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.