Category: Neuropharmacology
Objective: To evaluate the effect of the glycine transporter 1 (GlyT1) inhibitor bitopertin at preventing dyskinesia development in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD).
Background: Despite significant advances, dyskinesia remains an unmet need in the treatment of PD. We have previously shown that GlyT1 inhibition with ALX-5407 resulted in a reduction of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and that bitopertin diminished abnormal involuntary movements (AIMs) in the 6-OHDA-lesioned rat.
Method: Experiments were performed in Sprague-Dawley rats that were injected with 6-OHDA into the right medial forebrain. The degree of parkinsonism was assessed using the cylinder test. Rats were then divided in 3 groups and administered one of the following treatments once daily for 29 days: L-DOPA/vehicle, L-DOPA/bitopertin 0.03 mg/kg and L-DOPA/bitopertin 0.3 mg/kg and the development of axial, limbs and oro-lingual (ALO) AIMs was monitored. Animals then were allowed a 3-day washout, after which they underwent a L-DOPA challenge and the severity of ALO AIMs was rated.
Results: Over a 4-week period, rats treated with L-DOPA/bitopertin, regardless of the dose, constantly expressed milder integrated ALO AIMs, when compared to rats treated with L-DOPA/vehicle. On day 29, rats treated with L-DOPA/vehicle showed an increase of integrated ALO AIMs severity of 706% (P < 0.0001) when compared to day 1, while rats treated with L-DOPA/bitopertin 0.03 mg/kg and L-DOPA/bitopertin 0.3 mg/kg presented 72% (P > 0.05) and 242% (P < 0.0001) increases of integrated ALO AIMs severity, respectively, when compared to day 1. After the 3-day washout, rats treated with L-DOPA/bitopertin 0.03 mg/kg showed 33% (P < 0.01) lower integrated ALO AIMs scores, when compared to rats that had been administered L-DOPA alone during the induction phase.
Conclusion: Our results indicate that GlyT1 inhibition may interfere with the development of L-DOPA-induced dyskinesia and may be a promising strategy to attenuate the occurrence of this motor complication.
To cite this abstract in AMA style:
I. Frouni, W. Kang, D. Bédard, S. Belliveau, C. Kwan, A. Hamadjida, P. Huot. Bitopertin, a GlyT1 inhibitor, attenuates the development of dyskinesia in the 6-OHDA-lesioned rat [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/bitopertin-a-glyt1-inhibitor-attenuates-the-development-of-dyskinesia-in-the-6-ohda-lesioned-rat/. Accessed November 21, 2024.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/bitopertin-a-glyt1-inhibitor-attenuates-the-development-of-dyskinesia-in-the-6-ohda-lesioned-rat/