title: Rasagiline and selegiline, inhibitors of type B monoamine oxidase, induce type A monoamine oxidase in human SH-SY5Y cells.
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.
authors.affiliation: Department of Neurosciences, Gifu International Institute of Biotechnology, Kakamigahara, Gifu, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Inaba-Hasegawa
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
authors.forename: Wakako
authors.initials: W
authors.lastname: Maruyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Naoi
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012642:Selegiline / Q000494:pharmacology*; D014162:Transfection
chemical_list: D007189:Indans; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; C031967:rasagiline; D012642:Selegiline; D008995:Monoamine Oxidase