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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.

Abstract

Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.

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Figure 1: Dopamine synthesis and its metabolism by MAOA and MAOB.
Figure 2: The crystal structure of human MAOB.
Figure 3: Comparison of human MAOB and rat MAOA active site cavities.
Figure 4: The crystal structure of MAOB and effect of stereochemistry on rasagiline binding to human MAOB.
Figure 5: The mechanism of potentiation of cardiovascular effects of tyramine: the 'cheese reaction'.
Figure 6: The mechanism of neurotoxin-induced neuronal death and its prevention by propargylamines.
Figure 7: The proposed mechanism of neuroprotection and/or neurorescue by propargylamine MAO inhibitors.

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Acknowledgements

M.B.H.Y. would like to thank the National Parkinson Foundation, Miami, USA, the Michael J. Fox Foundation, New York, USA, and Technion Research and Development and Teva Pharmaceutical Co., Netanya, Israel, for their support. K.F.T. is grateful to the Health Research Board and Science Foundation of Ireland for support.

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Correspondence to Moussa B. H. Youdim.

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M.B.H.Y. has received research support and will profit from the sale of rasagiline and ladostigil, which are being developed by Teva Pharamaceutical Co., Israel, and M30, which is being developed by Varinel Inc., USA.

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DATABASES

OMIM

Alzheimer's disease

Amyotrophic lateral sclerosis

Huntington's disease

Parkinson's disease

Glossary

Microsomal fraction

An artefactual particulate fraction, obtained as a result of cell disruption and high-speed centrifugation, comprising fragments of the endoplasmic reticulum with which ribosomes and monooxygenase enzymes are associated.

Endoneurial vessels

The capillaries that normally constitute a blood–nerve barrier in peripheral nerves, and help to optimize the endoneurial environment.

Synaptosomes

A preparation of the presynaptic terminal, often containing a portion of the target cell — sometimes amounting to a complete dendritic spine — adhering to their external surface. This structure retains the anatomical integrity of the terminal and can take up, store and release neurotransmitters.

K m

(The Michaelis–Menten constant). A kinetic parameter corresponding to the substrate concentration that gives half-maximum velocity enzyme-catalysed reaction. Under certain conditions the Km for a substrate may equate to the dissociation constant of the enzyme–substrate complex, and the lower the value of Km, the tighter the substrate binds.

Norrie disease

A rare genetic disorder characterized by bilateral congenital blindness due to a maldeveloped retina. The Norrie disease gene and MAO genes are tandemly arranged on the human X chromosome, and syndromes resulting from chromosomal deletions in two or three of these genes have been identified.

Flavin moiety

A tricyclic heteronuclear organic ring, derived from riboflavin, that is capable of undergoing reduction-oxidation reactions. This structure is normally attached to an ADP to form the enzyme co-factor FAD.

Re face

A stereoheterotropic face of a trigonal atom is designated Re if the ligands of the trigonal atom appear in a clockwise sense in order of priority when viewed from that side of the face.

R and S isomers

The R/S system identifies optical isomers based on the configuration of ligands that have been assigned a priority. When the centre of a molecule is orientated so that the lowest priority of four ligands is pointed away from the viewer, the centre is labelled R if ligands of decreasing priority are arranged in a clockwise orientation, or S if this arrangement is anticlockwise.

Monotherapy

The use of a single drug or other therapy to treat a condition.

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Youdim, M., Edmondson, D. & Tipton, K. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7, 295–309 (2006). https://doi.org/10.1038/nrn1883

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  • DOI: https://doi.org/10.1038/nrn1883

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