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Rasagiline and selegiline, inhibitors of type B monoamine oxidase, induce type A monoamine oxidase in human SH-SY5Y cells

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

Type B monoamine oxidase (MAO-B) is proposed to be involved in the pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, through oxidative stress and synthesis of neurotoxins. MAO-B inhibitors, rasagiline and selegiline [(−)deprenyl], protect neuronal cells by direct intervention in mitochondrial death signaling and induction of pro-survival Bcl-2 and neurotrophic factors. Recently, type A MAO (MAO-A) was found to mediate the induction of anti-apoptotic Bcl-2 by rasagiline, whereas MAO-A increases in neuronal death and also serves as a target of neurotoxins. These controversial results suggest that MAO-A may play a decisive role in neuronal survival and death. This paper reports that rasagiline and selegiline increased the mRNA, protein and catalytic activity of MAO-A in SH-SY5Y cells. Silencing MAO-A expression with small interfering (si)RNA suppressed rasagiline-dependent MAO-A expression, but MAO-B overexpression in SH-SY5Y cells did not affect, suggesting that MAO-A, not MAO-B, might be associated with MAO-A upregulation. Rasagiline reduced R1, a MAO-A specific repressor, but selegiline did not. Mithramycin-A, an inhibitor of Sp1 binding, and actinomycin-D, a transcriptional inhibitor, reduced the rasagiline-dependent upregulation of MAO-A mRNA, indicating that rasagiline induced MAO-A transcriptionally through R1-Sp1 pathway, whereas selegiline by another non-defined pathway. These results are discussed in relation to the role of MAO-A and these MAO-B inhibitors in neuronal death and neuroprotection.

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Abbreviations

MAO:

Monoamine oxidase

MAO-A and MAO-B:

Type A and B MAO

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

SiRNA:

Small interfering RNA

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Acknowledgments

This work was supported by the Research Grant for Longevity Sciences (21A-13, 23A-2) from the Ministry of Health, Labour and Welfare (W. M., M. N).

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Author notes

  1. Makoto Naoi

    Present address: Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi, 470-0195, Japan

Authors and Affiliations

  1. Department of Neurosciences, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan

    Keiko Inaba-Hasegawa & Makoto Naoi

  2. Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi, 470-0195, Japan

    Keiko Inaba-Hasegawa

  3. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan

    Yukihiro Akao

  4. Department of Cognitive Brain Science, National Research Center for Geriatrics and Gerontology, Obu, Aichi, Japan

    Wakako Maruyama

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  1. Keiko Inaba-Hasegawa
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Correspondence to Makoto Naoi.

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Inaba-Hasegawa, K., Akao, Y., Maruyama, W. et al. Rasagiline and selegiline, inhibitors of type B monoamine oxidase, induce type A monoamine oxidase in human SH-SY5Y cells. J Neural Transm 120, 435–444 (2013). https://doi.org/10.1007/s00702-012-0899-3

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  • DOI: https://doi.org/10.1007/s00702-012-0899-3

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