Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20

Use of monoamine oxidase inhibitors in chronic

neurodegeneration

Peter Riederer & Thomas Müller

To cite this article: Peter Riederer & Thomas Müller (2016): Use of monoamine oxidase
inhibitors in chronic neurodegeneration, Expert Opinion on Drug Metabolism & Toxicology,
DOI: 10.1080/17425255.2017.1273901

To link to this article: http://dx.doi.org/10.1080/17425255.2017.1273901

Accepted author version posted online: 21

Dec 2016.

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Download by: [The UC San Diego Library] Date: 26 December 2016, At: 00:27
Publisher: Taylor & Francis

Journal: Expert Opinion on Drug Metabolism & Toxicology

DOI: 10.1080/17425255.2017.1273901
Use of monoamine oxidase inhibitors in chronic neurodegeneration

Peter Riederer*1, Thomas Müller2

1
Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy,

University Hospital, Würzburg, Füchsleinstrasse 15, 97080 Würzburg, Germany

2
Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Berlin, Germany

*Corresponding author:

Center of Mental Health Department of Psychiatry, Psychosomatics and Psychotherapy,

University Hospital Würzburg, Füchsleinstrasse 15, 97080 Würzburg, Germany

Email: peter.riederer@mail.uni-wuerzburg.de

Abstract

Introduction: Neurotransmission by biogenic monoamines is important for brain function.

Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and monoamine

oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels

in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of

“selective” monoamine oxidase inhibitors.

Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the

context with chronic neurodegeneration.

Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines.

In the aging brain, one of the two enzymes involved in degrading synaptic amines,
catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore,

metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine

turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative

disorders, symptoms, such as depression and apathy, are often treated with drugs that elevate

biogenic amine levels. This therapeutic strategy increases biogenic amine turnover, thereby

generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and

accelerate the course of neurodegeneration. We propose that antidepressant therapy should be

initiated first with monoamine oxidase inhibitors only. If adequate clinical response is not

achieved, only then they can be supplemented with a further antidepressant.

Keywords: Monoamine oxidase, selegiline, rasagiline, depression, moclobemide, DOPAL,

oxidative stress, antidepressants

Article highlights box

• Metabolism of biogenic amines by monoamine oxidase (MAO) B exacerbates chronic

neurodegenerative processes particularly via apoptosis.

• The specificity of MAO subtype inhibition is lost at higher doses, when a total

blockade of the monoamine oxidase enzyme takes place.

• In the course of long term therapy, “selective” MAO-B inhibitors also reduce MAO-A

activity.

• Oxidative stress is continuously generated through elevated biogenic amine turnover

by MAOs.

• Long term effects of classic antidepressant drugs with respect to initiating or

accelerating chronic neurodegenerative processes in the brain are not currently

considered during drug development or by therapeutic guidelines.

 • Early treatment of depression — for example, during the prodromal phase of

Parkinson’s disease or dementia disorders — should primarily use a non-selective

MAO inhibitor.

• The long term combination of antidepressants with MAO inhibitors may reduce the

likelihood of acute or chronic neurodegenerative events associated with elevated

biogenic amine turnover.

1. Introduction

Monoamine oxidase (MAO) inhibitors have an interesting history: the prototype MAO

inhibitor was discovered in the early 1950s by physicians testing drugs for the treatment of

tuberculosis. Of the two hydrazines investigated, isoniazid and iproniazid, isoniazid proved to

be the more effective antibiotic [1]. Iproniazid was not as useful in this respect, but it had an

unexpected effect of great value: it possessed mood-elevating properties. Patients taking

iproniazid exhibited greater vitality, participated more in social activities, and expressed the

desire to leave hospital despite the fact they were still severely ill. This serendipitous

discovery provided the basis for the first antidepressant medication.[2] A short time later, the

pharmacological profile of iproniazid identified it as a MAO inhibitor. Since this time, MAO

inhibitors have been used to treat depression and, since the 1960s, Parkinson disease (PD).

1.1. The role of MAO in the degradation of biogenic amines

Biogenic amines are metabolised by the enzymes catechol-O-methyltransferase (COMT) and

MAO, each of which is found in neurons and glial cells. MAO, located in the outer

mitochondrial membrane, occurs as two distinct isozymes, MAO-A and MAO-B, which

differ in their anatomic localisation and major substrates: MAO-A, primarily located in the

placenta, gut and liver, preferentially metabolises serotonin and noradrenaline; MAO-B is the

predominant form in brain, liver, and platelets [3]. Generally, MAO inhibitors elevate the

physiological availability of biogenic amines (noradrenaline, dopamine and serotonin) by

reducing their degradation, and this effect is currently regarded as the basis of the

amelioration of symptoms of depression by MAO inhibitors.

1.2. Four types of mechanism for MAO inhibition

Four classes of MAO inhibitor, based on their different modes of action, have been described.

The first type is irreversible, non-selective MAO-blocking compounds. The first three original

MAO inhibitors — phenelzine, tranylcypromine, and isocarboxazid — are looked upon as

irreversible enzyme inhibitors, covalently binding MAO and permanently blocking its

function. Local metabolic activity is recovered only after new enzyme is synthesised [3].

The second type reduces MAO-A activity in a reversible, selective fashion, exemplified by

moclobemide. These inhibitors have a lower potential for drug interactions at therapeutic

doses than non-selective MAO inhibitors; the duration of MAO-A inhibition by selective

inhibitors is shorter (16–24 hours) than inhibition induced by classic, non-selective MAO

inhibitors (greater than 10 days) [4]. The third inhibitor type includes irreversible, selective

MAO-B inhibitors, such as selegiline and rasagiline [3], while the final type is reversible

MAO-B inhibitors, including safinamide [3,5]. Generally, blocking only one MAO isoform is

only possible within a narrow concentration range of the administered compound. The

specificity of MAO subtype inhibition is lost at higher dosing. Then a total blockade of MAO

enzyme occurs [3,6]. There are also other compounds with MAO inhibiting properties, the

most known ones are amphetamines.

1.3. Amphetamines and MAO inhibitors

In addition to its better known and more potent actions as an inhibitor of the dopamine and

norepinephrine transporters, amphetamine is a reversible MAO inhibitor. For this reason,

amphetamines are sometimes employed as augmenting agents to boost the effects of MAO

inhibitors, especially in treatment-resistant depression. The actions of stimulants and MAO

inhibitors can thus be synergistic, not only with respect to their antidepressant efficacy and

but also their influence on blood pressure in some patients [7]. This synergism may also apply

to selegiline, an irreversible MAO-B inhibitor, which is metabolised to L-amphetamine and L-

methamphetamine [8]. The activity of these metabolites may augment the MAO-B-inhibitory

action of selegiline, whereas neither of the newer MAO-B inhibitors, rasagiline and

safinamide, are degraded to amphetamine-like derivatives [9,10,11]. Some MAO inhibitors,

such as tranylcypromine, have a somewhat resembling chemical structure similar to

amphetamine, and therefore also inhibit dopamine and norepinephrine transport; as a result,

they also combine MAO inhibitor properties with amphetamine-like dopamine- and

norepinephrine-releasing effects [12,13].

1.4. MAO, oxidative stress and neuronal death

In the human brain, neurons of the dorsal raphe nucleus mainly contain MAO-B, while those

of the locus coeruleus use MAO-A. It is interesting that neurons of the substantia nigra pars

compacta exhibit low immunoreactivity for MAO-A. In contrast to this divergence between

neuronal levels of MAO-isoforms in amine-containing cell bodies, astroglia are strongly

immunoreactive for both MAO-A and -B [14]. In the brain, MAO-A and MAO-B are

primarily located in glial cells, and are chiefly involved in the complex regulation of the

concentrations of the major biogenic amines in the synaptic cleft [3,6]. Oxidation of

monoamine substrates, particularly by MAO-B, increases the generation of reactive oxygen

species (ROS). ROS overflow contributes to the oxidative synthesis of neurotoxins such as

the tetrahydroisoquinolines (TIQ) and 6-hydroxydopamine [15,16]. Both N-methylated TIQ

and 6-hydroxydopamine have been implicated in accelerating chronic neurodegenerative

processes, particular when they are present in higher concentrations in the central nervous

system [17,18,19]. Generally, DNA damage caused by exogenous, endogenous or

environmental toxins, abnormal folding of proteins, or reduced neurotrophin synthesis alters

glial and neuronal function by initiating a cellular suicide programme, apoptosis. Various

types of cysteine protease (caspases) induce and promote apoptosis [20,21]. Evidence from

experimental research strongly suggests that selective inhibition of MAO-B restrains chronic

neurodegenerative processes, particularly by inhibiting apoptosis [22,23,24,25,26,27].

1.4.1. The impact of selective MAO-B inhibition on apoptosis

MAO-B inhibitors may intervene in apoptosis by (a) directly stabilising mitochondrial

membranes, (b) inducing anti-apoptotic, pro-survival processes, (c) preventing the opening of

mitochondrial permeability transition pore complexes and mitochondrial swelling, and (d)

reducing the mitochondrial membrane potential and cytochrome C release, consequently

suppressing various apoptotic processes, such as caspase activation and nuclear translocation

of glyceraldehyde-3-phosphate-dehydrogenase [22,28]. MAO-B inhibition also increases pro-

survival gene transcription by activating the nuclear transcription factor system [20]. However,

the anti-apoptotic actions of inhibitors, such as selegiline, respectively its derivative

desmethylselegiline, and rasagiline, respectively its metabolite aminoindan, are also evident at

concentrations that do not influence MAO-A or MAO-B activity [29]. Further, MAO-A has

been implicated in the pathophysiology of neurodegeneration, and also in gene induction by

MAO-B-inhibitors [29]. More recent evidence suggests that selegiline and rasagiline increase

MAO-A mRNA, protein and enzyme activity levels [29]. That is, depending on the dose and

duration of treatment, each MAO subtype exerts effects that modulate the expression and

activity of the other isoenzyme.

2. Objectives

The objective of this invited narrative review is to discuss aspects of the use of MAO

inhibitors in chronic neurodegenerative disorders.

2.1. Methods

The PubMed database was searched for the combination of the terms “monoamine oxidase”

and “neurodegeneration”.

3. General pharmacodynamic aspects of MAO inhibition

The pharmacodynamic properties of MAO inhibitors have been reviewed extensively [30].

When neurotransmitter metabolism is altered or the balance between neurotransmitter systems

is disturbed, non-motor symptoms such as depression or apathy can develop. Inhibition of the

enzymes COMT and MAO synergistically increases the levels of biogenic amine levels in the

synaptic cleft [31,32,33] ,so that beneficial effects on cognition and cortical information

processing can be expected. For example, it is recognised that increasing dopamine levels

selectively improves function in the mesolimbic system and prefrontal cortical structures,

enhancing cognitive performance and motivation, with a particular benefit in ameliorating

apathy [34]. The effects of central MAO-A and -B inhibition are related to their regional

localisation in the human brain. In contrast, stimulants of biogenic amine release, such as

amphetamine, enhance transmission of dopamine, norepinephrine and serotonin across the

brain, so that these psychostimulants possess a higher potential for abuse and tolerance than

MAO inhibitors with their more focused impact [35,36].

3.1. Antidepressant action of MAO inhibitors

Moclobemide is the most frequently used reversible, selective MAO-A inhibitor. Its efficacy

in modulating mood is similar to that of other classic antidepressant compounds, such as

amitriptyline, clomipramine, fluvoxamine and imipramine [37]. Numerous trials, meta-

analyses and reviews have shown that moclobemide maintains its antidepressant effects over

6–12 months of treatment [4].

3.2. MAO inhibition and tyramine: the “cheese effect”

In humans, inhibition of MAO-A elevates the concentration of serotonin, noradrenaline and,

eventually, dopamine. Blockade of amine metabolism by MAO leads to elevated

noradrenaline concentrations and may result in hypertension. A good measure of this adverse

reaction is the tyramine-based oral pressure test [38]. Dietary caution concerning tyramine-

containing items, such as cheese and red wine, is recommended for patients regularly taking a

MAO-A inhibitor, but, when the drug is dosed in an appropriate manner, the likelihood of a

dangerous reaction when tyramine is ingested is limited. [39,40,41]

3.3. MAO inhibition and the serotonin syndrome

Another pharmacodynamic problem may arise from the interaction of MAO inhibitors and

antidepressants, both of which influence serotonergic neurotransmission. There is an elevated

risk of the serotonin syndrome, characterised by hyperthermia, hyperactivity, tremor and other

symptoms, when MAO inhibitors are combined with compounds that raise serotonin

concentrations in the brain, including inhibitors of serotonin re-uptake, such as paroxetine,

clomipramine, sertraline, fluoxetine, citalopram, fluvoxamine, venlafaxine, and the serotonin

precursor, tryptophan. One should be aware of this possibility, but the syndrome is rare in the

clinical treatment of neurological and psychiatric disorders [42].

3.4. MAO-B inhibitors reduce MAO-A enzyme activity

Little is known about the effects of chronic MAO-B inhibition on MAO-A enzyme activity.

However, a closer look at the pharmacokinetic behaviour of the selective, irreversible MAO-

B inhibitors selegiline and rasagiline gives cause for concern. The mean elimination half-life

of selegiline is about 1.5 hours, and of rasagiline 1.0 hours in healthy controls or 1.3 hours in

patients. Daily oral administration of 10 mg selegiline, however, causes an up to 4-fold

increase in half-life, to 6 hours [43,44]. Experimental research in rats confirmed this finding.
They were treated with 5 mg/kg selegiline p.o. for 5 days, and sacrificed 2 hours after the last

dose. It was found that both MAO isoforms were strongly inhibited by this regimen (bowel:

MAO-B by 84%, MAO-A by 85%; liver: MAO-B by 92%, MAO-A by 32%; brain: MAO-B

by 92%, MAO-A by 18%) [43,44]. These findings were confirmed after subcutaneous

application of the same dose, thereby circumventing first pass metabolism in the liver (bowel:

MAO-B by 80%; MAO-A by 62%; liver: MAO-B by 91%, MAO-A by 34%; brain: MAO-B

by 99%, MAO-A by 85%) [43,44]. Another study found considerably reduced MAO-A

enzyme activity ex vivo in plasma from PD patients treated with rasagiline or selegiline [6].

These results show that so-called “selective” MAO-B inhibitors also reduce MAO-A enzyme

activity after long term administration. However, these outcomes were not confirmed by a

positron emission tomography in which MAO-A activity was assessed in subjects after

receiving selegiline, either orally or transdermally; neither formulation reduced brain MAO-A

activity [45]. One should consider that long term administration of selegiline was not assessed

in this study.

3.4.2. Conclusion: Is genuinely selective MAO-B inhibition important in clinical practice?

Long term daily selegiline administration increases its effects on MAO enzyme activity,

blocking MAO-A as well as MAO-B [6]. Selegiline and rasagiline irreversibly inhibit MAO-

B, so that recovery of activity requires de novo enzyme synthesis, and several weeks are

needed for full restitution; once MAO-B is fully inhibited, the two inhibitors also block

MAO-A. The beneficial effect of rasagiline through its induction of genes coding the neuronal

pro-survival Bcl-2 and neurotrophic factors, demonstrated in vitro, is also attributed to

inhibition of MAO-A. Selegiline and rasagiline each elevated the mRNA and protein levels

and the catalytic activity of MAO-A in SH-SY5Y cells [46]. While MAO-B inhibitors at

selective clinical doses reduce the oxidation of dopamine and phenylethylamine, scavenge

oxygen radicals, intervene in the mitochondrial apoptotic signal pathway, and promote
synthesis of anti-apoptotic Bcl-2 protein and neurotrophic factors, the role of MAO-B

inhibition itself in the neuroprotective action of MAO-B inhibitors, although long assumed to

be important, remains obscure [27,29,47,48]. In fact, MAO-A is involved in neuronal death

mechanisms when its expression is up-regulated in cellular models [47]. Accordingly, MAO-

A, not MAO-B, mediates the increased expression of genes for anti-apoptotic, pro-survival

Bcl-2 and neurotrophic factors by MAO-B inhibitors [47].

This finding may have important implications for the treatment of early and late stage PD. L-

DOPA supplementation in PD patients increases dopamine levels in the basal ganglia, as a

result of which elevated concentrations of the MAO-generated degradation product 3,4-

dihydroxyphenylacetaldehyde (DOPAL) and other oxidative stress-related substrates are

generated [18]. In addition, many PD patients are treated with other biogenic amine-

enhancing drugs, including other antidepressants; depression and apathy are frequent

prodromal symptoms of PD, and conventional antidepressants are prescribed before the

appearance of motor symptoms. These drugs block re-uptake of biogenic amines, leading to

increased concentrations in the synaptic cleft and, consequently, their increased metabolic

turnover, leading to greater production of aldehydes and oxidative stress. As a result,

generation of toxic compounds may influence and accelerate the natural course of PD [49,50].

If this is the case, early treatment of depression, including during the prodromal phase of PD,

with an “unspecific” MAO inhibitor is a condition sine qua non. In fact, non-selective doses

of selegiline (20–40 mg/day) have been found to have antidepressant efficacy in a variety of

clinical assessments [30,37]. The modes of action include inhibition of MAO-A and -B, as

well as slowing dopamine uptake [51]. However, this contrasts with the clinical finding that

rasagiline (1 mg/day) showed no long term antidepressant benefit [52].

3.5. MAO inhibition and neuroprotection

The role of MAO in chronic neurodegeneration is not fully understood. Up-regulation of

MAO-A activity, particularly after selective MAO-B inhibition, stimulates synthesis of ROS,

as shown in serum-deprived SH-SY5Y cells. Elevated generation of MAO-A mRNA and

increased catalytic MAO-A activity activates caspase-3, which induces cell apoptosis [27].

3.5.1. MAO inhibition and aldehyde generation

A further mode of action is the involvement of ROS in DOPAL metabolism. DOPAL is a

catabolic product of dopamine, following oxidative deamination by MAO-A/B in conjunction

with free radicals [53,54,55]. Aldehydes are highly reactive molecules formed during the

biotransformation of numerous endogenous and exogenous compounds, including biogenic

amines. DOPAL, in particular, causes generation of free radicals and activates mitochondrial

permeability transition pores, a mechanism implicated in neuronal death. There is an

increasing body of evidence that DOPAL is neurotoxic, and that neurodegenerative disorders

are associated with increased levels of this biogenic aldehyde [17].

Aldehyde metabolism involves several pathways and enzymes. Aldehyde dehydrogenases

belong to a group of NAD(P)+-dependent enzymes that catalyse the oxidation of aldehydes,

including those derived from catecholamines, to their corresponding carboxylic acids [56]. To

date, nineteen aldehyde dehydrogenase genes have been identified in the human genome, and

mutations in these genes, with subsequent errors in aldehyde metabolism, are implicated in

the pathology of several diseases [17,56]. Several pharmaceutical agents and environmental

toxins (e.g., 4-hydroxy-2-nonenal) are also known to disrupt or inhibit aldehyde

dehydrogenase. DOPAL may thus act as an endogenous toxin, even at physiological

concentrations, and may trigger neuronal cell death by inducing α-synuclein aggregation, in

combination with hydroxyl radicals [18]. Specific inhibition of MAO-A therefore results in

lower turnover of biogenic amines and, accordingly, lower DOPAL production, together with

a decline in apoptotic cell morphology and reduced ROS production [53,54,55]. All these
mechanisms are regarded as being potentially neuroprotective. Inhibition of both MAO

isoenzymes reduces dopamine turnover and the generation of ROS, DOPAL and other toxic

compounds [53]. Non-selective MAO inhibition may therefore be neuroprotective by

dampening the disease-accelerating effects of biogenic amine metabolism [53,55].

3.6. Pharmacodynamic interactions associated with MAO inhibition

Combining pethidine or dextromethorphan with MAO inhibitors is associated with serious

adverse reactions. Caution is also recommended when combining MAO inhibitors with other

sympathomimetic medicines. The combination of several MAO inhibitors is contraindicated,

as this would elevate the risk of a hypertensive crisis. One should also be careful when

combining MAO inhibitors with other antidepressants, but this combination is relatively safe

in clinical practice [57]. In the case of safinamide, a novel selective and reversible MAO

inhibitor, cautious combination with a serotonin or serotonin/norepinephrine re-uptake

inhibitor, or with a tricyclic or tetracyclic antidepressant is permissible [11]. However, from

the pharmacological point of view, one should remember that long term combination of other

low dose antidepressants with MAO inhibitors may be beneficial in terms of preventing acute

or chronic neurodegeneration.

4. Conclusion

Therapeutic drug development currently focuses on identifying increasingly selective

compounds for stimulating specific central biogenic amine receptors. The prodromal features

of chronic neurodegenerative diseases often share unspecific symptoms, including mild

psychiatric features, such as apathy, loss of self-confidence, feelings of inadequacy, and

disturbances of sleep and mood [58,59]. A common therapeutic strategy is to administer

antidepressant drugs, particularly biogenic amine re-uptake inhibitors, at least temporarily but

also for longer intervals. This, in turn, elevates central biogenic amine levels and induces up-
regulation of aldehyde production, with increased ROS generation as long term effect,

accelerating ageing of the brain and neurodegeneration. Personality traits and the

neuroplasticity of the brain in general may compensate for these processes to a certain extent,

but it is recognised that the incidence of chronic neurodegenerative disorders increases with a

rise in life expectancy. Biogenic re-uptake inhibitors are heavily promoted by the

pharmaceutical industry, and their side-effect profiles are well documented, including motor

and psychiatric symptoms, such as tremor, muscle stiffness, slowness of thought and

cognitive disturbances. However, these symptoms may also be early, unspecific features of

chronic neurodegenerative disorders, such as PD and dementia, so that the appropriate

treatment of such prodromal symptoms is of central importance. Therapy should aim to

reduce biogenic amine metabolism in order to minimise oxidative stress, which can trigger

and accelerate chronic neurodegenerative disorders.

5. Expert opinion

Endogenous modulation of enzyme activity is a normal physiological function. In the brain,

MAO and COMT are together responsible for metabolising biogenic amines. But COMT also

plays an essential role in detoxification via methylation processes [55,60]. Exposure to

endogenous, environmental and exogenous toxins increases with age [60], and COMT is

increasingly required for detoxification purposes. As a result, the capacity for COMT-

catalysed degradation of biogenic amines declines, and alternative pathways, particularly

catabolism by MAO, become more critical. This behaviour resembles the alteration in L-

DOPA degradation by COMT following inhibition of DOPA decarboxylase [61]. Accordingly,

oxidative stress is exacerbated via the elevation of MAO activity, contributing to chronic

neurodegeneration, brain atrophy, and the onset of disorders such as PD and Alzheimer

disease [49] (Figure 1). The long term risk of brain deposits of misfolded proteins, such as α-

synuclein, amyloid or tau protein, also increases [17,18,62]. These proteins have
predominantly been discussed as triggers of disease, but it has been suggested that their

deposition can also occur as a reaction to an overload of detoxification cascades, including

heightened oxidative stress. That is: these misfolded proteins may be more spectators in the

neurodegenerative disease process than killers [63]. In clinical practice, prodromal symptoms

are often treated with biogenic amine re-uptake inhibitors that elevate their synaptic

concentrations and turnover. Both MAO and COMT possess a certain compensatory capacity,

but substrate overload causes synthesis of the biomarker homocysteine, with concomitant

deficits of methyl-group donating vitamins in the case of COMT, or oxidative stress

generation in the case of MAO [55].

Clinicians have generally employed selective MAO-B inhibitors either to both block the

metabolism of biogenic amines and to facilitate antiapoptotic molecular processes, or just to

inhibit apoptosis. For the first strategy, 5–10 mg selegiline or 1 mg rasagiline are the preferred

clinical doses. However, it is likely that longer term treatment with these drugs will also

inhibit MAO-A. From the clinical point of view, this less selective pharmacological action

might be beneficial in the sense of improvement of motor activity in PD, and also because of

its antidepressant effect, although adverse reactions may also be increased. In the second

strategy, a lower MAO inhibitor dose than that which inhibits the MAO-isoenzymes is

adequate.

It is important to note that there is still no clinical evidence for a disease-modifying or

neuroprotective effect of selegiline or rasagiline. Experimental research has established that

MAO inhibition has a certain neuroprotective effect, modifying or slowing the progression of

disease in various chronic neurodegenerative disease models. This effect remains to be

confirmed in the clinical setting, but it is plausible that MAO inhibitors may also exert a

certain protective effect in chronic neurodegenerative disease.

5.1. Oxidative stress and brain repair: dopamine supplementation in PD as an example

Free radicals play an essential role in a variety of normal regulatory systems. However, ROS

also mediate acute or chronic inflammatory or neurodegenerative tissue destruction, either

alone or in concert with proteases. ROS also control protein synthesis, such as that of

neurotrophins which initiate cellular repair and regeneration. However, there are also proteins

that inhibit the regeneration of axons, as well as protection of myelin and glial structures, such

as myelin-associated glycoprotein and repulsive guidance molecule A [64].

This interplay of brain repair mechanisms and oxidative stress generation is well studied in

the context of L-DOPA therapy in PD. L-DOPA elicits an increase of oxidative stress

indirectly mirrored by a fall in cysteine and cysteinyl-glycine levels as indicators of increased

glutathione (GSH) synthesis and consumption [55,62,64]. Experimental models indicate that

the loss of nigrostriatal dopaminergic neurons in PD is attributable to oxidative stress

secondary to increased dopamine turnover, reduced GSH levels, and elevated iron levels in

the substantia nigra [62]. Neuronal survival is thus vulnerable to further oxidative challenge,

and the pro-oxidant effects of L-DOPA may exacerbate an already compromised cellular

system and aggravate the situation it is meant to alleviate [55,64]. The physiological capacity

for ROS scavenging is predicated on a still adequately functional GSH system, but dealing

with ROS toxicity may become impossible as long term L-DOPA exposure leads to ever

rising ROS levels. ROS have the potential to disrupt sulfhydryl homeostasis in cells and to

alter the function of proteins with reactive cysteine residues, a situation that is exacerbated if

one or both of the glutaredoxin or thioredoxin enzyme systems is impaired, as they are

respectively responsible for reversing protein-S-glutathionylation and inter- or intramolecular

disulfites [65]. This scenario culminates in a vicious circle of spiralling exposure to ROS

triggering increasing rates of apoptosis, with long term clinical consequences in the peripheral

and central nervous systems during chronic L-DOPA therapy; for instance, polyneuropathy as

a marker in the peripheral nervous system [55].

One solution would be to combine L-DOPA with a MAO inhibitor, which may slow the

progression of PD in the long term. In addition to many experimental findings, a slowing

effect of MAO inhibition on disease progression has also been observed in the clinic over a

period of five years [66]. The increase in L-DOPA dose over time — a marker for increased

severity of disease — was slower for patients receiving selegiline as adjunct therapy than for

those receiving L-DOPA only. If this effect was attributable solely to a symptomatic effect of

the MAO inhibitor, the L-DOPA dose curves for the two groups should have been parallel, but,

as the curves for the two arms diverged, a disease-modifying effect of MAO inhibition could

be implied [6,66].

5.2. Consequences for antidepressant drug therapy?

One may assume a similar long term process during treatment with antidepressant drugs, as

they similarly increase the concentrations of biogenic amines in the synaptic cleft. Greater

oxidative stress is continuously generated through elevated biogenic amine turnover by MAO.

From this point of view, one should conclude that antidepressant therapy should commence

with a MAO inhibitor (Figure 2), and only if the clinical response is inadequate should it be

supplemented with an agent specifically chosen to directly increase synaptic 5-HT, or both 5-

HT and noradrenaline, or catecholamine levels in general. This approach will reduce the risk

of chronic neurodegeneration induced by MAO-triggered oxidative stress. This is a

provocative hypothesis, as it categorises antidepressants as risk factors for PD and Alzheimer

disease in patients vulnerable for these neurodegenerative disorders. Ours hypothesis warrants

further epidemiological research, but it is already recognised that patients with chronic

neurodegenerative disorders often take antidepressants before they are diagnosed, to

ameliorate prodromal symptoms such as apathy and depression.

5.3. Five-year view

Current drug development strategies for the pharmacotherapy of depression and related

syndromes focus on stimulating specific receptor subtypes. There are major concerns about

the safety and tolerability of psychoactive drugs; for example, with respect to avoiding weight

gain. The long term effects of these antidepressant drugs on initiating or accelerating chronic

neurodegenerative processes in the brain are not considered by current research strategies.

Clinicians prefer prescribing more or less transmitter-specific antidepressant compounds, each

of which elevate synaptic concentrations of biogenic amines, with the consequence that the

metabolic turnover of biogenic amines by COMT and MAO is increased [67,68]. Overload of

both pathways leads to up-regulation of cell death mechanisms. In this respect, one should

also consider that many patients empirically employ herbal medicines as adjuncts, including

St John’s Wort, a reversible MAO inhibitor [69]. Research into brain repair and disease

pathologies are increasingly directed to the roles of cells that support neuronal survival, such

as glia. There is hope that these investigations will provide new insights into the pathogenesis

and pathophysiology of chronic neurodegenerative diseases.

Acknowledgements

This review is dedicated to Prof. Dr. Gerhard Bringmann at the occasion of his 65th

anniversary. The authors would like to thank Paul Foley for editing this manuscript.

Funding

This paper was not funded.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or

entity with a financial interest in or financial conflict with the subject matter or materials

discussed in the manuscript. This includes employment, consultancies, honoraria, stock

ownership or options, expert testimony, grants or patents received or pending, or royalties.

References

Papers of special note have been highlighted as either of interest (•) or of considerable

interest (••) to readers.

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17

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•• Extensive review on safinamide

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• Interesting paper on the action of aldehydes

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and implications for therapy. Ann N Y Acad Sci 2007;1122:155-168

22. Akao Y, Maruyama W, Shimizu S, et al. Mitochondrial permeability transition mediates

apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by

Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. J Neurochem 2002;82:913-923

23. Bar-Am O, Amit T, and Youdim MB. Aminoindan and hydroxyaminoindan, metabolites

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propargylamine-1(R)-aminoindan, and its optical (S)-isomer, TV1022. Ann N Y Acad Sci

2001;939:320-329

25. Maruyama W, Yamamoto T, Kitani K, et al. Mechanism underlying anti-apoptotic activity

of a (-)deprenyl-related propargylamine, rasagiline. Mech Ageing Dev 2000;116:181-191

26. Naoi M, Maruyama W, Yi H, et al. Neuroprotection by propargylamines in Parkinson's

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27. Naoi M, Maruyama W, and Yi H. Rasagiline prevents apoptosis induced by PK11195, a

ligand of the outer membrane translocator protein (18 kDa), in SH-SY5Y cells through

suppression of cytochrome c release from mitochondria. J Neural Transm 2013;120:1539-

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• New insights into the antiapoptotic mechanisms of rasagiline

28. Akao Y, Maruyama W, Yi H, et al. An anti-Parkinson's disease drug, N-propargyl-1(R)-

aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic

SH-SY5Y cells. Neurosci Lett 2002;326:105-108

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A MAO expression. J Neural Transm (Vienna ) 2016;123:91-106

30. Gerlach M and Riederer P. Monoamin-Oxidase-Hemmer in: Neuro-Psychopharmaka

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41. Chen JJ and Wilkinson JR. The monoamine oxidase type B inhibitor rasagiline in the

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42. Fernandes C, Reddy P, and Kessel B. Rasagiline-induced serotonin syndrome. Mov

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43. Magyar K, Szatmary I, Szebeni G, et al. Pharmacokinetic studies of (-)-deprenyl and some

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44. Magyar K. The pharmacology of selegiline. Int Rev Neurobiol 2011;100:65-84

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46. Hoy SM and Keating GM. Rasagiline: a review of its use in the treatment of idiopathic

Parkinson's disease. Drugs 2012;72:643-669

47. Naoi M, Maruyama W, and Inaba-Hasegawa K. Type A and B monoamine oxidase in

age-related neurodegenerative disorders: their distinct roles in neuronal death and survival.

Curr Top Med Chem 2012;12:2177-2188

• Paper on the role of MAO in neurodegeneration

48. Naoi M, Maruyama W, and Inaba-Hasegawa K. Revelation in the neuroprotective

functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms.

Expert Rev Neurother 2013;13:671-684

49. Berg D, Godau J, Seppi K, et al. The PRIPS study: screening battery for subjects at risk

for Parkinson's disease. Eur J Neurol 2013;20:102-108

50. Przuntek H, Muller T, and Riederer P. Diagnostic staging of Parkinson's disease:

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•• The first conceptual paper on non motor symptoms in Parkinson’s disease

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Figures

Figure 1

neuron

substitution of biogenic amines with conventional antidepressants

COMT
MAO
oxidative stress ↑↑

Figure 1. Increased oxidative stress during the scenario with conventional antidepressant
therapy without MAO inhibition and elevated oxidative stress causing hypothetical
acceleration of the chronic neurodegenerative process.
COMT, Catechol-O-methyltransferase; MAO, Monoamine Oxidase
Figure 2

neuron

elevated levels of biogenic amines following MAO inhibition

COMT
MAO
oxidative stress ↑↑

Figure 2. Antidepressant therapy with MAO inhibition, which counteracts oxidative stress by
MAO triggered metabolism of biogenic amines.
COMT, Catechol-O-methyltransferase; MAO, Monoamine Oxidase