Abstract
Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson’s disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (− 36% with 0.1 mg/kg, P < 0.05; − 38% with 1 mg/kg, P < 0.01; − 47% with 10 mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.
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PH has research support from Parkinson Canada, Fonds de Recherche Québec–Santé, the Weston Brain Institute, the Michael J Fox Foundation for Parkinson’s Research, the Natural Sciences and Engineering Research Council of Canada and Healthy Brains for Healthy Lives.
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AH, SN, JC and PH conceived and designed research. AH, SN, CK, IF, DB and JC conducted experiments. PH analysed data. PH wrote the manuscript. All authors read and approved the manuscript.
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Experiments were approved by McGill University and the Montreal Neurological Institute Animal Care Committees, which are in accordance with the regulations defined by the Canadian Council on Animal Care.
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Hamadjida, A., Nuara, S.G., Kwan, C. et al. Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned marmoset. Naunyn-Schmiedeberg's Arch Pharmacol 393, 2157–2164 (2020). https://doi.org/10.1007/s00210-020-01933-y
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DOI: https://doi.org/10.1007/s00210-020-01933-y