Objective: To determine the effect of glycine transporter 1 (GlyT1) inhibition with bitopertin on dyskinesia in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD).
Background: We hypothesised that enhancing N-methyl-D-aspartate (NMDA) transmission along the hyper-direct pathway would result in a reduction of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in PD. As direct enhancement of glutamatergic transmission may result in excitotoxicity, we elected to increase surrounding levels of the NMDA co-agonist glycine, via inhibition of the GlyT1. We administered the clinic-ready GlyT1 inhibitor bitopertin to 6-OHDA-lesioned rats and assessed its effect on L-DOPA-induced abnormal involuntary movements (AIMs).
Method: Hemi-parkinsonism was induced by stereotaxic injection of 6-OHDA into the medial forebrain bundle. The degree of parkinsonism was assessed using the cylinder test. Rats were then primed with L-DOPA to induce stable axial, limbs and oro-lingual (ALO) AIMs. Following the dyskinesia induction period, rats were administered bitopertin (0.03, 0.1, 0.3, 1 and 3 mg/kg s.c) or vehicle in combination with L-DOPA and the severity of ALO AIMs was rated. The effect of bitopertin on L-DOPA anti-parkinsonian action was also determined, by the cylinder test.
Results: The addition of bitopertin (0.03, 0.1 and 3 mg/kg s.c) to L-DOPA resulted in significantly diminished global cumulative ALO AIMs by 23% (P < 0.05), 23% (P < 0.01) and 31% (P < 0.05), when compared to L-DOPA alone. The anti-dyskinetic effect of bitopertin was accompanied by an enhancement of L-DOPA anti-parkinsonian action by 36% (P < 0.05).
Conclusion: Our results suggest that GlyT1 inhibition may simultaneously target parkinsonism and L-DOPA-induced dyskinesia and represents a possible novel approach to alleviate motor complications.
To cite this abstract in AMA style:
I. Frouni, W. Kang, C. Kwan, D. Bedard, A. Hamadjida, P. Huot. The GlyT1 inhibitor bitopertin reduces in the 6-OHDA-lesioned rat model of Parkinson’s disease [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/the-glyt1-inhibitor-bitopertin-reduces-in-the-6-ohda-lesioned-rat-model-of-parkinsons-disease/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-glyt1-inhibitor-bitopertin-reduces-in-the-6-ohda-lesioned-rat-model-of-parkinsons-disease/