Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

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Monoamine oxidase: from genes to behavior.

Oxidative stress and antioxidant therapy in Parkinson's disease

Dopamine (DA) neurotransmission in the central nervous system (CNS) is found throughout chordates, and its emergence predates the divergence of chordates. Many of the molecular components of DA systems, such as biosynthetic enzymes, transporters and receptors, are shared with those of other monoamine systems, suggesting the common origin of these systems. In the mammalian CNS, the DA neurotransmitter systems are diversified and serve for visual and olfactory perception, sensory-motor programming, motivation, memory, emotion, and endocrine regulations. Some of the functions are conserved among different vertebrate groups, while others are not, and this is reflected in the anatomical aspects of DA systems in the forebrain and midbrain. Recent findings concerning a second tyrosine hydroxylase gene (TH2) revealed new populations of DA synthesizing cells, as evidenced in the periventricular hypothalamic zones of teleost fish. It is likely that the ancestor of vertebrates possessed TH2 DA-synthesizing cells, and the TH2 gene has been lost secondarily in placental mammals. All the vertebrates possess DA cells in the olfactory bulb, retina and in the diencephalon. Midbrain DA cells are abundant in amniotes while absent in some groups, e.g. teleosts. Studies of protochordate DA cells suggest that the diencephalic DA cells were present before the divergence of the chordate lineage. In contrast, the midbrain cell populations have probably emerged in the vertebrate lineage following the development of the midbrain-hindbrain boundary. The functional flexibility of the DA systems, and the evolvability provided by duplication of the corresponding genes permitted a large diversification of these systems. These features were instrumental in the adaptation of brain functions to the very variable way of life of vertebrates.

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The evolution of dopamine systems in chordates.

The development of monoamine oxidase (MAO) inhibitors has followed a winding path. At the origin was the finding of E. A. Zeller that iproniazid, a hydrazine derivative designed to improve the tuberculostatic action of isoniazid, caused potent inhibition of MAO in vitro and in vivo. The inhibitor also exerted in vivo activity in the brain, subsequent pharmacological research indicating that this inhibition led to changes of cerebral functions [1]. Although the drug had no overt behavioral effects in animals when given alone, it modified the action of reserpine, one of the first modern psychotropic drugs. Thus, administration of iproniazid prior to reserpine unexpectedly antagonized the decreases in locomotor activity and in 5-hydroxy-tryptamine (5 HT) levels induced by reserpine in the brain, the animals sometimes even showing locomotor stimulation [1]. Since one serious side effect of reserpine in man was known to be mental depression, the antagonism of reserpine by iproniazid hinted at the possibility that this drug might be of use in the treatment of mood disorders. However, the actual breakthrough for the development of iproniazid as an antidepressant came from clinical observations. Various investigators had reported psychostimulant side effects of the MAO inhibitor in patients with tuberculosis and other chronic diseases.

The new generation of monoamine oxidase inhibitors.

See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. 

The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson’s disease. Inhibitors of MAOB are used clinically in Parkinson’s disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson’s disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson’s disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson’s disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is ‘substantially’ localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson’s disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and ‘turnover’ of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson’s disease, also distinguishes astrocyte behaviour in Parkinson’s disease from that in the two ‘Parkinson-plus’ conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.

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Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.

The histochemical distribution of monoamine oxidase A and B in rat brain was investigated using a coupled peroxidatic technique with benzylamine and tyramine as substrates and clorgyline and (−)-deprenyl as selective inhibitors. Benzylamine oxidase was absent in all areas. Both forms of monoamine oxidase were present, at low levels, in all areas; in addition several regions showed high activity of one or other form or both. Substantial activity of monoamine oxidase B was identified in the pineal gland, the lining of the ventricles, several hypothalamic regions, and the raphe nuclei. The locus coeruleus and interpeduncular nucleus possessed considerable type A activity. The substantia nigra and striatum showed no staining above the low general level, although the ventral tegmental area showed higher levels of both A and B.

J. Willoughby

Papers

Histochemical localisation of monoamine oxidase A and B in rat brain.