Rambam Maimonides Medical Journal
DISCOVERIES FROM THE BENCH TO THE BEDSIDE
Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson’s Disease with Neuroprotective Potential
John P.M. Finberg, Ph.D.*
Departments of Molecular Pharmacology, The Bruce Rappaport Faculty of Medicine, and the Rappaport Institute for Research in the Medical Sciences,Technion-Israel Institute of Technology, Haifa 31096, Israel
ABSTRACT Rasagiline (Azilect) is a highly selective and potent propargylamine inhibitor of monoamine oxidase (MAO) type B. Like other similar propargylamine inhibitors, rasagiline binds covalently to the N5 nitrogen of the flavin residue of MAO, resulting in irreversible inactivation of the enzyme. Therapeutic doses of the drug whichinhibit brain MAO-B by 95% or more cause minimal inhibition of MAO-A, and do not potentiate the pressor or other pharmacological effects of tyramine. Metabolic conversion of the compound in vivo is by hepatic cytochrome P450-1A2, with generation of 1-aminoindan as the major metabolite. Rasagiline possesses no amphetamine-like properties, by contrast with the related compound selegiline (Deprenyl,Jumex, Eldepryl). Although the exact distribution of MAO isoforms in different neurons and tissues is not known, dopamine behaves largely as a MAO-A substrate in vivo, but following loss of dopaminergic axonal varicosities from the striatum, metabolism by glial MAO-B becomes increasingly important. Following subchronic administration to normal rats, rasagiline increases levels of dopamine in striatalmicrodialysate, possibly by the build-up of β-phenylethylamine, which is an excellent substrate for MAO-B, and is an effective inhibitor of the plasma membrane dopamine transporter (DAT). Both of these mechanisms may participate in the anti-Parkinsonian effect of rasagiline in humans. Rasagiline possesses neuroprotective properties in a variety of primary neuronal preparations and neuron-likecell lines, which is not due to MAO inhibition. Recent clinical studies have also demonstrated possible neuroprotective properties of the drug in human Parkinsonian patients, as shown by a reduced rate of decline of symptoms over time. KEY WORDS: monoamine oxidase, dopamine, Parkinson’s disease, neuroprotection, cheese effect
Abbreviations: MAO, monoamine oxidase; DA, dopamine; DAT, plasmamembrane dopamine transporter; NET, plasma membrane noradrenaline transporter; COMT, catechol O-methyl transferase; L-dopa, 3,4-dihydroxyphenylalanine.
Citation: Finberg JPM. Pharmacology of rasagiline, a new MAO-B inhibitor drug for the treatment of Parkinson's disease with
neuroprotective potential. RMMJ 2010;1(1):e0003. doi:10.5041/RMMJ. 10003
Copyright: © 2010 John PM Finberg. This is anopen-access article. All its content, except where otherwise noted, is
distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Conflict of interest: John Finberg is a co-discoverer of rasagiline and benefitsfinancially from sales of the drug.
* E-mail: email@example.com
June 2010 Volume 1 Issue 1 e0003
Pharmacology of Rasagiline INTRODUCTION The most important and debilitating symptoms of Parkinson’s disease are those resulting from dopamine (DA) depletion in the nigro-striatal pathway, although the disease process starts at an earlier stage, and is markedby symptoms such as reduced olfactory sensitivity, autonomic dysfunction, and affective disorder.1 All currently available treatments are symptomatic (Table 1), despite a large effort to find new drugs which can counteract the accelerated rate of neuronal loss, and a major research effort to understand the mechanisms involved in neurodegeneration. The original “DA replacement” therapy, i.e....