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Review
. 2022 Sep 21;23(19):11059.
doi: 10.3390/ijms231911059.

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies

Makoto Naoi  1 , Wakako Maruyama  1 , Masayo Shamoto-Nagai  1
Affiliations
Review

Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies

Makoto Naoi et al. Int J Mol Sci. .

Abstract

Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson's disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and "disease-modifying or neuroprotective" therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies.

Keywords: Parkinson’s disease; gene induction; mitochondria; monoamine oxidase; multiple-targeted drugs; neuroprotection; rasagiline; selegiline; synucleinopathy; α-synuclein.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Role of MAO-A and MAO-B in the pathogenesis of PD. MAO-A in catecholaminergic neurons and MAO-B in glial cells produce ROS and neurotoxins, and induce death of DA neurons, neuroinflammation and αSyn accumulation. MAO-A mediates toxicity of endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, and gene-induction by rasagiline in dopaminergic cells. MAO-B oxidizes monoamines, produces ROS and MPP+ from MPTP, and mediates gene induction by selegiline in glial cells. ALP, autophagy-lysosome pathway; UPS, ubiquitin-proteasome system.
Figure 2
Figure 2
Chemical structure of selegiline and rasagiline and their metabolites. Aminoindan, a metabolite of rasagiline, has neuroprotective function, in contrast to (R)-methamphetamine produced from selegiline.
Figure 3
Figure 3
Apoptosis process and inhibition by rasagiline and selegiline. (A) ROS/RNS and neurotoxins induce the mPTP opening and stepwise activation of apoptosis, which rasagiline and selegiline completely prevent. Mutated αSyn binds to and inhibits ATP synthase and opens the mPTP. (B) Modulation of the mPTP formation by rasagiline and selegiline. PK11195, a TSPO ligand, opens a pore composed of ANT and CypD at the IMM, shown as superoxide flash, which CysA and rasagiline prevent. Then, the mPTP open with Ca2+ release occurs, which Bcl-2 and selegiline suppress. (C) Nuclear condensation induced by ONOO−-generating SIN-1 in SH-SY5Y cells. Rasagiline inhibits the nuclear condensation visualized by Hoechst 33342 staining.
Figure 4
Figure 4
MAO-A and MAO-B are associated with gene induction by rasagiline and selegiline. Knockdown of MAO-A with siRNA downregulated gene expression by rasagiline in neuroblastoma SH-SY5Y cells, whereas MAO-B knockdown upregulated gene induction by selegiline in glioblastoma U118MG cells.
Figure 5
Figure 5
Chemical structure of propargylamine derivatives. (A) 8-Hydroxyquinone derivatives of rasagiline (HLA-20, M30) inhibit MAO-B and chelate metals. (B) Propargyl derivatives of rivastigmine (TV3326, TV3279) inhibit ChE and MAO-B with a carbamate moiety and exert neuroprotection by a propargylamine moiety. (C) Propargylamine derivatives of donepezil. (D) Indanone derivatives of rasagiline are H3 receptor agonists, inhibit MAO, and improve cognitive functions. (E) N-Methyl-phenyl-selegiline inhibits MAO-B, chelates copper (II), iron (II), and zinc (II), and inhibits Aβ1–42 aggregates.
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References

    1. Shih J.C., Riederer P., Maruyama W., Naoi M. Special issue: Monoamine Oxidase A and B: Eternally Enigmatic Isoenzymes. J. Neural Transm. 2018;125:1517–1757. doi: 10.1007/s00702-018-1920-2. - DOI - PMC - PubMed
    1. Knoll J., Magyar K. Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv. Biochem. Psychopharmacol. 1972;5:393–408. - PubMed
    1. Finberg J.P., Youdim M.B. Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours. Neuropharmacology. 2002;43:1110–1118. doi: 10.1016/S0028-3908(02)00216-2. - DOI - PubMed
    1. Brás I.C., Dominguez-Meijide A., Gerhardt E., Koss D., Lázaro D.F., Santos P.I., Vasili E., Xylaki M., Outeiro T.F. Synucleinopathies: Where we are and where we need to go. J. Neurochem. 2020;153:433–454. doi: 10.1111/jnc.14965. - DOI - PubMed
    1. Spillantini M.G., Goedert M. The α-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Ann. N. Y. Acad. Sci. 2000;920:16–27. doi: 10.1111/j.1749-6632.2000.tb06900.x. - DOI - PubMed

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