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.

The therapeutic potential of monoamine oxidase inhibitors.

Our understanding of the pathogenesis of diseases has advanced enormously in recent decades. As a consequence, drug discovery has gradually shifted from an entirely humanphenotype-based endeavor to today’s reductionist approach centered on single molecular targets. The focus has shifted from the early animal models to isolated proteins via cellular models. This change has led to a decrease in complexity but also to a decrease in relevance to the human condition. In this context, drug research has become (and still is) aimed mainly at the discovery of small molecules able to modulate the biological function of a single protein target thought to be fully responsible for a certain disease. Much effort has been devoted to achieving selectivity for that given target, and indeed, nowadays, many ligands endowed with outstanding in vitro selectivity are available. This one-molecule, one-target paradigm has led to the discovery of many successful drugs, and it will probably remain a milestone for years to come. However, it should be noted that a highly selective ligand for a given target does not always result in a clinically efficacious drug. This may be because (a) the ligand does not recognize the target in vivo, (b) the ligand does not reach the site of action, or (c) the interaction with the respective target does not have enough impact on the diseased system to restore it effectively. Reasons for the latter might lie in both the multifactorial nature of many diseases and the fact that cells can often find ways to compensate for a protein whose activity is affected by a drug, by taking advantage of the redundancy of the system, i.e., of the existence of parallel pathways. Medicinal chemists are often faced with these frustrating aspects of drug research. Drawbacks a and b can be addressed through the well-established rational ligand modification approaches. But issue c is more problematic and needs to be carefully discussed. This is one of the aims of the present article.

https://pubs.acs.org/doi/pdf/10.1021/jm800210c

Multi-Target-Directed Ligands To Combat Neurodegenerative Diseases

• Considerable evidence suggests that the acute effects of antidepressant treatments on brain norepinephrine (NE) and serotonin (5-HT) systems cannot account fully for their delayed therapeutic action. This review evaluates the effects of long-term antidepressant treatment on biogenic amine metabolism and on various indexes of presynaptic and postsynaptic receptor function. In contrast to variable effects on NE and 5-HT turnover and on presynaptic receptor sensitivity, almost all long-term antidepressant treatments produce consistent alterations in a number of measures of postsynaptic amine receptor sensitivity. Longterm treatment has been found to reduce β-adrenergic sensitivity while enhancing responses to serotonergic and α-adrenergic stimulation, suggesting that modulation of receptor sensitivity may be a mechanism of action common to tricyclic antidepressants, "atypical" antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy. These findings provide support for hypotheses of amine receptor abnormalities in depression and indicate the need for expanded studies of amine receptor function in patients.

Receptor Sensitivity and the Mechanism of Action of Antidepressant Treatment: Implications for the Etiology and Therapy of Depression

A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5-hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO-A and -B, and isoform-selective inhibitors. Selective inhibitors of MAO-B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO-A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.

Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness.

In an open, uncontrolled study the longterm (9 years) effect of treatment with Madopar alone (n = 377) or in combination with l-deprenyl (selegiline, selective monoamine oxidase type B inhibitor) (n = 564) have been compared in Parkinsonian patients. In patients who lost their response to conventional Madopar therapy the addition of l-deprenyl resulted in a significant recouping of levodopa effect. The survival analysis revealed a significant increase of life expectancy in Madopar--l-deprenyl group regardless of the fact whether or not the significant demographic differences between the two groups were taken into account. Although the mechanism underlying this action of l-deprenyl is not known, the results are interpreted as indicating l-deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons. l-Deprenyl is the first anti-Parkinson drug having such a property. This hypothesis is not far fetched since l-deprenyl selectively prevents the degeneration of striatal dopaminergic neurons induced in animals by the illicit drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since latter compound is known to cause Parkinsonism in man and primates or Parkinson-like neurochemical and pathological changes in other animals the implications of the present study involving monoamine oxidase activity and l-deprenyl are apparent.

Increased life expectancy resulting from addition of l-deprenyl to Madopar® treatment in Parkinson's disease: A longterm study

1 Tranylcypromine (20 mg/kg) administration to rats totally inhibited brain monoamine oxidase (MAO) oxidation of 5-hydroxytryptamine (5-HT), phenylethylamine and dopamine as measured in vitro. When l-3,4-dihydroxyphenylalanine (l-DOPA) (50 mg/kg) was given 30 min after the tranylcypromine, brain dopamine and noradrenaline concentrations rose markedly and the rats displayed characteristic behavioural changes and locomotor activity.



2 Clorgyline (5 mg/kg) administration inhibited 5-HT oxidation by almost 100% but phenylethylamine by only 29% while (-)-deprenil (5 mg/kg) injection almost totally inhibited phenylethylamine oxidation and inhibited 5-HT metabolism by only 31%. Administration of l-DOPA after pretreatment with either drug did not alter brain dopamine or noradrenaline concentrations and the animals did not display any behavioural changes.



3 Administration of clorgyline plus (-)-deprenil (5 mg/kg of each) almost totally inhibited oxidation of both phenylethylamine and 5-HT; there was a large rise of brain dopamine and noradrenaline concentrations and the animals displayed the behavioural changes observed when tranylcypromine and l-DOPA had been given.



4 The effects of tranylcypromine (20 mg/kg) on brain 5-HT, dopamine and noradrenaline concentrations up to 48 h after injection were recorded. Brain 5-HT concentrations were considerably elevated for 18 h after injection and then fell steadily. In contrast, brain dopamine concentrations rose slightly and remained at this level for 48 h while noradrenaline levels doubled and also remained at this level for 48 hours.



5 When l-tryptophan (50 mg/kg) was given at various times after tranylcypromine the characteristic hyperactivity syndrome appeared at 12 h but not 18 h after tranylcypromine and a further rise in brain 5-HT was only observed at 12 hours. When l-DOPA (50 mg/kg) was given at various times after tranylcypromine a further large rise in brain dopamine and noradrenaline occurred at 12 h but not at 18 h and all the behavioural changes were observed only at 12 hours.



6 Measurement of MAO activity at the above times after tranylcypromine showed that the half-life of recovery of the enzyme activity with 5-HT and dopamine as substrates was 4.5 days and 8.5 days with phenylethylamine as substrate. Inhibition of MAO oxidation of dopamine and 5-HT was approximately 85%, 18 h after tranylcypromine injection.



7 It is concluded from both the studies with clorgyline and deprenil and the recovery of MAO activity after tranylcypromine, that dopamine is metabolized by both Type A and Type B MAO in vivo and that it is only when both forms are almost totally inhibited that there is an increase in dopamine and 5-HT functional activity, as judged by the appearance of the hyperactivity syndromes.

/pdf/evidence-for-dopamine-deamination-by-both-type-a-and-type-b-8ztndfxiqv.pdf

Evidence for dopamine deamination by both type A and type B monoamine oxidase in rat brain in vivo and for the degree of inhibition of enzyme necessary for increased functional activity of dopamine and 5-hydroxytryptamine.

1 A single electroconvulsive shock (ECS) of 150 V for 1 s increased the concentration of rat brain 5-hydroxyindoleacetic acid (5-HIAA) but did not alter brain 5-hydroxytryptamine (5-HT) or tryptophan concentrations 3 h later. 2 A single ECS decreased 5-HT synthesis 3 h and 6 h later. Synthesis was back to normal after 24 hours. The ECS-treated rats did not show greater hyperactivity produced by the increased brain 5-HT accumulation following administration of L-tryptophan and tranylcypromine at any time up to 24 h later. This suggests that a single electroshock does not alter 5-HT functional activity. 3 Twenty-four hours after the final ECS of a series of 10 shocks given once daily, the rats were given tranylcypromine and L-tryptophan. They displayed greater hyperactivity than control rats not treated with ECS, suggesting that ECS increases 5-HT functional activity. Brain concentrations of 5-HT, 5-HIAA and tryptophan were then unchanged by ECS. 5-HT synthesis and accumulation of 5-HT following tranylcypromine and L-tryptophan were not altered by ECS. 4 The hyperactivity following administration of the 5-HT agonist 5-methoxy N,N-dimethyltryptamine was enhanced by repeated (10 day) ECS, suggesting altered post-synaptic responses to 5-HT receptor stimulation. 5 Repeated ECS enhanced locomotor activity following tranylcypromine and L-DOPA. It did not alter brain noradrenaline or dopamine concentrations. 6 The latent period before a pentylenetetrazol-induced convulsion was shortened by repeated ECS. 7 Following repeated ECS there appears to be increased neuronal sensitivity to certain stimuli producing centrally mediated behavioural stimulation. This is discussed in relation to the mechanism by which electroconvulsive therapy (ECT) produces its therapeutic effect.

/pdf/electroconvulsive-shock-increases-the-behavioural-responses-2bu5h1od0a.pdf

Electroconvulsive shock increases the behavioural responses of rats to brain 5-hydroxytryptamine accumulation and central nervous system stimulant drugs

The concentration of 5-methoxytryptamine in rat brain and its effects on behaviour following its peripheral injection.

1 The content and distribution of 5-hydroxytryptamine (5-HT) between subcellular fractions from rat whole brain (excluding cerebellum) were examined following repeated lithium administration. 2 Lithium chloride (3 mEq/kg body wt. s.c.) administered twice daily for 3 days produced no change in the 5-HT content of primary subcellular fractions (P1-nuclear; P2-crude synaptosomal; SNT-soluble) measured on the 4th day. 3 Similarly, repeated lithium treatment alone did not appear to produce increases in the 5-HT content of either cytoplasmic (S) or vesicular (M2) fractions derived from hypo-osmotically disrupted synaptosomes (P2) when compared to control rats receiving NaCl only. 4 One hour after monoamine oxidase inhibition with tranylcypromine, there was a further selective 25% increase in 5-HT accumulation in the lithium-treated rats over control values in the soluble cytoplasmic fraction (S) and in fractions containing occluded cytoplasm only. This increase did not occur in the synaptic vesicle fraction (M2). This corresponds to an increase in 5-HT turnover rate due to the lithium treatment of approx. 50%. 5 These findings lend additional support to the hypothesis that lithium treatment alters the intraneuronal storage or compartmentation of 5-HT between vesicles and cytoplasm.

Ann F.C. Tordoff

Papers

Evidence for dopamine deamination by both type A and type B monoamine oxidase in rat brain in vivo and for the degree of inhibition of enzyme necessary for increased functional activity of dopamine and 5-hydroxytryptamine.

Electroconvulsive shock increases the behavioural responses of rats to brain 5-hydroxytryptamine accumulation and central nervous system stimulant drugs

The concentration of 5-methoxytryptamine in rat brain and its effects on behaviour following its peripheral injection.

Eefects of repeated lithium administration on the subcellular distribution of 5-hydroxytryptamine in rat brain