A review of the mechanisms and role of monoamine oxidase inhibitors in Parkinson's disease.

Abstract

Monoamine oxidase (MAO), discovered in the 1930s by Balschko, is one of the most important enzymes in neurotransmitter metabolism. MAO inhibitors have played a major role in our understanding of the functional roles of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) neurotransmission in the CNS. Nonselective MAO inhibitors were studied as antidepressants in the late 1950s and 1960s, although their usefulness was limited by their potential to cause a “cheese reaction.” The cheese reaction is associated with the presence of tyramine and other indirectly acting sympathomimetic amines present in food (e.g., cheeses) and alcoholic drinks (e.g., wine). MAO metabolizes most such amines. As a consequence of MAO inhibition, tyramine is not metabolized, which enables it to enter the circulatory system and induce a release of NE from peripheral adrenergic neurons (figure 1). The consequence can be a severe cardiovascular response that leads to hypertensive crisis. Figure 1. The mechanism of potentiation of cardiovascular effects of tyramine, the cheese reaction, and NE release and metabolism after MAO-A inhibition. The demonstration that MAO was not a single enzyme but existed in several forms was strengthened by the observation that the MAO inhibitor clorgyline could differentiate between two forms of MAO.1,2⇓ Johnson2 termed these enzymes type A and type B. The MAO-A enzyme is responsible for the deamination of NA and 5-HT, whereas the MAO-B enzyme metabolizes phenylethylamine (PEA). Tyramine and dopamine are equally well metabolized by both MAO-A and MAO-B (table). 3,4⇓ View this table: Table Some natural and synthetic substrates of monoamine oxidase The presence of MAO-A and MAO-B in postmortem human brains suggested the possibility of developing MAO inhibitors directed at each subtype for the treatment of diseases such as PD and depression.5,6⇓ l-Deprenyl (selegiline), a selective irreversible MAO-B inhibitor, was the first drug shown to …