The therapeutic potential of monoamine oxidase inhibitors

Key Points Monoamine oxidase (MAO) inhibitors were among the first antidepressants to be discovered and introduced into the clinic. Early forms have almost disappeared from use as a consequence of their side effects, which include the 'cheese reaction' — that is, stimulation of cardiovascular sympathetic nervous system activity due to a build-up of dietary amines. The identification of two forms of MAO, known as MAOA and MAOB, and their respective selective inhibitors has contributed to a better understanding of their physiological roles, regulation of neurotransmitter metabolism and the mechanism of the 'cheese reaction', and has led to the development of selective inhibitors that avoid this side effect. The two enzymes differ structurally in their substrate–inhibitor recognition sites, but not in their active sites, which contain a covalently bound flavin moiety. Knowledge of the three-dimensional structures of MAOA and MAOB has provided new insights into the way in which MAO interacts with substrates and inhibitors, and has revealed intriguing species differences for MAOA. The discovery that the synthetic compound MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a substrate of MAOB, which converts this compound to the neurotoxin MPP + (1-methyl-4-phenylpyridinium), causing a parkinsonism syndrome in some mouse strains and primates including humans, provided a basis for our understanding of the participation of MAO in dopaminergic neurodegeneration, and MAOB inhibitors as neuroprotective drugs with disease-modifying activity. The propargylamine irreversible MAOB inhibitors, including l -deprenyl (Selegiline) and rasagiline, have shown efficacy in the treatment of Parkinson's disease. These drugs exert a neuroprotective activity not related to MAO inhibition, as shown in cultured neurons and in vivo models of neurodegeneration. The molecular mechanism of this neuroprotective activity involves regulation of B-cell lymphoma/leukaemia 2 (BCL2) family proteins and protein kinase-dependent signalling pathways as well as interactions with glyceraldehyde-3-phosphate dehydrogenase and induction of some antioxidant enzymes. Although considerable advances have been made in our understanding of the structure of MAO, its neurobiology and the mechanisms of action of its selective inhibitors in neuropsychiatric disorders, much remains to be learnt about MAO and its interactions with both substrates and inhibitors. Youdim and colleagues describe how the recent sol