Monoamine oxidase A inhibition as monotherapy reverses parkinsonism in the MPTP-lesioned marmoset
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ORIGINAL ARTICLE
Monoamine oxidase A inhibition as monotherapy reverses parkinsonism in the MPTP-lesioned marmoset Adjia Hamadjida 1 & Stephen G. Nuara 2 & Imane Frouni 1,3 & Cynthia Kwan 1 & Dominique Bédard 1 & Jim C. Gourdon 2 & Philippe Huot 1,3,4,5 Received: 24 February 2020 / Accepted: 17 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Monoamine oxidase (MAO) type B (MAO-B) inhibition was shown to confer anti-parkinsonian benefit as monotherapy and adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in clinical trials. Here, we explore the anti-parkinsonian effect of MAO type A (MAO-A) inhibition as monotherapy, as the enzyme MAO-A is also encountered within the primate and human basal ganglia, where it metabolises dopamine, albeit to a lesser extent than MAO-B. In six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, we assessed the anti-parkinsonian effect of the reversible MAO-A inhibitor moclobemide (0.1 and 1 mg/kg) as monotherapy and compared it to that of L-DOPA and vehicle treatments. Moclobemide significantly reversed parkinsonism (by 39%, P < 0.01), while eliciting only mild dyskinesia and psychosis-like behaviours (PLBs). In contrast, LDOPA anti-parkinsonian effect was accompanied by marked dyskinesia and PLBs. MAO-A inhibition with moclobemide may provide anti-parkinsonian benefit when administered without L-DOPA and might perhaps be considered as monotherapy for the treatment of Parkinson’s disease in the early stages of the condition. Keywords Parkinson’s disease . MPTP . Marmoset . Moclobemide
Introduction As the cardinal manifestations of Parkinson’s disease (PD) are caused by degeneration of dopaminergic neurons from the substantia nigra pars compacta with resulting reduction of Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01927-w) contains supplementary material, which is available to authorized users. * Philippe Huot [email protected] 1
Neurodegenerative Disease Group, Montreal Neurological Institute, 3801 University St, Montreal, Quebec H3A 2B4, Canada
2
Comparative Medicine & Animal Resource Centre, McGill University, Montreal, Quebec, Canada
3
Département de pharmacologie et physiologie, Université de Montréal, Montreal, Quebec, Canada
4
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
5
Movement Disorder Clinic, Division of Neurology, Department of Neuroscience, McGill University Health Centre, Montreal, Quebec, Canada
dopamine within the striatum, the treatment of PD consists of employing strategies that will enhance striatal dopaminergic transmission (Connolly and Lang 2014). To this end, several agents are used, notably L-3,4-dihydroxyphenylalanine (LDOPA), dopamine agonists, catechol-O-methyltransferase inhibitors, amantadine and anti-cholinergic drugs (Kulisevsky et al. 2018; Dietrichs and Odin 2017). Monoamine oxidase (MAO) type B (MAO-B) inhibition is also an effective anti-parkinsonian approach, as monotherapy and
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