Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned mar
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ORIGINAL ARTICLE
Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned marmoset Adjia Hamadjida 1 & Stephen G. Nuara 2 & Cynthia Kwan 1 & Imane Frouni 1,3 & Dominique Bédard 1 & Jim C. Gourdon 2 & Philippe Huot 1,3,4,5 Received: 6 February 2020 / Accepted: 29 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 LDOPA 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. Keywords Parkinson’s disease . MPTP . Marmoset . Moclobemide . L-DOPA
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01933-y) contains supplementary material, which is available to authorised users. * Philippe Huot [email protected] 1
Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, Montreal, QC H3A 2B4, Canada
2
Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada
3
Département de pharmacologie et physiologie, Université de Montréal, Montreal, QC, Canada
4
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
5
Movement Disorder Clinic, Division of Neurology, Department of Neuroscience, McGill University Health Centre, Montreal, QC, Canada
Chronic administration of L-3,4-dihydroxyphenylalanine (LDOPA) to patients with Parkinson’s disease (PD) leads to motor complications, including dyskinesia and motor fluctuations (Hely et al. 2005). Therapies for motor fluctuations include strategies to reduce the metabolism of dopamine with monoamine oxi
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