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Pharmacological Aspects of the Neuroprotective Effects Of 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
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