate (NMDA) transmission along the hyper-direct pathway, thereby leading to a reduction of dyskinesia and an improvement of psychosis.
Method: Six common marmosets (Callithrix jacchus, 3 females and 3 males) were rendered parkinsonian by MPTP injection. Following repeated administration of L-DOPA/benserazide (L-DOPA) to induce stable dyskinesia and PLBs, they were administered acute challenges of ALX-5407 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA, after which the severity of each of dyskinesia, PLBs and parkinsonian disability were assessed.
Results: When added to L-DOPA, ALX-5407 (0.01, 0.1 and 1 mg/kg) significantly reduced the severity of global dyskinesia by 32% (P < 0.05), 52% (P < 0.01) and 41% (P < 0.01), when compared to L-DOPA/vehicle. The anti-dyskinetic effect of ALX-5407 (0.1 and 1 mg/kg) was accompanied by a decrease of global PLBs severity by 52% (P < 0.01), and 37% (P < 0.05) when compared to vehicle. The benefits on dyskinesia and PLBs were achieved without compromising the therapeutic effect of L-DOPA on parkinsonism.
Conclusion: Our results suggest that GlyT1 inhibition may simultaneously attenuate dyskinesia and PLBs without interfering with L-DOPA anti-parkinsonian action. However, the therapeutic effects of ALX-5407 did not follow a dose-response curve, with apparent loss of efficacy at the highest dose administered; whether this phenomenon is specific to this molecule or would also be encountered with other GlyT1 inhibitors remains undetermined.
To cite this abstract in AMA style:
I. Frouni, SG. Nuara, D. Bédard, A. Hamadjida, JC. Gourdon, P. Huot. Effect of the GlyT1 inhibitor ALX-5407 on dyskinesia, psychosis-like behaviours and parkinsonism in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/effect-of-the-glyt1-inhibitor-alx-5407-on-dyskinesia-psychosis-like-behaviours-and-parkinsonism-in-the-mptp-lesioned-marmoset/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-the-glyt1-inhibitor-alx-5407-on-dyskinesia-psychosis-like-behaviours-and-parkinsonism-in-the-mptp-lesioned-marmoset/