title: Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection.
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 (Ca(2+)) and superoxide (O2(-)) (Ishibashi et al. in Biochem Biophys Res Commun 344:571-580, 2006). The association of the pore opening with Ca(2+) efflux and ROS increase was proved by the inhibition of Bcl-2 overexpression and cyclosporine A treatment. Potency to release Ca(2+) 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 Ca(2+) or cause cell death. Rasagiline and selegiline inhibited mitochondrial Ca(2+) efflux through the mitochondrial permeability transition pore dose dependently. Ca(2+) efflux was confirmed as the initial signal in mitochondrial apoptotic cascade, and the suppression of Ca(2+) efflux may account for the neuroprotective function of rasagiline and selegiline. The quantitative measurement of Ca(2+) efflux can be applied to determine anti-apoptotic activity of neuroprotective compounds. The role of mitochondrial Ca(2+) release in neuronal death and also in neuroprotection by MAO-B inhibitors is discussed.
authors: Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi, 470-0195, Japan.
authors: Yuqiu
authors: Y
authors: Wu
authors: Central Research Laboratory, Hamamatsu Photonics, Hamamatsu, Shizuoka, Japan.
authors: Kimiko
authors: K
authors: Kazumura
authors: Department of Cognitive Brain Science, National Research Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
authors: Wakako
authors: W
authors: Maruyama
authors: Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi, 470-0195, Japan.
authors: Toshihiko
authors: T
authors: Osawa
authors: Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi, 470-0195, Japan. mnaoi@dpc.agu.ac.jp.
authors: Makoto
authors: M
authors: Naoi
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000633:toxicity; D007546:Isoquinolines / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000633:toxicity; D018079:Receptors, GABA / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: C000595707:BCL2 protein, human; D007189:Indans; D007210:Indoleacetic Acids; D007546:Isoquinolines; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011524:Protoporphyrins; D018079:Receptors, GABA; C499229:TSPO protein, human; C031967:rasagiline; D013481:Superoxides; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D012642:Selegiline; D016572:Cyclosporine; C028025:protoporphyrin IX; D002118:Calcium; C037850:PK 11195
keywords: Apoptosis; Calcium; Membrane permeability transition pore; Mitochondria; Neuroprotection; Outer membrane translocator protein 18 kDa; PK11195; Rasagiline; Selegiline