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Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection

  • Translational Neurosciences - Original Article
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Abstract

Rasagiline and selegiline, inhibitors of type B monoamine oxidase (MAO-B), protect neurons from cell death in cellular and animal models. Suppression of mitochondrial membrane permeabilization and subsequent activation of apoptosis cascade, and induction of anti-apoptotic, pro-survival genes are proposed to contribute the anti-apoptotic function. Rasagiline suppresses neurotoxin- and oxidative stress-induced membrane permeabilization in isolated mitochondria, but the mechanism has been not fully clarified. In this paper, regulation of the mitochondrial permeability transition pore by rasagiline and selegiline was examined in apoptosis induced by PK11195, a ligand of the outer membrane translocator protein 18 kDa (TSPO) in SH-SY5Y cells. The pore opening was quantitatively measured using a simultaneous monitoring system for calcium (Ca2+) and superoxide (O2 −) (Ishibashi et al. in Biochem Biophys Res Commun 344:571–580, 2006). The association of the pore opening with Ca2+ efflux and ROS increase was proved by the inhibition of Bcl-2 overexpression and cyclosporine A treatment. Potency to release Ca2+ was correlated with the cytotoxicity of TSPO antagonists, PK11195, FGIN-1-27 and protoporphyrin IX, whereas a TSPO agonist, 4-chloro-diazepamine, did not significantly increase Ca2+ or cause cell death. Rasagiline and selegiline inhibited mitochondrial Ca2+ efflux through the mitochondrial permeability transition pore dose dependently. Ca2+ efflux was confirmed as the initial signal in mitochondrial apoptotic cascade, and the suppression of Ca2+ efflux may account for the neuroprotective function of rasagiline and selegiline. The quantitative measurement of Ca2+ efflux can be applied to determine anti-apoptotic activity of neuroprotective compounds. The role of mitochondrial Ca2+ release in neuronal death and also in neuroprotection by MAO-B inhibitors is discussed.

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Abbreviations

ANT:

Adenine nucleotide translocator

Cyp-D:

Cyclophilin D

CysA:

Cyclosporin-A

Cyt c:

Cytochrome c

ΔΨm:

Mitochondrial membrane potential

ER:

Endoplasmic reticulum

ETC:

Electron transport chain

EthD-1:

Ethidium homodimer-1

MMP:

Mitochondrial membrane permeabilization

Mptp:

Mitochondrial permeability transition pore

TSPO:

Outer membrane transporter protein (18 kDa)

VDAC:

Voltage-dependent anion channel

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Acknowledgments

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

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Authors and Affiliations

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

    Yuqiu Wu, Toshihiko Osawa & Makoto Naoi

  2. Central Research Laboratory, Hamamatsu Photonics, Hamamatsu, Shizuoka, Japan

    Kimiko Kazumura

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

    Wakako Maruyama

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  1. Yuqiu Wu
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  2. Kimiko Kazumura
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  3. Wakako Maruyama
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  4. Toshihiko Osawa
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  5. Makoto Naoi
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Correspondence to Makoto Naoi.

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Wu, Y., Kazumura, K., Maruyama, W. et al. Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection. J Neural Transm 122, 1399–1407 (2015). https://doi.org/10.1007/s00702-015-1398-0

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