Journal of Neural Transmission https://doi.org/10.1007/s00702-018-1853-9

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Pharmacological aspects of the neuroprotective efects of irreversible MAO‑B inhibitors, selegiline and rasagiline, in Parkinson’s disease

Éva Szökő1 · Tamás Tábi1 · Peter Riederer2 · László Vécsei3,4 · Kálmán Magyar1

Received: 4 January 2018 / Accepted: 31 January 2018 © Springer-Verlag GmbH Austria, part of Springer Nature 2018

Abstract The era of MAO-B inhibitors dates back more than 50 years. It began with Kálmán Magyar’s outstanding discovery of the selective inhibitor, selegiline. This compound is still regarded as the gold standard of MAO-B inhibition, although newer drugs have also been introduced to the feld. It was revealed early on that selective, even irreversible inhibition of MAO-B is free from the severe side efect of the non-selective MAO inhibitors, the potentiation of tyramine, resulting in the so-called ‘cheese efect’. Since MAO-B is involved mainly in the degradation of dopamine, the inhibitors lack any antidepressant efect; however, they became frst-line medications for the therapy of Parkinson’s disease based on their dopamine-sparing activity. Extensive studies with selegiline indicated its complex pharmacological activity profle with MAO-B-independent mechanisms involved. Some of these benefcial efects, such as neuroprotective and antiapoptotic properties, were connected to its propargylamine structure. The second MAO-B inhibitor approved for the treatment of Parkinson’s disease, rasagiline also possesses this structural element and shows similar pharmacological characteristics. The preclinical studies performed with selegiline and rasagiline are summarized in this review.

Keywords MAO-B inhibition · Selegiline · Rasagiline · Neuroprotection

Introduction inhibitor in the 1960s (Knoll et al. 1965). The R-(−)-isomer of deprenyl, later called selegiline, was identifed as the The inhibitors of the catecholamine-degrading enzyme, more potent MAO inhibitor (Magyar et al. 1967). In 1968, monoamine oxidase (MAO), have long established thera- Johnston discovered that the enzyme is heterogeneous and peutic use. Deprenyl was frst synthesized as a psychic ener- the isoform inhibited more potently by clorgyline was named gizer (Varga and Tringer 1967), tested for antidepressant MAO-A (Johnston 1968). Magyar and Knoll subsequently efects and later on characterized as an irreversible MAO found that selegiline is also a selective inhibitor, preferen- tially afecting the other isoform called MAO-B (Knoll and Magyar 1972). Because of diferent substrate specifcity and In memory of Professor Kálmán Magyar (1933–2017) tissue distribution of the two isoenzymes, their physiologi- Kálmán Magyar : Deceased. cal roles difer considerably. The well-known antidepressant efect of the previously used non-selective MAO inhibitors * László Vécsei was found to be the consequence of blocking MAO-A activ- [email protected]‑szeged.hu ity. The irreversible inhibition of MAO-A, however, is also 1 Department of Pharmacodynamics, Semmelweis University, responsible for their severe adverse efect, the life-threaten- Nagyvárad tér 4, Budapest 1089, Hungary ing hypertensive crisis after the consumption of tyramine- 2 Center of Mental Health, Department of Psychiatry, rich meals. This was named ‘cheese efect’ because of the Psychosomatics and Psychotherapy, University Hospital high tyramine content of cheese products. Selegiline, in its Würzburg, Magarete‑Höppel‑Platz 1, 97080 Würzburg, selective MAO-B inhibitory dose, is free from this danger- Germany ous side efect (Knoll et al. 1968) but also lacks antidepres- 3 Department of Neurology, University of Szeged, sant activity. As it preferentially reduces the degradation Semmelweis u. 6, Szeged 6725, Hungary of dopamine in the central nervous system (Riederer et al. 4 MTA-SZTE Neuroscience Research Group, Semmelweis 1978), it gained importance in the treatment of Parkinson’s u. 6, Szeged 6725, Hungary

Vol.:(0123456789)1 3 É. Szökő et al. disease from 1975 (Birkmayer et al. 1975, 1977; Parkinson In following studies, the efcacy of selegiline against the Study Group 1993). active toxin ­MPP+ was analyzed in various experimental The distribution of MAO isoenzymes in the brain was designs. First, Mytilineou and Cohen reported that selegiline extensively studied in post-mortem tissues by Riederer and pretreatment prevented the dopamine depletion induced by co-workers. MAO-B was shown predominantly in the glia ­MPP+ in rat embryonic midbrain neuronal culture (Mytili- (Konradi et al. 1989) and its activity was raised in aged neou and Cohen 1985). On the other hand, this efect was patients (Kornhuber et al. 1989). In post-mortem brain stud- not confrmed in the study by Vaglini et al. (1996). The ies, increased dopamine (Riederer and Youdim 1986), and results of the in vivo animal experiments were also con- especially phenylethylamine levels, (Riederer et al. 1984), troversial; failure, partial efect, and prevention of deple- were found in the nigrostriatal system of selegiline-treated tion by selegiline were reported alike (Bradbury et al. 1985; parkinsonian patients. Based on these fndings, it was sug- Mihatsch et al. 1988; Vizuete et al. 1993). In these studies, gested that the catecholamine-releasing efect of the elevated the ­MPP+-induced toxicity was followed by striatal dopa- phenylethylamine may contribute to the dopamine-sparing mine depletion, but this did not necessarily correspond to activity of selegiline (Reynolds et al. 1978; Youdim and the dopaminergic cell loss. Riederer 1993). MPP+ was identifed as a mitochondrial toxin in dopa- Since it was found that selegiline was able to reduce oxi- minergic neurons (Nicklas et al. 1985; Heikkila et al. 1985). dative stress (Cohen and Spina 1989) and prevent the dopa- It inhibits the activity of Complex I of the electron transport mine-depleting efect of the neurotoxin 1-methyl-4-phenyl- chain (Nicklas et al. 1987) which results in compromised 1,2,3,6-tetrahydropyridine (MPTP) (Langston et al. 1984; energy production (Mizuno et al. 1987) and increased oxi- Cohen et al. 1984), further studies were initiated to clarify dative stress (Cleeter et al. 1992). Similar alterations can its pharmacological properties. The results of these experi- be induced by the decreased Complex I expression found ments indicated possible MAO-B inhibition-independent in post-mortem Parkinsonian brain (Mizuno et al. 1989; neuroprotective, antiapoptotic, neurorescue activities, and Schapira et al. 1989; Reichmann and Riederer 1989) along the importance of the propargylamine moiety in these with its increased iron content (Sian-Hülsmann et al. 2011) efects. About 30 years later, rasagiline, another MAO-B causing signifcant oxidative damage. An additional source inhibitor with propargylamine structure, was introduced into of enhanced oxygen free radical generation is the auto-oxi- the therapy of Parkinson’s disease. The pharmacological dation of the enormous amount of dopamine released after studies aiming to understand the neuroprotective, antiapop- toxin-induced cell damage. The suggested components of totic and neurorescue efects of these two drugs are reviewed the protective efect of MAO-B inhibitors against MPTP and discussed in this paper. toxicity are summarized in Fig. 1. To obtain further information about the supposed protec- tive efect of selegiline, the involvement of its suggested antioxidant properties (Cohen and Spina 1989; Gotz et al. Protective efect of selegiline 1995) was studied. Although inhibition of MAO-B itself against neurotoxins reduces hydrogen peroxide production, other components of its antioxidant activity were also hypothesized. As early The dopaminergic neurotoxin, MPTP, was discovered acci- as 1989 Knoll reported that chronic selegiline treatment of dentally when rapid onset and severe Parkinson’s syndrome aged rats enhanced the activity of superoxide dismutase developed in a drug addict using an in-house synthesized in the striatum (Knoll 1989). This was later confrmed by pethidine analogue. Later on, the nigrostriatal damage Carillo et al. in young animals, as well. Furthermore, in induced by the compound was also confrmed (Davis et al. addition to superoxide dismutase, increased catalase activ- 1979). It was soon found that MAO-B inhibitors, pargyline ity was also observed (Carrillo et al. 1991). In another study, and selegiline, prevented MPTP toxicity, suggesting the increased antioxidant enzyme activity after selegiline treat- involvement of MAO-B in the conversion of pro-toxin ment could only be measured in the striatum of aged rats. MPTP to its active form, 1-methyl-4-phenyl-pyridinium Besides the antioxidant enzymes, the level of glutathione (MPP­ +) (Langston et al. 1984; Cohen et al. 1984). Subse- was found to be elevated. No efect was detected in the cor- quently, it was also shown that MPP­ + generated by MAO-B tex or hippocampus or any brain regions of young animals can enter into and damage dopaminergic neurons and is (Takahata et al. 2006). In in vitro cell culture experiments, responsible for MPTP toxicity. Besides MAO inhibitors, it was shown that selegiline treatment, similar to nerve dopamine uptake blockers also provided protection, indi- growth factor (NGF), dose-dependently induced superox- cating the prominent role of this transporter in the selec- ide dismutase mRNA expression. Selegiline also potentiated tive accumulation of the toxin (Fuller and Hemrick-Luecke the efect of NGF, which suggests its action on superoxide 1985). dismutase mRNA induction is NGF-independent (Li et al.

1 3 Pharmacological aspects of the neuroprotective efects of irreversible MAO‑B inhibitors,…

Fig. 1 Targets of selegiline and rasagiline in MPTP toxicity

1998). This is in line with the fndings of Thifault et al., inhibitor, MDL 72974, failed to prevent DSP-4 toxicity, indi- who found selegiline inhibited oxygen consumption of iso- cating another mechanism in the protective efect of sele- lated mitochondria and suggested that this impairment can giline (Finnegan et al. 1990). As DSP-4 accumulates in the induce an adaptive increase in superoxide dismutase activity noradrenergic terminals by uptake transporters, their inhibi- (Thifault et al. 1997). However, the antioxidant property tion by selegiline and/or its metabolites was also proposed due to the induction of antioxidant enzymes develops slowly (Magyar et al. 1996, 1998; Magyar and Haberle 1999). How- following chronic treatment and thus cannot fully explain ever, the metabolites, R-(−)-methamphetamine and R-(−)- the rapid neuroprotective efect of selegiline. Its acute efect amphetamine, possessing stronger uptake inhibitory activity, on ­MPP+-induced hydroxyl radical formation was reported showed weaker protection compared to selegiline against without signifcant infuence on dopamine overfow, sug- DSP-4 induced noradrenaline depletion in the hippocam- gesting the crucial role of direct antioxidant activity (Wu pus. Uptake inhibition thus cannot be the sole mechanism et al. 1993). This was supported by the similar efect of responsible for the protective efect (Haberle et al. 2001). other hydroxyl radical scavengers and antioxidants (Wu et al. Similarly, selegiline was also found to be protective against 1996; Khaldy et al. 2000). Reduced lactate release, a marker 6-hydroxy-dopamine and 3,4-methylenedioxy-methamphet- of hypoxia, from ­MPP+-damaged neurons treated with sele- amine, other toxins causing biogenic amine depletion, but giline is also indicative of its protective efect (Matsubara the exact mechanism of action has not yet been clarifed et al. 2001). Selegiline could also protect nigral neurons (Salonen et al. 1996; Sprague and Nichols 1995). against other types of oxidative stress-inducing agents, like Although these toxins are very useful in modelling some rotenone and iron overload (Saravanan et al. 2006; Budni aspects of Parkinson’s disease, their efect is far from the et al. 2007; de Lima et al. 2005), further supporting the pathophysiology of the disorder. Later, other neuronal importance of its antioxidant property. insults, probably more closely related to the pathomecha- Selegiline was found to provide protection against other nism of neurodegenerative disorders, were used to study the monoamine-depleting neurotoxins, as well. DSP-4 (N-(2- protective efect of selegiline. chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) is selectively accumulated in noradrenergic nerve terminals and thus specifcally reduces noradrenaline levels in several Protective efect of selegiline in models brain regions. Furthermore, it also decreases dopamine-beta- of neuronal degeneration hydroxylase activity in the brain, consistent with the degen- eration of noradrenergic neurons (Ross 1976). The protective NMDA receptor-mediated excitotoxicity is one of the mech- efect of the MAO-B inhibitor selegiline and the non-selec- anisms participating in neuronal death. Selegiline and its tive inhibitor pargyline against DSP-4-induced noradrena- metabolite desmethylselegiline prevented NMDA-induced line depletion was reported, while the MAO-A inhibitor neurotoxicity in cultured dopaminergic mesencephalic neu- clorgyline was found inefective (Gibson 1987). This sug- rons. Desmethylselegiline was actually found to be more gested the role of MAO-B inhibition in protection. Later, potent in this test than its parent compound, suggesting however, the structurally unrelated and selective MAO-B the contribution of this metabolite to the neuroprotective

1 3 É. Szökő et al. efect of selegiline (Mytilineou et al. 1997a, b). Protection reduced cell loss to about 15% (Tatton and Greenwood against NMDA toxicity was also demonstrated in hippocam- 1991). The rescue efect of selegiline was also observed in pal slices, and at the same time, it was also shown that the primary mesencephalic neuronal and glial co-culture. Sele- drug did not interfere with the NMDA-dependent long-term giline was administered 24 h after ­MPP+ insult and increased potentiation process (Niittykoski et al. 2003). In an in vivo the dopamine level, TH positive cell and astrocyte count in experiment, retinal damage was induced by intravitreal the cultures (Koutsilieri et al. 1994, 1996). Rescue efect was NMDA injection. Parenteral, but not local, selegiline admin- shown on non-dopaminergic neurons after axotomy of facial istration was found to be protective, while local desmethylse- motor neurons as well. The authors suggested that selegiline legiline was also efective. This fnding further indicates the could compensate the loss of target-derived trophic support possible contribution of the metabolite desmethylselegiline (Salo and Tatton 1992). In their further detailed study on to the neuroprotective efect (Takahata et al. 2003). mutant mice with inherited motor neuron degeneration, sele- It was also shown that selegiline can protect mitochondria giline failed to show protection (Oh et al. 1994). The neuro- against pro-oxidant-induced damage. It prevented swelling, rescue efect was also observed in a rat model of traumatic collapse of membrane potential and cytochrome c release. brain injury, where selegiline improved cognitive functions Direct interaction and inhibition of some components of the although motor functions remained unchanged. Consistent mitochondrial permeability transition pore were proposed with the symptomatic efect, the injury-induced loss of DBH (De Marchi et al. 2003). positive cells in the hippocampus was reduced (Zhu et al. Protein aggregation and the formation of deposits are 2000). The kainite-induced hippocampal cell loss and the hallmarks of several neurodegenerative disorders. In Par- consequent behavioral changes were also afected by sele- kinson’s disease, α-synuclein is the main component of giline treatment. As the improvement remained after cessa- the characteristic Lewy bodies. In an in vitro experiment, tion of selegiline dosing, the neurorescue rather than symp- selegiline was shown to modify the aggregation process tomatic efect is confrmed (Gelowitz and Paterson 1999). resulting in the formation of large non-toxic aggregates The infuence of selegiline on trophic factor production (Braga et al. 2011). The structure of selegiline-bound alpha- was extensively examined. One of the frst reports showed synuclein is probably more compact. A similar efect of its that subchronic selegiline treatment potentiated the lesion- metabolite, methamphetamine was also reported (Kakish induced production of basic fbroblast growth factor (bFGF) et al. 2015). In a mouse study, selegiline reversed the cogni- and glial fbrillary acidic protein (GFAP) in rat neostriatum tive defcit induced by amyloid beta-peptide in both acute (Biagini et al. 1994). Potentiation of cAMP-induced bFGF and subchronic dosing schedules (Pazini et al. 2013). mRNA elevation in rat cortical astrocytes was also shown Ischemia–reperfusion is a well-established model of neu- (Riva et al. 1997). The increased production of other neu- ronal injury and degeneration that is most closely related to rotrophic factors; NGF, brain-derived neurotrophic factor brain infarction in stroke. Chronic selegiline pretreatment (BDNF), and glia-derived neurotrophic factor (GDNF), in effectively reduced the infarct size after transient brain cultured mouse astrocytes 24 h after high-dose selegiline ischemia (Knollema et al. 1995). Besides the infarct size, and desmethylselegiline treatment was also demonstrated the markers of apoptosis, cleaved caspase and DNA frag- (Mizuta et al. 2000). In addition to increasing the release of mentation, were also signifcantly decreased (Unal et al. neurotrophic factors from astrocytes, its possible efect on 2001). Ischemia-induced lipid peroxidation and memory activated microglia-related neuronal damage was also pro- defcit were also alleviated (Maia et al. 2004). Combina- posed and studied in a model system. Neuroblastoma cells tion treatment with selegiline and Ginkgo biloba extract was were treated with conditioned media of activated monocytic more efective in preventing ischemia-induced neuronal loss THP-1 cells. Selegiline treatment of the monocytes, but not (Kwon et al. 2004). However, pretreatment applied shortly the neuroblasts, dose-dependently prevented the damage of before or after global forebrain ischemia was inefective in the latter. Other examined MAO inhibitors were inefective, preventing cell death (Ballabriga et al. 1997). confrming the suggested MAO-independent mechanism (Klegeris and McGeer 2000). Selegiline-induced enhanced NGF production and the consequent protection against exci- Neurorescue activity of selegiline totoxic and ischemic damage of neurons were reported in a thorough study. In the in vitro cell culture experiment, Selegiline studies gained a new impetus from the reports increased NGF production was demonstrated in response to of Tatton and co-workers that it efectively rescued dying a rather low (10 pM–1 nM) selegiline concentration. Moreo- neurons in delayed administration protocols. MPTP admin- ver, increased production of NGF was also shown in the istration to mice induced about 40% decrease in the tyrosine- cerebral cortex of rats after intraperitoneal administration hydroxylase positive cell count in the substantia nigra over of selegiline accompanying the protection against ischemic 20 days. Selegiline treatment started 72 h after the toxin insult (Semkova et al. 1996).

1 3 Pharmacological aspects of the neuroprotective efects of irreversible MAO‑B inhibitors,…

Furthermore, in cultured dopaminergic neurons, it was these model cells (Suuronen et al. 2000). Contrary to this also shown that neurite length was similarly increased by fnding, selegiline in submicromolar concentration prevented selegiline and BDNF, although selegiline increased the apoptotic cell death induced by either serum deprivation average neuritic branch length, while the formation of new or hypoxia in cultured retinal neurons (Xu et al. 1999). In branches was increased by BDNF (Kontkanen and Castren another study, a similar low selegiline dose could delay 1999). Consistent with its neurotrophic factor inducing and/ the serum deprivation evoked excessive apoptosis in two or mimicking efect, selegiline induced the diferentiation of melanoma cell lines of neuroectodermal origin by 2 days, various stem cells into neuron phenotype. In these in vitro while its enantiomer pair, S-(+)-deprenyl was inefective. experiments, selegiline was typically found efective in a In this study high, millimolar, doses of selegiline and des- low concentration (around 10­ −8 M) that cannot consider- methylselegiline were shown to increase apoptotic cell death ably inhibit MAO-B activity. Increased neurotrophic factor even without serum withdrawal (Szende et al. 2000). These expression and diferentiation to neurons were demonstrated findings confirmed the bell-shaped dose dependence of in embryonic stem cells (Esmaeili et al. 2006), bone-marrow the antiapoptotic efect, indicating the importance of care- stromal cells (Ghorbanian et al. 2010), embryonal carci- ful experimental design and reconsideration of the dosing noma stem cells (Bakhshalizadeh et al. 2011), and neural schedule of selegiline (Magyar et al. 2004; Magyar 2011). stem cells (Hassanzadeh et al. 2015) following selegiline The antiapoptotic efect of selegiline and related prop- treatment. argyl compounds was also demonstrated against various neurotoxins in in vitro cell culture experiments. It partially protected the MPP­ +-treated SK-N-SH neuroblastoma cells Antiapoptotic activity of selegiline with attenuation of toxin-induced alterations of several apop- tosis markers, including cytochrome c release and caspase After revealing that selegiline can induce the synthesis of 3 activation (Sharma et al. 2003; Chetsawang et al. 2008). neurotrophic factors and antioxidant enzymes, it was sug- In SH-SY5Y neuroblastoma cells, selegiline pretreatment gested that its neuroprotective-neurorescue efect is based protected the cells against the apoptotic efect of the hypoth- on a complex action on the regulation of cell survival esized endogenous toxin, N-methyl-R-salsolinol detected by mechanisms (Tatton and Chalmers-Redman 1996; Magyar a reduction in DNA fragmentation. In addition to the toxin, et al. 2006). In diferentiated PC12 cells, selegiline and its apoptosis induced by reactive oxygen and nitrogen species metabolite desmethylselegiline modifed the serum and NGF was also studied (Naoi et al. 2000). It is worth mention- withdrawal-induced expression of several genes. In addition ing that in these experiments on neuroblastoma cells, the to the previously reported increase in antioxidant enzymes, efective selegiline concentration was much higher, in the superoxide dismutase and glutathione peroxidase, altered micromolar range. This discrepancy might be explained by expression of other apoptosis-related proteins was also the possibly difering nature of diferentiated and undifer- observed. It prevented the elevation of c-JUN and GAPDH entiated cells. and the reduction of BCL-2 levels, as well as the mitochon- In recent studies, the apoptosis-preventing efect of sele- drial translocation of BAX. All these changes may result in giline was also reported in various animal experiments. an antiapoptotic efect by maintaining mitochondrial mem- Pretreatment with selegiline attenuated the 3-nitropropi- brane potential and preventing the opening of permeability onic acid-induced striatal and cortical apoptosis demon- transition pores (Tatton and Chalmers-Redman 1996). On strated by reduced caspase 3 activation and altered BCL-2/ cerebellar granule cells, selegiline and another propargyl BAX ratio. Furthermore, the toxin-induced behavioral compound prevented the impaired mitochondrial function changes were also improved (Wahdan et al. 2017). Admin- related to apoptosis without afecting low potassium-induced istering selegiline following MPTP lesion in mice induced apoptotic cell death. These fndings further confrmed that an antiapoptotic change in BCL-2 and BAX expression selegiline selectively inhibits the mitochondrial route of besides increased trophic factor production. At the same apoptosis (Paterson et al. 1998). The efect of selegiline and time, the drug rescued the toxin-induced gait defcit (Zhao the related propargylamines was dose dependent; the maxi- et al. 2013). When administered after focal brain ischemia, mal antiapoptotic efect developed at a concentration level selegiline reduced the infarct size, induced the antiapop- of 10­ −9 M. Further concentration increase was accompa- totic genes, and promoted NOTCH-JAGGED signaling in nied by a decline in the efect (Tatton et al. 2002). This low the astrocytes. It was accompanied by reduced peri-infarct concentration of selegiline was previously found efective edema, likely due to preserving brain microcirculation (Nar- in preventing okadaic acid-induced apoptotic response in dai et al. 2015). The proposed mechanisms contributing to cultured hippocampal and cerebellar granule cells, as well the antiapoptotic activity of selegiline are shown in Fig. 2. as in Neuro-2a neuroblastoma cells. However, selegiline did The cytoprotective, antioxidant, and antiapoptotic efects not provide protective activity against serum withdrawal in of selegiline are not restricted to damaged neuronal cells.

1 3 É. Szökő et al.

Fig. 2 Putative targets of selegiline and rasagiline involved in their efects independent of MAO-B enzyme inhibition

In cultured airway epithelial cells, cigarette smoke extract- also improved the sexual activity (Knoll 1988; Knoll et al. induced oxidative stress and inflammation were dose- 1989) and learning performance of aged animals (Cara- dependently reversed by selegiline in the ­10−8–10−6 M georgiou et al. 2003). As potential mechanisms responsible range. The authors suggested that the antioxidant property of for longevity induction, its antioxidant, cytoprotective, and the drug is also responsible for its anti-infammatory efect neuronal activity stimulating, so-called enhancer efect on through preventing the activation of infammation-related monoaminergic transmissions, are suggested (Knoll and transcription factors Nrf2 and NF-κB (Cui et al. 2017). Miklya 1994; Kaur et al. 2003; Singh et al. 2012; Kitani Chronic low-dose selegiline was shown to increase the total et al. 2002). scavenger capacity of plasma and prevent the fat-rich diet- During the studies on the neuroprotective efect of sele- induced increase in the liver fat content (Bekesi et al. 2012). giline, it emerged that the pharmacophore includes the pro- Renal cells could also be rescued from hypoxia-induced pargylamine moiety. This was supported by the observed apoptotic death in an animal study (Toronyi et al. 2002). activity of its desmethyl metabolite. However, desmethyl- In a rabbit model of cardiac failure, 8 weeks of selegiline selegiline was shown to be a minor metabolite, representing treatment improved left ventricular function by rescuing less than 1% of the administered dose (Szökő et al. 2004b). myocytes from apoptosis (Qin et al. 2003). Other aromatic and aliphatic propargyl compounds with or The benefcial efect of selegiline on aging has also without MAO inhibitory activity were also examined. Their been reported in several papers since the frst one pub- efects in in vitro and in vivo antiapoptotic and neuroprotec- lished by Birkmayer et al. (1985). Chronic treatment with tive tests were similar to those of selegiline (Paterson et al. selegiline considerably increased the lifespan of rats and 1998; Waldmeier et al. 2000a, b).

1 3 Pharmacological aspects of the neuroprotective efects of irreversible MAO‑B inhibitors,…

Neuroprotective and neurorescue efects overexpressing alpha-synuclein, the use of paraquat-induced of rasagiline signifcant oxidative stress and caspase 3 activation that was prevented by rasagiline (Chau et al. 2010). In another Besides selegiline, several propargyl compounds were syn- in vitro model, rasagiline attenuated microglia activation- thesized and studied in the 1970s for their MAO inhibitory related oxidative stress and pro-inflammatory cytokine efect. Among these, an aminoindane structure, J-508, was release, features that may contribute to its neuroprotective found to be about ten times more potent an inhibitor of properties (Trudler et al. 2014). MAO-B, although its selectivity for MAO-B over MAO-A The mechanism of neuroprotective-antiapoptotic efect of inhibition was not better than that of selegiline (Magyar rasagiline was extensively studied in cell culture experiments et al. 1979; Magyar 1994). The desmethyl derivative of this mainly using SH-SY5Y dopaminergic neuroblastoma cells. compound, rasagiline, was developed later as the second Induction of neurotrophic factors, mainly GDNF (Maruyama MAO-B inhibitor approved for the treatment of Parkinson’s et al. 2002a, 2004) and antiapoptotic BCL protein family disease. Its neuroprotective and neurorescue efects were members (Akao et al. 2002b; Inaba-Hasegawa et al. 2012) also extensively studied. were reported. Probably, these contribute to protection of Initially, in vitro and in vivo tests, similar to those previ- mitochondrial integrity and prevention of mitochondrial per- ously done with selegiline, were performed with rasagiline meability transition pore opening which were also demon- to demonstrate its neuroprotective, antioxidant, antiapop- strated (Maruyama et al. 2000b, 2002b; Wu et al. 2016). The totic, and neurorescue efects. Similar to selegiline, it was importance of mitochondrial protection in the antiapoptotic found efective against various neurotoxins. It increased the efect was also confrmed in cerebellar granule cells, where survival of dopaminergic neurons in the substantia nigra and rasagiline prevented cytosine beta-d-arabinofuranoside, the stereotypical behavior induced by 6-hydroxydopamine l-buthionine-(S,R)-sulfoximine, or glutamate but not low (Blandini et al. 2004). In in vitro experiments on SH-SY5Y potassium or serum deprivation-induced apoptosis (Bonneh- cells, the inhibition of toxin-induced mitochondrial impair- Barkay et al. 2005). ment-related apoptosis was demonstrated as a mechanism Prevention of mitochondrial depolarization and the open- of the protective efect. Similar results were reported when ing of permeability transition pores by rasagiline were also peroxynitrite donating SIN-1 or N-methyl-(R)-salsolinol reported using isolated mitochondria suggesting a direct were used to induce neuronal damage (Maruyama et al. mitochondrial target (Akao et al. 2002a). Prevention of 2000a, 2001b). Rasagiline showed neurorescue activity nuclear translocation of GAPDH was also demonstrated and when administered chronically to post-MPTP-lesioned mice. the enzyme was suggested as another possible target for pro- It increased dopaminergic cell survival in the midbrain by pargylamine compounds (Maruyama et al. 2001a; Ou et al. upregulation of the tyrosine kinase receptor (Trk)–phos- 2009; Waldmeier et al. 2000b). Chronic rasagiline treatment phatidylinositol 3 (PI3) kinase–Akt pathway (Weinreb et al. was shown to increase the expression and activation of pro- 2006; Sagi et al. 2007). It also reduced the degeneration of tein kinase C and, at the same time, to benefcially afect neurons in the paraventricular nucleus of the hypothalamus amyloid processing (Bar-Am et al. 2004). In a cell culture in spontaneously hypertensive rats in a dose-dependent man- study, this efect was shown dependent on alpha-secretase ner. This efect was accompanied by a reduction in blood activity and protein kinase C and ERK kinase signaling. A pressure. The antihypertensive medications, captopril and similar efect of the non-MAO inhibitor S-enantiomer of hydralazine, were inefective in preventing neurodegenera- rasagiline was also demonstrated, indicating that the protec- tion, suggesting direct neuroprotection by rasagiline as a tion is unrelated to MAO-B inhibition but dependent on the primary efect (Eliash et al. 2005). propargylamine structure (Yogev-Falach et al. 2003). The induction of catalase and superoxide dismutase (anti- oxidant enzymes) activities by chronic rasagiline treatment in substantia nigra and striatum, but not in hippocampus, Safnamide, the reversible MAO‑B inhibitor was demonstrated. Interestingly, the activity of the enzymes also increased in peripheral tissues, kidney, and heart (Car- Recently, a third MAO-B inhibitor, safnamide was also rillo et al. 2000). Similar to selegiline, it was proven efective introduced into the therapy. It has a different chemical against ischemic insults. In NGF-diferentiated PC12 cells, it structure and pharmacological properties compared to sele- protected against oxygen–glucose deprivation-induced cell giline and rasagiline. In isolated rat brain mitochondria, it death (Abu-Raya et al. 1999). In an in vivo animal study, it potently and reversibly inhibits MAO-B with an IC50 value reduced the infarct size and improved the neurological and of 98 nM, while its potency on MAO-A is about 5000 times cognitive functions when administered after middle cerebral lower (Caccia et al. 2006). In line with these in vitro results, artery occlusion (Speiser et al. 2007). In a cell-culture model it provides complete MAO-B inhibition in 0.6 mg/kg single dose without afecting MAO-A activity in humans (Marzo

1 3 É. Szökő et al. et al. 2004). Besides MAO-B inhibition, it was found to survival of tyrosine-hydroxylase positive neurons was selec- block voltage-dependent sodium and N-type calcium chan- tively improved by both MAO-B inhibitors at the relatively nels, although in much higher concentrations. In in vitro high concentration of 1–10 µM. The MAO-A inhibitor experiments, the diference between IC50 values of chan- clorgyline and R-(−)-methamphetamine, had no efect on nels blocking and MAO-B inhibition was 2–3 orders of cell viability in this concentration range. The survival of magnitude. As a consequence of its efect on ion channels, GABAergic neurons was not afected by any examined com- it also inhibits the release of glutamate (Caccia et al. 2006; pounds (Finberg et al. 1998; Goggi et al. 2000). Rasagiline Fariello 2007). and selegiline similarly inhibited Ca­ 2+ efux from mito- Neuroprotection by safinamide was also studied. It chondria after opening of the mitochondrial permeability prevented the MPTP-induced toxicity consistent with its transition pores and attenuated superoxide generation (Wu MAO-B inhibitory efect and its weak dopamine uptake et al. 2015). Using hippocampal slices, it was observed that inhibitor activity (Fariello 2007) may also contribute. Four glutamate-mediated excitotoxicity was attenuated by both hours after MPTP insult, it failed to afect dopamine deple- rasagiline and selegiline; however, more detailed analysis tion; however, some sparing efect on dopaminergic neu- revealed diferent mechanisms, i.e., modulation of diferent rons was observed. In pretreatment, it also alleviated neu- glutamate receptor responses (Dimpfel and Hofmann 2011). ron loss induced by kainate. The neurodegeneration induced In an in vivo study of focal cerebral ischemia, rasagiline in by ischemia was also reduced by both pre- and post-insult 3 mg/kg dose, but not in 1 mg/kg, accelerated the sympto- treatment (Caccia et al. 2006). These protective efects were matic recovery, while the fnal neurological scores were not reported at high safnamide doses, indicating the probable improved. At the same time, it reduced the infarct size. Sele- role of its channel blocking property and the consequential giline in the same dose did not show these efects. Higher inhibition of glutamate release. Clinical properties of safna- doses were not examined; thus, the inefectiveness may have mide along with those of the irreversible MAO-B inhibitors been caused by the well-known potency diference between were recently reviewed (Dezsi and Vecsei 2017). the two drugs (Speiser et al. 1999). In another in vivo model There is continuous interest in studying reversible of neurodegeneration using ubiquitin–proteasome system MAO-B inhibitors. In addition to safnamide, several other inhibitor lactacystin, selegiline and rasagiline pretreatment natural and synthetic compounds were reported as reversible were efective alike. When treatment started after the insult, MAO-B inhibitors and examined in preclinical and early selegiline was found less efective (Zhu et al. 2008). clinical studies. Sembragiline, a compound structurally Some of the studies also aimed to evaluate the infuence related to safnamide, is a highly selective MAO-B inhibi- of their metabolites on the protective efect. Some selegiline tor with long lasting efect (Borroni et al. 2017). Its pos- metabolites keep the propargylamine structure. The neuro- sible benefcial efect in moderate Alzheimer’s disease has protective efect of desmethylselegiline was observed in recently been evaluated in a phase 2 clinical trial without various tests, including demonstration of its benefcial efect conclusive results (Nave et al. 2017). In preclinical stud- against NMDA toxicity (Mytilineou et al. 1997b; Takahata ies, not only further biaryl compounds (Yeon et al. 2018), et al. 2003) and in inducing the production of neurotrophic but new chemical structures, like furanochalcones (Suresh factors (Mizuta et al. 2000) and antiapoptotic proteins (Tat- et al. 2018) are also being investigated. Among natural ton and Chalmers-Redman 1996). Its N-oxide metabolite compounds, chrysin was reported having MAO-B inhibi- was only identifed later (Katagi et al. 2001; Tabi et al. tory activity, besides several other pharmacological efects 2003; Szökő et al. 2004b) because of shortcomings in the resembling to those of selegiline and rasagiline (Guo et al. previously used analytical method, gas chromatography. The 2016). neuroprotective efect of selegiline-N-oxide against DSP-4 induced noradrenaline depletion was found to be compara- ble with that of the parent compound (Szökő et al. 2004a). Comparison of the efects of selegiline The main non-propargyl metabolites of selegiline are and rasagiline R-(−)-methamphetamine and R-(−)-amphetamine (Szoko et al. 1999; Tabi et al. 2003; Shin 1997), while rasagiline is The majority of the reported efects of rasagiline are similar converted to 1-R-aminoindan (Siddiqui and Plosker 2005). to those previously published with selegiline. Some direct Since S-enantiomers of amphetamines have considerable comparative studies were performed, as well. Prevention psychomotorstimulatory and neurotoxic efects, it was sug- of MPTP-induced neurotoxicity was compared in monkeys gested that the metabolites of selegiline may counteract its and their efects were found similar in terms of biochemi- neuroprotective efect. The R-amphetamines, however, are cal, histological, and behavioral means. As MAO-B inhibi- much weaker releasers of catecholamines and are formed tion signifcantly contributes to the reduced MPTP toxicity, in a rather low concentration during selegiline metabolism this result could be expected (Kupsch et al. 2001). In vitro (Magyar and Tothfalusi 1984; Magyar et al. 2004). In an

1 3 Pharmacological aspects of the neuroprotective efects of irreversible MAO‑B inhibitors,… in vitro cell culture study, a high concentration of meth- Conclusions amphetamine did not prevent against serum and NGF withdrawal-induced death of PC12 cells and reduced the Although several pharmacological experimental data in protection by selegiline or rasagiline (Bar Am et al. 2004). support of the neuroprotective efect of both irreversible However, during therapeutic use of selegiline, much lower MAO-B inhibitors were published, the results of in vitro concentrations of amphetamines are formed (Heinonen et al. experiments could hardly be translated to a clinical efect. 1989), so the counteraction of the selegiline efect is not Even the preclinical data are inconsistent regarding the very probable. Data on the efect of 1-R-aminoindane are efective concentrations of the drugs and the suggested role controversial as well. It was found efective in a rather high of their metabolites, which may be the sources of some concentration of 1 μM in a model of serum and NGF with- discrepancies between the fndings of in vitro and in vivo drawal-induced PC12 cell death (Bar Am et al. 2004) and studies. Some of the preclinical results suggest diferences dexamethasone-induced apoptosis of SH-SY5Y neuroblas- between the protective efect of selegiline and rasagiline. toma and 1242-MG glioblastoma cells (Tazik et al. 2009). However, the recent meta-analysis of randomized clinical However, in another test using cerebellar granule cells, it trials (Marconi and Zwingers 2014), drug utilization analysis was not found efective against various cell insults in the of delaying levodopa prescription in patients on selegiline or wide concentration range studied (Bonneh-Barkay et al. rasagiline treatment (Peretz et al. 2016), and a head-to-head 2005). Based on these results, the importance of the propar- 3-year retrospective case–control study (Cereda et al. 2017) gylamine structure in the neuroprotective efect of MAO-B concluded similar efcacy and neuroprotective potential of inhibitors is rather accepted. This is further confrmed by the two drugs. the results that N-propargylamine itself showed neuroprotec- tive activity against serum withdrawal-induced apoptosis of Acknowledgements Supported by GINOP 2.3.2-15-2016- PC12 cells (Weinreb et al. 2005). 00034.2017.-1.2.1-NKP-2017-00002. The linguistic correction was made by Jennifer Tusz (Edmonton, Canada).

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