Monoamine Oxidase Inhibitor(MAO-I)-Mediated Neuroprotectionfor Treating Parkinson’s Disease

Toshiharu Nagatsu and Akira Nakashima

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2DA Synthesis and Metabolism in the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4MAO-A and MAO-B in the Human Brain in Relation to PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Clinical Studies on MAO-B Inhibitor (MAO-B-I) in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Molecular Mechanisms of Possible Neuroprotection of DA Neurons by MAO-B Inhibitors(MAO-B-Is) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Mechanism of sPD Hypothesized from Causative Proteins of fPD . . . . . . . . . . . . . . . . . . . . . . . . . 10Mechanism Based on Catecholaldehyde Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Neurotoxin Hypothesis and Neuroprotection by MAO-B-Is . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Neuroprotective Mechanism of MAO-I that May Not Be Related to MAO Inhibition . . . . . 13MAO-B Inhibitors (MAO-B-I) and Pro-inflammatory Cytokines from ActivatedMicroglia in Neuroinflammation in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

AbstractMonoamine oxidases (MAO)-A andMAO-B catalyze the oxidative deaminationof monoamine neurotransmitters, such as dopamine (DA), noradrenaline, andserotonin, in the central and peripheral nervous system. Parkinson’s disease(PD) is an aging-related movement disorder, caused by a deficiency of the

T. Nagatsu (*)Center for Research Promotion and Support, Fujita Health University School of Medicine,Toyoake, Aichi, Japane-mail: tnagatsu@fujita-hu.ac.jp; tnagatsu@riem.nagoya-u.ac.jp; tnagatsu@gamma.ocn.ne.jp

A. NakashimaDepartment of Physiological Chemistry, Fujita Health University School of Medicine, Toyoake,Aichi, Japane-mail: anakashi@fujita-hu.ac.p

© Springer Nature Switzerland AG 2020P. Riederer, G. Laux et al. (eds.), NeuroPsychopharmacotherapy,https://doi.org/10.1007/978-3-319-56015-1_238-2

1

neurotransmitter DA in the striatum of the brain, caused by degeneration of thenigrostriatal DA neurons. During the1960s, L-DOPA, a direct precursor of DA,which is synthesized in vivo from tyrosine in DA neurons by tyrosine hydroxy-lase and is converted to DA by aromatic L-amino acid decarboxylase, wasintroduced to treat this DA deficiency in the striatum. In addition to L-DOPA asa treatment, MAO-B inhibitors (MAO-B-Is) have been used since the 1970s, firstselegiline (L-(-)-deprenyl), then rasagiline, and more recently safinamide, as aneffective therapy for PD by preventing the degradation of DA. Furthermore,monotherapy with MAO-B-I, selegiline, rasagiline, or safinamide has been pro-ved to be effective in the case of early PD. Accumulating data suggest that MAO-B-Is may also have neuroprotective efficacy due to several mechanisms that mayor may not be related to MAO inhibition. DA oxidation and formation ofmisfolded α-synuclein oligomers may be linked to dysfunctions of mitochondria,the autophagy-lysosomal system, and ubiquitin-proteasome system, resulting inDA neuron death in PD; and MAO-I may prevent these processes to affordneuroprotection. However, many clinical and basic studies have suggested, butnot yet convincingly proved, neuroprotective effects of MAO-I in PD. It remainsto be proved if the administration of MAO-B-I several decades before the onset ofPD could prevent the occurrence of PD based on neuroprotection and, if so, toconfirm the molecular mechanism involved.

AbbreviationsAADC Aromatic L-amino acid decarboxylaseALDH Aldehyde dehydrogenaseDA DopamineDOPAC 3,4-Dihydroxyphenylacetic acidDOPAL 3,4-DihydroxyphenylacetaldehydeL-DOPA L-3,4-Dihydroxyphenylalanine/levodopaMAO Monoamine oxidaseMAO-I MAO inhibitorMPP+ 1-Methyl-4-phenyl-pyridiniumMPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinePD Parkinson’s diseaseROS Reactive oxygen speciesTH Tyrosine hydroxylaseVMAT2 Vesicular monoamine transporter 2

Introduction

Parkinson’s disease (PD) is an aging-related movement disorder mainly caused by adeficiency of the neurotransmitter dopamine (DA) in the striatum of the brain as aresult of progressive degeneration of nigrostriatal DA neurons, which degenerationis responsible for the main motor symptoms. DA in DA neurons is synthesized fromtyrosine: first by tyrosine hydroxylase (TH) to L-3,4-dihydroxyphenylalanine

2 T. Nagatsu and A. Nakashima

(L-DOPA, levodopa) and then by aromatic L-amino acid decarboxylase (AADC;also called DOPA decarboxylase, DDC) to DA. The pathological hallmark of mostPD is intracellular inclusions termed Lewy bodies, mainly composed of α-synucleinprotein, although no Lewy bodies are seen in the case of rare autosomal recessiveyoung-onset familial PD. DA deficiency in the striatum in PD is due to the loss ofDA neurons in the substantia nigra.

Most PD is sporadic (sPD) without any hereditary history. A small percentage(5–10%) of PD is either autosomal dominant or autosomal recessive familial PD(fPD) as well as parkinsonism due to MPTP intoxication, post encephalitic parkin-sonism, PINK-1-parkinsonism, and SWEE and in many cases with LRRK-2 muta-tion, and the chromosomal locations of several causative genes have been identified(PARK1~PARK23 in 2018) since 1997 (PARK1). Several causative genes of fPD, themutations of which produce PD, have been identified, such as the SNCA/alpha-synuclein gene (PARK1/4; Polymeropoulos et al. 1997), parkin (PARK2; Kitada et al.1998), PINK1 (PARK6; Valente et al. 2004), DJ-1 (PARK7; Bonifati et al. 2003), andLRRK2 (leucine-rich repeat kinase-2 gene; PARK8; Paisan-Ruiz et al. 2004;Zimprich et al. 2004). Rare fPDs are generally of the young-onset type and eitherautosomal dominant and Lewy body-positive or autosomal recessive and Lewybody-negative. In contrast, the more prevalent sPD has an old-age onset and isLewy body-positive.

The cause of sPD is unknown, but sPD is speculated to be caused by combinedeffects of both some susceptibility genes, the expression of which may be increasedduring aging, and unidentified endogenous or environmental compounds that areneurotoxic toward DA neurons. The presence of various causative genes in fPDsuggests that DA cell death in sPD may occur initially by several different causes andlater by common molecular pathways. The common factors in the prevalent sPD andrare fPD of the autosomal dominant type are DA deficiency and Lewy body-bearingα-synuclein, which may trigger the onset of DA cell death.

During the1960s, the administration of L-DOPA, which is a direct precursor ofDA in DA neurons, was established as an effective pharmacotherapy for reversingthe deficiency in the neurotransmitter DA in the striatum. Furthermore, in addition toL-DOPA treatment, since the 1970s monoamine oxidase (MAO) type B inhibitors(MAO-B-Is) , first selegiline (L-(-)-deprenyl) and then rasagiline (N-propargyl-1R-aminoindan) and more recently safinamide (Fig. 1), have been introduced to preventdegradation of DA by MAO activity as an effective pharmacotherapy for PD. Later,monotherapy with MAO-B-I has been proved to be effective in the case of earlyPD. Accumulating clinical and basic findings suggest that MAO-B-I, selegiline,rasagiline, or safinamide may have neuroprotective and disease-modifying efficacyas a result of several mechanisms that may or may not be related to MAO inhibition.

In this chapter we discuss the results of clinical trials and the possible molecularmechanism responsible for the efficacy of MAO-B-Is for treatment of PD, i.e., thepossibility of neuroprotection of DA neurons by MAO-I.

Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating. . . 3

DA Synthesis and Metabolism in the Brain

DA is synthesized in DA neurons from L-tyrosine via L-DOPA by TH and then byAADC. TH is specifically localized in catecholamine (DA, noradrenaline, andadrenaline) neurons, which enzyme is especially abundant in nigrostriatal DAneurons, whereas AADC is localized in DA neurons as well as in serotonin neuronsand glial cells in the brain and in various non-neuronal cells such as liver and kidneyin the periphery. DA as a neurotransmitter is released from the DA nerve terminalsinto synaptic clefts and interacts with DA receptors in the post-synaptic neurons.Then DA is taken up back into the cytoplasm of the pre-synaptic DA neurons via DAtransporter and from the cytoplasm is again stored in synaptic vesicles via vesicularmonoamine transporter 2 (VMAT2). DA is also metabolized by MAO in DAneurons as well as in other neurons and in glial cells and by catechol-O-methyltransferase (COMT) in glial cells.

Neurodegeneration of the nigrostriatal DA neurons in PD causes decreases in DAlevels (Ehringer and Hornykiewicz 1960); in the levels of mRNA, protein, andactivity of TH and AADC; and in the level of tetrahydrobiopterin (BH4), a cofactorof TH (Lloyd et al. 1975; Nagatsu et al. 1977; Nagatsu and Nagatsu 2016).

MAO-A and MAO-B in the Human Brain in Relation to PD

MAO [amine: oxygen oxidoreductase (deaminating) (flavin-containing); E.C. 1.4.3.4.] catalyzes the following reaction: RCH2NH2 + H2O + O2 = RCHO +

Selegiline (deprenyl) Rasagiline

Safinamide

HCC

CH2

NCH3CH

CH3

CH2

CCH2 CH

HN

CH3

O

NH2

FO

CH2

C

NH

CH2HC

Fig. 1 Structures ofmonoamine oxidase-Binhibitors (MAO-B-Is),selegiline, rasagiline, andsafinamide

4 T. Nagatsu and A. Nakashima

NH3 + H2O2 (Fig. 2) The monoamine substrates for MAO include physiologi-cally and pathologically important neurotransmitters, such as DA, noradrenaline,adrenaline, and serotonin, which regulate movement, emotion, motivation, reward,cognition, memory, and learning in the brain. Thus, MAO is closely related to higherbrain functions by regulating the levels of monoamine neurotransmitters and possi-bly to the pathogenesis of PD (Nagatsu and Nagatsu 2016; Nagatsu and Sawada2006a). MAO in the brain produces 3,4-dihydroxyphenylacetaldehyde (DOPAL)from DA as substrate. Two types of MAO, MAO-A and MAO-B, are localized in theouter membrane of mitochondria in various cells in the central and peripheral tissues.The structures of human MAO-A and MAO-B were determined from their cDNAand by genomic DNA cloning. Human MAO-A and MAO-B are each composed oftwo identical subunits, with Mr 59,700 (527 amino acids) and Mr 58,000 (520 aminoacids), respectively, for each subunit. MAO-A and MAO-B genes are situated on theX chromosome at Xp 11.2–22.1, each consisting of 15 exons and having an identicalexon-intron organization (Chen and Shih 1998). MAO-B in the human brain wasdetected in vivo by positron-emission tomography (PET) using [11C]selegiline(Fowler et al. 1998). The PET study indicated that MAO-B levels in the humanbrain were highest in the basal ganglia, which include the nigrostriatal DA neurons,and showed an average increase of 7.1 � 1.3% per decade during aging, whichincrease is thought to be important in the pathology of aging-related sPD.

Clinical Studies on MAO-B Inhibitor (MAO-B-I) in PD

MAO, especially type B, is speculated to play important roles in PD and aging. Asdescribed above, MAO-B is localized mainly in glial cells as well as in serotonergicneurons in the human brain, and its expression increases during aging (Fowler et al.1998). Presently three MAO-B-Is are used for pharmacotherapy of PD: firstselegiline, then rasagiline, and more recently safinamide. Selegiline and rasagilineare irreversible MAO-B-Is, whereas safinamide (1-[2-(4-benzyloxyphenoxy)ethyl]imidazole; Chung et al. 2015) is a reversible one and also a sodium-channel blocker.

(DA) (DOPAL)3,4-dihydroxphenylacetaldehydedopamine

+ HHO CH2 CH2

C

O

HCH2

NH2HO

HO

HO2O + O2

MAO + NH3 + H2O2

(B)

(A)

Fenton reaction+ Fe2+ +H2O2

hydroxy radical

Fe3+ OH- + OH

Fig. 2 Reactions in monoamine oxidase (MAO) and in formation of oxygen radical from theproduct H2O2 via the Fenton reaction

Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating. . . 5

First selegiline and then rasagiline were extensively studied with respect to theirclinical efficacy on PD pharmacotherapy and on the molecular mechanism ofpossible protection against DA neuron death.

Historically possible neuroprotective effect of MAO-B-I was first suggested onclinical studies on MAO-B-I selegiline and then on rasagiline. Although theL-DOPA therapy, which was established in the 1960s, addresses symptoms (i.e.,supplementation of decreased DA in the PD brain) and not the cause, L-DOPA stillremains the gold standard in 2017, as compared with DA receptor agonists that wereintroduced in the 1970s to compensate the deficiency in DA (Birkmayer andHornykiewicz 1961; Cotzias et al. 1969; Fahn 2015; Mizuno in this eBook). Theclinical efficacy of MAO-B-I selegiline was initially thought to be a result oftreatment of symptoms, i.e., due to prevention of degradation of DA formed fromadministered L-DOPA. However, the concept of neuroprotection by selegiline hasemerged based on various clinical and molecular pharmacological data.

The clinical efficacy of the MAO-B-I selegiline (L-(-)-deprenyl; Riederer 2014;Riederer and Müller in this eBook; Fig. 1) in combination with L-DOPA to protectagainst degradation of DA by MAO and to supplement DAwas reported for the firsttime by Birkmayer and co-workers (1975). In a study involving long-term treatmentof PD patients with L-DOPA alone or in combination with selegiline, a significantincrease in life expectancy was observed for the L-DOPA-selegiline group. Thepreliminary findings of a clinical study on the efficacy of selegiline for treatment ofPD showed that the use of selegiline delays the onset of disability associated withearly untreated cases of PD (Birkmayer et al. 1985). A double-blind, placebo-controlled clinical study on early PD patients also showed that early selegilinetherapy delays the requirement for L-DOPA therapy, possibly by slowing progres-sion of the disease (Tetrud and Langston 1989).

The Parkinson Study Group in the USA (1993) reported the results of theirmulticenter controlled clinical trial of “Deprenyl and Tocopherol AntioxidativeTherapy of PD” (the US “DATATOP” study). The results of a 5-year clinical trialstarted in 1987 suggested that selegiline monotherapy (10 mg per day) but not thatwith tocopherol (vitamin E, an antioxidant, 2000 IU per day) delays the onset ofdisability associated with early, otherwise untreated PD. Studies in France (Allainet al. 1993) also showed that selegiline is effective as a monotherapy, suggestingeither neuroprotection or efficacy in treatment of symptoms. The clinical efficacy ofselegiline plus L-DOPA was also reported in Finland (Myllylä et al.1997) and in aNorwegian-Danish study (Larsen et al. 1999). The SELEDO (selegiline plus levo-dopa) study in Germany also proved that the early combination of selegiline andL-DOPAwas clearly superior to levodopa monotherapy alone (Przuntek et al. 1999).

Further studies on the impact of sustained selegiline administration to L-DOPA-treated patients showed that such patients who had been treated with selegiline for upto 7 years, compared with those whose treatment was changed to a placebo afterabout 5 years, experienced slower motor decline. These data do not delineatewhether the observed effects of selegiline were related to symptomatic DA actions,disease-modifying mechanisms, or both (Shoulson et al. 2002).

A systematic search of the literature for randomized trials comparing MAO-B-Iswith placebo or L-DOPA from 1966 to December 2003 concluded the following:

6 T. Nagatsu and A. Nakashima

MAO-B-Is reduce disability, the need for L-DOPA, and the incidence of motorfluctuations, without substantial side effects or increased mortality. However, sincefew trials have compared MAO-B-Is with other anti-parkinsonian drugs, uncertaintyremains about the relative benefits and risks of MAO-B-Is (Ives et al. 2004). Thelong-term effects of selegiline in monotherapy and in combination with L-DOPA inthe early phase of PD were again confirmed in Sweden, indicating that selegilinedelays the progression of the signs and symptoms of PD (Pålhagen et al. 2006). Astudy group in Singapore reported that selegiline use for 3 years or more for early PDwas associated with a slower progression of PD as evaluated by Hoehn and Yahrstage transition times, suggesting a modifying effect on disease progression, whicheffect was not observed with either L-DOPA or DA agonists (Zhao et al. 2011).

Furthermore, another MAO-B-I, rasagiline (N-propargyl-1R-aminoindan; Fig. 1),the selective, irreversible MAO-B-I, has shown effectiveness in early PD whengiven as a once-daily treatment (Ives et al. 2004; Youdim in this eBook).

The PD MED Collaborative Group in UK (2014) aimed at asking the question asto whether initial treatment for PD should consist of L-DOPA, DA agonists, orMAO-B-Is; and it concluded that very small but persistent benefits in terms ofpatient-rated mobility scores were obtained when treatment was initiated withL-DOPA compared with L-DOPA-sparing therapy and that an MAO-B-I as theinitial L-DOPA-sparing therapy was at least as effective as DA agonists.

In Japan it was reported that the clinical outcome as evaluated by the selectedUPDRS motor score was better for L-DOPA-treated patients who had receivedselegiline within 5 years from disease onset compared with those who had beengiven selegiline approximately 10 years from the onset, confirming that earlyaddition of selegiline to L-DOPA treatment is beneficial for patients with PD(Mizuno et al. 2010). In the USA, the FDA approved selegiline as an adjunct toL-DOPA for PD treatment in 1989. In the same year, Newsweek published an articleon selegiline as a promising drug for slowing disease progression. Much later, in1998, this drug was approved in Japan for combined therapy with L-DOPA and thenfor monotherapy in 2015.

A case-control retrospective study analyzed data from patients with PD attendingthe Parkinson’s Institute in Milan, Italy, over a 6-year period (2009–2015) andcompared the effects of selegiline or rasagiline on L-DOPA treatment outcomes.Comparison was made between patients with PD treated with either selegiline orrasagiline for 3 years and with a control group who have never received MAO-B-Is.Long-term use of MAO-Is resulted in a lower frequency of dyskinesia in patientswith PD. The use of MAO-Is for 3 years was associated with a significant reductionin the daily dose of L-DOPA needed. With optimized therapy, rasagiline andselegiline showed equal efficacy in controlling motor symptoms in PD patients(Cereda et al. 2017).

A secondary analysis by NET-PD LSI (National Institute of Neurological Dis-eases and Stroke-Exploratory Trials in PD Long-Term Study 1) in the USA identifieda significant association between longer duration of MAO-B-I exposure and lessclinical decline, supporting the possibility that MAO-B-Is slow the progression ofclinical disease (Hauser et al. 2017).

Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating. . . 7

Although many clinical studies on PD have suggested neuroprotective effects ofMAO-B-Is, clinical trials have not yet convincingly demonstrated disease-modifying benefits in PD patients; and the mechanism accounting for their beneficialeffects remains unclear. A definitive prospective clinical trial should be furtherconducted (Hauser et al. 2017), and the molecular mechanism must be clarified.

Since the causative events, supposedly DA oxidants and α-synuclein oligomers asdescribed below, are speculated to start very early in the disease, several decadesbefore starting of the motor symptoms in sPD, MAO-I administration at the firststage of movement disorders might not be early enough to prevent PD symptoms.

Molecular Mechanisms of Possible Neuroprotection of DANeurons by MAO-B Inhibitors (MAO-B-Is)

The molecular mechanism of possible neuroprotective effects of MAO-B-Isselegiline and rasagiline on DA neurons has been extensively studied in vitro incell cultures and in vivo in PD animal models (Nagatsu and Sawada 2006b; Robakisand Fahn 2015).

The mechanism and the related factors for possible protection of DA neurons inPD by MAO-I, which are assumed to be either related to or not related to MAOactivity (Fig. 3; Table 1), remain unclear (Michel et al. 2016).

The current hypothesis on DA neuron degeneration in PD is centered on andaggregates of toxic misfolded α-synuclein oligomers. DA oxidation contents in thehuman brain are most abundant in nigrostriatal DA neurons, which are the mostvulnerable neurons in PD and most abundant in neuromelanin (NM)-containingDA neurons, a substance produced from DA. DA itself outside of synaptic vesiclesis easily oxidized non-enzymatically, and enzymatically by MAO, to 3,4-dihydroxyphenlacetaldehyde (DOPAL), and then both DA and DOPAL producequinones that cause DA cell death (Goldstein et al. 2013). DA oxidation representsan important link between mitochondrial and lysosomal dysfunctions in PD(Burbulla et al. 2017), and MAO-Is are assumed to protect against this pathologicalprocess.

Although DA is a common substrate of both MAO-A and MAO-B, MAO-B-Ishave been shown to be clinically more effective in PD, as described before. How-ever, MAO-B-I selegiline, after its long-term administration, may also inhibitMAO-A (Müller et al. 2017). MAO-A in the human brain is mainly located inneurons, whereas MAO-B is preferentially found in serotonergic and glial cells. Thetype of MAO in rodent DA neurons has been considered as MAO-A, but a recentstudy on iPS cell-derived DA neurons from PD patients revealed that the type isactually MAO-B (Woodard et al. 2014).

8 T. Nagatsu and A. Nakashima

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Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating. . . 9

Mechanism of sPD Hypothesized from Causative Proteins of fPD

The discoveries of the causative genes of various fPDs (PARKs) have greatlycontributed to investigation into the molecular mechanism of sPD. Based on theinformation obtained from postmortem brains from fPD patients and fPD-derivediPS cells, DA oxidation, oxidative/endoplasmic reticulum (ER) stress, aggregationof toxic misfolded α-synuclein oligomers, mitochondrial dysfunction, alterations inthe ubiquitin-proteasome and autophagy-lysosome systems, and neuroinflammationare assumed to be a central mechanism resulting in neurodegeneration, as describedbelow in more detail (Burbulla et al. 2017; Chen et al. 2015; Sánchez-Danés et al.2012; Woodard et al. 2014; Riederer et al. 2019). DA and α-synuclein proteinoligomers (causative protein of autosomal dominant fPD type 1/4; PARK1/4; Poly-meropoulos et al. 1997) are assumed to be key molecules for neurodegeneration inPD. Parkin protein (PARK2), which is an RBR E3 ubiquitin ligase (Shimura et al.2000) and, the causative protein product of the autosomal recessive fPD type 2 gene(parkin, PARK2; Kitada et al. 1998), is directly linked to the ubiquitin-proteasomesystem. Parkin in collaboration with PTEN-induced putative kinase 1 (PINK1;Valente et al. 2004), the gene product of fPD type 6 (PARK6), is involved inregulating quality control within mitochondria and in autophagy of dysfunctionalmitochondria (mitophagy) by the autophagy-lysosome system (Hattori and Mizuno2017). These data on fPD suggest a possible neuroprotective mechanism of MAO-Irelated to prevention of DA cell death at the upstream of the signal transduction ofeither the ubiquitin-proteasome system or autophagy-lysosomal system or both.

Mechanism Based on Catecholaldehyde Hypothesis

MAO-I may prevent oxidative stress caused by 3,4-dihydroxyphenylacetaldehyde(DOPAL) and H2O2 formed from the substrate DA by MAO (Goldstein et al. 2016).DOPAL and H2O2 are formed by MAO-B mainly in glial astrocytes. DOPAL andH2O2 might be released from glial cells or DA neurons and may be transferred toother DA neurons and microglia causing neuroinflammation. H2O2 and DOPAL are

�

Fig. 3 (continued) Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; BDNF, brain-derivedneurotrophic factor; CAD, caspase-activated DNase; Cyt C, cytochrome c; DA, dopamine;DAT, dopamine transporter; L-DOPA, L-3,4-dihydroxyphenylalanine; DOPAC,3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-dihydroxyphenylacetaldehyde; GAPDH, glyceralde-hyde-3-phosphate dehydrogenase; GDNF, glial cell line-derived neurotrophic factor; GSH, gluta-thione; ICAD, inhibitor of caspase-activated DNase; IL, interleukin; MAO, monoamine oxidase;MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NGF,nerve growth factor; NQO1, NAD(P)H quinone oxidoreductase 1; Nrf, nuclear factor (NF)-erythroid (E)-2-related factor 2; pADPr, poly(ADP-ribose); PTP, permeability transition pore;ROS, reactive oxygen species; SOD, superoxide dismutase; TH, tyrosine hydroxylase; TNF-α,tumor necrosis factor-α; Trx, thioredoxin; VMAT2, vesicular monoamine transporter 2;ΔΨm, mitochondrial transmembrane potential

10 T. Nagatsu and A. Nakashima

assumed to cause DA cell death by the following mechanisms: oxidative stress toproduce reactive oxygen species (ROS); mitochondrial dysfunction; formation oftoxic α-synuclein oligomers; dysfunction in autophagy of mitochondria(mitophagy); increase in levels of pro-apoptotic factors; decrease in the levels ofantiapoptotic factors; neuroinflammation triggered by microglia producingpro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin(IL)-1β; and decrease in levels of neurotrophic factors produced mainly formastrocytes, such as brain-derived neurotrophic factor (BDNF), nerve growth factor(NGF), and glial cell-line derived-neurotrophic factor (GDNF; Mallajosyula et al.2008; Mizuta et al. 2000; Tang et al. 1998). MAO-B-I may prevent theseneurodegeneration processes (Fig. 3).

DA in the cytoplasm outside of synaptic vesicles in the presynaptic DA neurons ismetabolized from intraneuronal MAO to produce H2O2 and toxic DOPAL. DOPALis normally metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehydedehydrogenase (ALDH). However, VMAT2 levels in synaptic vesicles and ALDHones in the cytoplasm of DA neurons are decreased in PD patients, and these

Table 1 Changes in cell death-related factors in dopamine neurons in Parkinson’s disease and theirrecovery by selegiline. Main factors are underlined

Effects of monoamine oxidase-B inhibitor (selegiline)

Changes in Parkinson’s diseasePossible changes by selegiline fordopamine Neuroprotection

ALDH: aldehyde dehydrogenase Decrease Increase

Complex 1 in mitochondria Decrease Increase

DA: dopamine Decrease Increase

DA in synaptic vesicle Decrease Increase

DA in cytoplasm Increase Decrease

DA in synapse Decrease Increase

DOPAC: 3,4-dihydroxyphenylacetic acid Decrease Increase

DOPAL: 3,4-dihydroxyphenylacetaldehyde Increase Decrease

GAPDH: glyceraldehyde 3-phospahte dehydrogenase Increase Decrease

GDNF: glial cell line-derived neurotrophic factor Decrease Increase

GSH: glutathione Decrease Increase

Iron Increase Decrease

MAO-B: monoamine oxidase B Increase Decrease

MT: metallothionein Decrease Increase

NGF (nerve trophic factor) Decrease Increase

Nrf2: NF-E2-related factor 2 Nuclear translocation Increase

Oxidative stress Increase Decrease

PARP-1: poly(ADP-ribosyl)polymerase-1 Increase ?

ROS: reactive oxygen species Increase Decrease

α-Synuclein (oligomers) Increase Decrease

TH: tyrosine hydroxylase Decrease Increase

Trx: thioredoxin Decrease Increase

VMAT2: vesicular monoamine transporter 2 Decrease Increase

Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating. . . 11

neurodegenerative processes may result in the increased levels of toxic DOPAL andH2O2 (Casida et al. 2014; Fitzmaurice et al. 2013; Grünblatt and Riederer 2016; Liuet al. 2014). DOPAL in the cytoplasm may promote the production of toxicα-synuclein oligomers finally resulting in cell death (catecholaldehyde hypothesis;Casida et al. 2014; Goldstein et al. 2011, 2013; Liu et al. 2014). Another MAOproduct, H2O2 is oxidized to cytotoxic ROS catalytically with iron and neuromelaninformed from DA (Le 2014; Singh et al. 2014; Fenton reaction; Fig. 2). Ironaccumulates in the DA neurons in the substantia nigra and may play a key role inPD (Dexter et al. 1987; Hirsch et al. 1991; Jellinger et al. 1992; Jiang et al. 2017; Le2014; Sofic et al. 1988). A novel iron chelator-brain selective MAO-A/MAO-Binhibitor showed neuroprotective and neuro-restorative activities in animal modelsof PD and aging (Bar-Am et al. 2015; Youdim et al. 2005; Youdim in this eBook).

Neurotoxin Hypothesis and Neuroprotection by MAO-B-Is

The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as thefirstly recognized synthetic neurotoxin that produces PD symptoms in humans hasgreatly contributed to our understanding of the molecular mechanism of PD(Langston et al. 1983). MPTP is a pro-neurotoxin; after its systemic injection, itrapidly crosses the blood-brain barrier to enter the brain and is metabolized to1-methyl-4-phenyl-2,3-dihydro-pyridinium (MPDP+) by MAO-B in glial cells.MPDP+ is spontaneously oxidized to 1-methyl-4-phenyl-pyridinium (MPP+), theactive PD-producing neurotoxin. MPP+ is taken up via DA transporters across theplasma membrane and into the presynaptic terminals of DA neurons in the striatum.As acute reactions, MPP+ is taken up into synaptic vesicles from the cytoplasm byvesicular transporter 2 (VMAT2) to release DA from the nerve terminals; and it alsoinhibits and inactivates TH to decrease DA synthesis (Ozaki et al. 1988). In thechronic phase, MPP+ is transported from the nerve terminals in the striatum to thecell bodies in the substantia nigra by retrograde axonal flow. MPP+ also accumulateswithin the inner mitochondrial membrane, where it inhibits complex I (NADHubiquinone oxidoreductase), one of the five enzyme complexes of the inner mito-chondrial membrane involved in oxidative phosphorylation for ATP formation;interrupts electron transport; releases ROS causing oxidative stress; and depletesATP. Inhibition of mitochondrial complex I opens mitochondrial permeability pores,subsequently triggering the apoptotic cell death of DA neurons. Thus, MPP+decreases DA acutely and chronically to produce PD-like symptoms. Oxidation ofMPTP to toxic MPP+ by mitochondrial MAO-B in glial cells is essential for MPTPneurotoxicity, and selegiline as an MAO-B-I completely prevents the symptom ofPD by MPTP in an acute MPTP mouse model. Just as in MPTP-PD model,mitochondrial dysfunction, especially decreased activity of complex I, has alsobeen confirmed in the nigrostriatal region in the postmortem brain in PD (Mizunoet al. 1989; Reichman and Riederer 1989; Schapira et al. 1989).

Assuming that some MPTP-like neurotoxins in the environment may trigger PD,their endogenous counterparts have been investigated in postmortem brains and in

12 T. Nagatsu and A. Nakashima

cerebrospinal fluid from patients with PD (Naoi et al. in this eBook). Two groups ofMPTP-like compounds, i.e., tetrahydroisoquinolines synthesized from dopamine(Nagatsu 2002) and beta-carbolines synthesized from indoleamines (Collins andNeafsey 1985; Collins and Nearsey 2000; Matsubara 2000; Maruyama et al. in thiseBook), were found in the brain of PD patients. 1-Benzyl-tetrahydroisoquinoline(Kotake et al. 1998), N-methyl-(R)-salsolinol (Naoi et al. 1996), and 2,9-dimethyl-beta-carbolinium (Collins and Neafsey 2000; Matsubara 2000) were suggested to beendogenous precursor neurotoxins similar to MPTP; these compounds inhibit com-plex I in mitochondria, and their toxicity is negated by MAO-B-I. Specific inhibitoryactivity toward complex I of isoquinolines and beta-carbolines suggests that thesecompounds might be possible endogenous neurotoxins producing PD. However,their in vivo toxicity and clinical significance in human PD remain unclear. Epide-miological studies have suggested that insecticide exposure is associated with anincreased risk of development of PD. Rotenone, an insecticide, which also inhibitscomplex I in mitochondria in the brain, was found to produce PD in rats (Betarbetet al. 2000). Benomyl, another insecticide, which inhibits ALDH in the cytoplasm ofDA neurons, also produces parkinsonism symptoms in animals. It increases DOPALlevels formed from DA by MAO, supporting the toxic catecholaldehyde hypothesisof PD and MAO-I-mediated neuroprotection (Casida et al. 2014; Fitzmaurice et al.2013; Liu et al. 2014).

Neuroprotective Mechanism of MAO-I that May Not Be Relatedto MAO Inhibition

It is known that the neuroprotective effects of selegiline can be observed in cellculture experiments at lower concentrations than those required for MAO-B inhibi-tion, thus suggesting that selegiline’s neuroprotective effects may be caused by someother mechanisms in addition to inhibition of MAO-B.

In an inducible transgenic cellular model of PD in which MAO-B is over-expressed, increased nitration of Tyr-39 on endogenous α-synucelin can be abro-gated by the addition of selegiline (Danielson et al. 2009). Selegiline blocks theformation of smaller toxic aggregates of α-synuclein in vitro by perturbingDA-dependent fibril disaggregation to protect DA neurons (Braga et al. 2011; Onoet al. 2007).

A question is the effect of MAO-I on DNA damage repair protein, poly(ADP-ribose) (PAR) polymerase-1 (PARP-1), which was thought to be decreasedin PD. On the contrary, Kim et al. (2018) identified PARP-1 activation and thegeneration of PAR as a key mechanism of pathological α-synuclein-inducedneurodegeneration: fibrillar aggregates of α-synuclein activate PARP-1 and triggergeneration of PAR; PAR directly binds to and accelerates the formation of toxicα-synuclein fibrils to cause PARP-mediated neuronal death (parthanatos) via acti-vation of nitric oxidase synthase (NOS) and induction of DNA damage, whichfurther activates PARP-1 in a vicious circle. Inhibitors of PARP-1 activation couldbe expected as potential neuroprotective therapeutics in PD.

Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating. . . 13

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a celldeath cascade wherein a variety of stimuli activate nitric oxide synthase with itsproduct NO nitrosylating GAPDH, thereby conferring on it the ability to bind to Siah(seven in absentia homolog), an E3 ubiquitin ligase, whose nuclear localizationsignal enables the GAPDH/Siah protein complex to be translocated to the nucleuswhere degradation of Siah targets elicits cell death. Selegiline preventsS-nitrosylation of GAPDH, the binding of GAPDH to Siah, and translocation ofGAPDH to the nucleus (Hara et al. 2006).

Selegiline was shown to protect human DA neuroblastoma SH-SY5Y cells inculture from the DNA damage induced by nitric oxide or peroxynitrate almostcompletely. This protection was significant even after selegiline was washed fromthe cells, suggesting that this MAO-I may activate the intracellular system againstapoptosis (Maruyama et al. 1998).

Selegiline alters the expression of a number of mRNAs or proteins active againstcell death in nerve and glial cells, and these alterations in gene expression/proteinsynthesis are the result of a selective action on transcription, i.e., the transcription ofgenes for neurotrophins such as GDNF, BDNF, and NGF (Mizuta et al. 2000); theoncoproteins Bcl-2 and Bax; the scavenger proteins Cu/Zn superoxide dismutase(SOD1) and Mn superoxide dismutase (SOD2); glutathione (GSH;-Mytilineou et al.1998); and thioredoxin (Ando et al. 2005). Also, selegiline induces the production ofthioredoxin, leading to elevated expression of antioxidative Mn superoxidedismutase (MnSOD) and antiapoptotic Bcl-2 for protection against MPP+-inducedneurotoxicity in human SH-SY5K cells and in mouse primary neuronal culture ofmidbrain DA neurons (Ando et al. 2005).

These results suggest that selegiline acts on gene expression to maintain mito-chondrial function and to decrease cytoplasmic oxidative radical levels in thenigrostriatal region by augmenting various antioxidant systems and thereby reducingapoptosis (Tatton et al. 1996).

Selegiline induces the nuclear translocation of nuclear factor erythroid 2-relatedfactor 2 (Nrf2), which induces the expression of antioxidative proteins such as anti-heme oxygenase-1 (HO-1) and peroxiredoxin (PrxI), via activation of the PI3K-Nrf2system, in SH-SY5Y cells (Nakao et al. 2006).

MAO-B doxycycline-inducible transgenic mice with elevated levels of MAO-Bin their astrocytes show the following selective changes: loss of DA neurons in thesubstantia nigra, increased mitochondrial oxidative stress, increased local microglialactivation, increased extracellular H2O2, and decreased locomotor movement.Selegiline may arrest the progression of DA cell death by antioxidant effects byinhibiting MAO-B in astrocytes (Mallajosyula et al. 2008).

MAO-B Inhibitors (MAO-B-I) and Pro-inflammatory Cytokines fromActivated Microglia in Neuroinflammation in PD

Neuroinflammation, especially accompanied by activated microglia in the brain, hasbeen considered to play an important role in PD pathogenesis (Hirsch et al. 2012;McGeer and McGeer 2007; Nagatsu and Sawada 2005).

14 T. Nagatsu and A. Nakashima

Microglia may be activated by H2O2 produced in astrocytes (Mallajosyula et al.2008). MAO-B-I prevents this activation by inhibiting H2O2 production. As the firstfeatures of inflammation in PD, McGeer and collaborators reported an increasednumber of major histocompatibility complex (MHC) class II antigen [humanleucocyte antigen-DR (HLA-DR)]-positive microglial cells in the substantia nigra(McGeer et al. 1988). We and other investigators found increased levels ofpro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Mogi et al. 1994a, b;Imamura et al. 2003); decreased levels of neurotrophins such as BDNF and NGF(Mogi et al. 1999; Imamura et al. 2005); and increased levels of apoptosis-relatedfactors such as sFAS, TNF-α Receptor 1 (p.55), p53, interferon-γ, NF-κB, β2-MG(MHCI), Bcl-2, caspase 1, and caspase 3 in the nigrostriatal region of postmortembrains and/or in the ventricular or lumbar cerebrospinal fluid (CSF) from patientswith sPD and in animal PD models (Nagatsu et al. 2000). Since selegiline increasesthe production of neurotrophins such as BDNF from glial cells, MAO-B-I would beexpected to prevent the progression of toxic injury by inflammatory cytokines fromactivated toxic microglia and DOPAL and H2O2 from astrocytes in the inflammatoryprocess in PD.

Conclusions

Many cell culture studies in vitro and PD animal models in vivo have suggestedneuroprotective efficacy of MAO-B-Is, but large clinical trials of MAO-I for treat-ment of PD have not yet succeeded in definitely demonstrating protection againstneurodegeneration. The sequence and interaction of the signaling pathways in DAneuron death and mechanism of neuroprotection by MAO-I remain to be clarified.Since the main cause of PD, probably oxidation of DA and formation of misfoldedα-synuclein oligomers, is assumed to start several decades before the onset of motorsymptoms of PD, preventive daily administration of a small dose of MAO-B-I mightprevent the occurrence of PD. For such preventive pharmacotherapy, very earlybiological markers to indicate risk factors of PD would be required.

Conflict of Interest

There are no conflicts of interest to declare.

Cross-References

▶ From Anti-Parkinson’s Disease Drug Rasagiline to Novel Multitarget Iron Che-lators with Acetylcholinesterase and Monoamine Oxidase Inhibitory andNeuroprotective Properties for Alzheimer’s Disease

▶ Parkinsonian Toxins: From MTPT to Endogenous Toxins▶ Parkinsonian Toxins: MPTP to Endogenous Neurotoxins

Monoamine Oxidase Inhibitor (MAO-I)-Mediated Neuroprotection for Treating. . . 15

▶Rasagiline for Treating Parkinson’s Disease▶ Safinamide for Treating parkinson’s Disease▶ Selegiline for Treating Parkinson’s Disease

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