Time filter

Source Type

Wu Y.,Aichi Gakuin University | Kazumura K.,Hamamatsu Photonics K K | Maruyama W.,National Research Center for Geriatrics and Gerontology | Osawa T.,Aichi Gakuin University | Naoi M.,Aichi Gakuin University
Journal of Neural Transmission | Year: 2015

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. © 2015, Springer-Verlag Wien.


PubMed | Aichi Gakuin University, National Research Center for Geriatrics and Gerontology and Hamamatsu Photonics K K
Type: Journal Article | Journal: Journal of neural transmission (Vienna, Austria : 1996) | Year: 2015

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.


Naoi M.,Gifu International Institute of Biotechnology | Maruyama W.,National Research Center for Geriatrics and Gerontology | Inaba-Hasegawa K.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University
International Review of Neurobiology | Year: 2011

In Parkinson's disease, type B monoamine oxidase (MAO-B) is proposed to play an important role in the pathogenesis through production of reactive oxygen species and neurotoxins from protoxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In addition, inhibitors of MAO-B protect neurons in the cellular and animal models of Parkinson's and Alzheimer's diseases. However, the role of type A MAO (MAO-A) in neuronal death and neuroprotection by MAO-B inhibitors has been scarcely elucidated. This chapter presents our recent results on the involvement of MAO-A in the activation of mitochondrial death signal pathway and in the induction of prosurvival genes to prevent cell death with MAO-B inhibitors. The roles of MAO-A in the regulation of neuronal survival and death are discussed in concern to find a novel strategy to protect neurons in age-associated neurodegenerative disorders and depression. © 2011 Elsevier Inc.


Maruyama W.,National Research Center for Geriatrics and Gerontology | Naoi M.,Gifu International Institute of Biotechnology | Naoi M.,Aichi Gakuin University
Journal of Neural Transmission | Year: 2013

Neuroprotection has been proposed in neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, to delay or halt disease progression or reverse neuronal deterioration. The inhibitors of type B monoamine oxidase (MAO), rasagiline and (-)deprenyl, prevent neuronal loss in cellular and animal models of neurodegenerative disorders by intervening in the death signal pathway in mitochondria. In addition, rasagiline and (-)deprenyl increase the expression of anti-apoptotic Bcl-2 protein family and neurotrophic factors. Neurotrophic factors, especially glial cell line-derived neurotrophic factor (GDNF) and brain-derived derived neurotrophic factor (BDNF), are required not only for growth and maintenance of developing neurons, but also for function and plasticity of distinct population of adult neurons. GDNF and BDNF have been reported to reduce Parkinson and Alzheimer's diseases, respectively. GDNF protects the nigra-striatal dopamine neurons in animal models of Parkinson's disease, and its administration has been tried as a disease-modifying therapy for parkinsonian patients. However, the results of clinical trials have not been fully conclusive and more practical ways to enhance GDNF levels in the targeted neurons are essentially required for future clinical application. Rasagiline and (-)deprenyl induced preferentially GDNF and BDNF in cellular and non-human primate experiments, and (-)deprenyl increased BDNF level in the cerebrospinal fluid of parkinsonian patients. In this paper, we review the induction of GDNF and BDNF by these MAO inhibitors as a strategy of neuroprotective therapy. The induction of prosurvival genes is discussed in relation to a possible disease-modifying therapy with MAO inhibitors in neurodegenerative disorders. © 2012 Springer-Verlag.


Naoi M.,Aichi Gakuin University | Maruyama W.,National Research Center for Geriatrics and Gerontology | Inaba-Hasegawa K.,Aichi Gakuin University
Expert Review of Neurotherapeutics | Year: 2013

In Parkinson's disease, cell death of dopamine neurons in the substantia nigra progresses and neuroprotective therapy is required to halt neuronal loss. In cellular and animal models, selegiline [(-)deprenyl] and rasagiline, inhibitors of type B monoamine oxidase (MAO)-B, protect neuronal cells from programmed cell death. In this paper, the authors review their recent results on the molecular mechanisms by which MAO inhibitors prevent the cell death through the induction of antiapoptotic, prosurvival genes. MAO-A mediates the induction of antiapoptotic bcl-2 and mao-a itself by rasagiline, whereas a different mechanism is associated with selegiline. Rasagiline and selegiline preferentially increase GDNF and BDNF in nonhuman primates and Parkinsonian patients, respectively. Enhanced neurotrophic factors might be applicable to monitor the neurorescuing activity of neuroprotection. © 2013 Expert Reviews Ltd.


Naoi M.,Aichi Gakuin University | Riederer P.,University of Würzburg | Maruyama W.,National Research Center for Geriatrics and Gerontology
Journal of Neural Transmission | Year: 2016

Monoamine oxidase types A and B (MAO-A, MAO-B) regulate the levels of monoamine neurotransmitters in the brain, and their dysfunction may be involved in the pathogenesis and influence the clinical phenotypes of neuropsychiatric disorders. Reversible MAO-A inhibitors, such as moclobemide and befloxatone, are currently employed in the treatment of emotional disorders by inhibiting the enzymatic degradation of dopamine, serotonin and norepinephrine in the central nervous system (CNS). It has been suggested that the irreversible MAO-B inhibitors selegiline and rasagiline exert a neuroprotective effect in Parkinson’s and Alzheimer’s diseases. This effect, however, is not related to their inhibition of MAO activity; in animal and cellular models, selegiline and rasagiline protect neuronal cells through their anti-apoptotic activity and induction of pro-survival genes. There is increasing evidence that MAO-A activity, but not that of MAO-B, is implicated in the pathophysiology of neurodegenerative disorders, but also in gene induction by MAO-B inhibitors; on the other hand, selegiline and rasagiline increase MAO-A mRNA, protein, and enzyme activity levels. Taken together, these results suggest that each MAO subtype exerts effects that modulate the expression and activity of the other isoenzyme. The roles of MAO-A and -B in the CNS should therefore be re-evaluated with respect to the “type-specificity” of their inhibitors, which may not be unconditional during chronic treatment. Mao-a expression, in particular, may be implicated in pathogenesis and phenotypes in neuropsychiatric disorders. MAO-A expression is modified by mao polymorphisms affecting its transcriptional efficiency, as well as by mutations and polymorphism of parkin, Sirt1, FOXO, microRNA, presenilin-1, and other regulatory proteins. In addition, childhood maltreatment has been shown to have an impact upon adolescent social behavior in children with mao-a polymorphisms of low transcriptional activity. Low MAO-A activity may increase the levels of serotonin and norepinephrine, resulting in disturbed neurotransmitter system development and behavior. This review discusses genetic and environmental factors involved in the regulation of MAO-A expression, in the contexts of neuropsychiatric function and of the regulation of neuronal survival and death. © 2015, Springer-Verlag Wien.


Inaba-Hasegawa K.,Gifu International Institute of Biotechnology | Inaba-Hasegawa K.,Aichi Gakuin University | Akao Y.,Gifu University | Maruyama W.,National Research Center for Geriatrics and Gerontology | And 2 more authors.
Journal of Neural Transmission | Year: 2013

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. © 2012 Springer-Verlag.


Naoi M.,Gifu International Institute of Biotechnology | Naoi M.,Aichi Gakuin University | Maruyama W.,National Research Center for Geriatrics and Gerontology | Yi H.,Gifu International Institute of Biotechnology
Journal of Neural Transmission | Year: 2013

Rasagiline protects neuronal cells from cell death caused by various lines of insults. Its neuroprotective function is due to suppression of mitochondrial apoptosis signaling and induction of neuroprotective genes, including Bcl-2 and neurotrophic factors. Rasagiline inhibits the mitochondrial membrane permeabilization, an initial stage in apoptosis, but the mechanism has been elusive. In this paper, it was investigated how rasagiline regulates mitochondrial death cascade in apoptosis induced in SH-SY5Y cells by PK11195, a ligand of the outer membrane translocator protein of 18 kDa. Rasagiline prevented release of cytochrome c (Cyt-c), and the following caspase 3 activation, ATP depletion and apoptosis, but did not inhibit the mitochondrial membrane potential collapse, in contrast to Bcl-2 overexpression. Rasagiline stabilized the mitochondrial contact site and suppressed Cyt-c release into cytoplasm, which should be the critical point for the regulation of apoptosis. Monoamine oxidase was not associated with anti-apoptotic activity of rasagiline in PK11195-induced apoptosis. © 2013 Springer-Verlag Wien.


Inaba-Hasegawa K.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University | Maruyama W.,National Research Center for Geriatrics and Gerontology | Naoi M.,Gifu International Institute of Biotechnology
Journal of Neural Transmission | Year: 2012

Rasagiline and (-)deprenyl (selegiline), irreversible type B monoamine oxidase (MAO-B) inhibitors, protect neuronal cells through gene induction of pro-survival Bcl-2 and neurotrophic factors in the cellular models of neurodegenerative disorders. In this paper, the role of MAO in the up-regulation of neuroprotective Bcl-2 gene by these inhibitors was studied using type A MAO (MAO-A) expressing wild SH-SY5Y cells and the transfectionenforced MAO-B overexpressed cells. Rasagiline and (-)deprenyl, and also befloxatone, a reversible MAO-A inhibitor, increased Bcl-2 mRNA and protein in SH-SY5Y cells. Silencing MAO-A expression with short interfering (si) RNA suppressed Bcl-2 induction by rasagiline, but not by (-)deprenyl. MAO-B overexpression inhibited Bcl-2 induction by rasagiline and befloxatone, but did not affect that by (-)deprenyl, suggesting the different mechanisms behind Bcl-2 gene induction by theseMAO-B inhibitors. The novel role of MAO-A in Bcl-2 induction by rasagiline is discussed with regard to the molecular mechanism underlying neuroprotection by the MAO inhibitors. © Springer-Verlag 2011.


PubMed | Aichi Gakuin University, National Research Center for Geriatrics and Gerontology and University of Würzburg
Type: Journal Article | Journal: Journal of neural transmission (Vienna, Austria : 1996) | Year: 2016

Monoamine oxidase types A and B (MAO-A, MAO-B) regulate the levels of monoamine neurotransmitters in the brain, and their dysfunction may be involved in the pathogenesis and influence the clinical phenotypes of neuropsychiatric disorders. Reversible MAO-A inhibitors, such as moclobemide and befloxatone, are currently employed in the treatment of emotional disorders by inhibiting the enzymatic degradation of dopamine, serotonin and norepinephrine in the central nervous system (CNS). It has been suggested that the irreversible MAO-B inhibitors selegiline and rasagiline exert a neuroprotective effect in Parkinsons and Alzheimers diseases. This effect, however, is not related to their inhibition of MAO activity; in animal and cellular models, selegiline and rasagiline protect neuronal cells through their anti-apoptotic activity and induction of pro-survival genes. There is increasing evidence that MAO-A activity, but not that of MAO-B, is implicated in the pathophysiology of neurodegenerative disorders, but also in gene induction by MAO-B inhibitors; on the other hand, selegiline and rasagiline increase MAO-A mRNA, protein, and enzyme activity levels. Taken together, these results suggest that each MAO subtype exerts effects that modulate the expression and activity of the other isoenzyme. The roles of MAO-A and -B in the CNS should therefore be re-evaluated with respect to the type-specificity of their inhibitors, which may not be unconditional during chronic treatment. Mao-a expression, in particular, may be implicated in pathogenesis and phenotypes in neuropsychiatric disorders. MAO-A expression is modified by mao polymorphisms affecting its transcriptional efficiency, as well as by mutations and polymorphism of parkin, Sirt1, FOXO, microRNA, presenilin-1, and other regulatory proteins. In addition, childhood maltreatment has been shown to have an impact upon adolescent social behavior in children with mao-a polymorphisms of low transcriptional activity. Low MAO-A activity may increase the levels of serotonin and norepinephrine, resulting in disturbed neurotransmitter system development and behavior. This review discusses genetic and environmental factors involved in the regulation of MAO-A expression, in the contexts of neuropsychiatric function and of the regulation of neuronal survival and death.

Loading National Research Center for Geriatrics and Gerontology collaborators
Loading National Research Center for Geriatrics and Gerontology collaborators