R-(-)-Deprenyl inhibits monocytic THP-1 cell neurotoxicity independently of monoamine oxidase inhibition.
R-(-)-Deprenyl (deprenyl, selegiline), a monoamine oxidase B (MAO-B) inhibitor, delays progression of Parkinson's disease. This action could be mediated by inhibition of MAO-B but there may also be unrelated mechanisms. Direct neuroprotective and antiapoptotic actions of deprenyl have previously been observed in vitro. Here we describe an antineurotoxic action of deprenyl which is independent of direct neuronal effects. We employed a previously described assay in which human neuroblastoma SH-SY5Y cells are exposed to cell-free supernatants of stimulated human monocytic THP-1 cells. Deprenyl reduced the secretion of neurotoxic products by such stimulated cells in a concentration-dependent manner, while the MAO inhibitors iproniazid, isocarboxazid, nialamide, tranylcypromine, phenelzine, and clorgyline were without effect. No antineurotoxic action was observed when deprenyl was added directly to SH-SY5Y cells. Messenger RNAs for MAO-A and MAO-B were not detected in THP-1 cells by reverse transcriptase-polymerase chain reaction analysis of total RNA extracts. Such mRNAs were easily detected in extracts of SH-SY5Y cells under comparable conditions. MAO enzymatic activity was also undetectable in THP-1 cell lysates, while it was readily observed in SH-SY5Y cells. It was concluded that the effect of deprenyl on THP-1 cells was not mediated by MAO and that deprenyl itself was not protecting neurons. These data suggest that deprenyl may have utility in neurodegenerative diseases due to its antineurotoxic actions.
Klegeris
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Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
McGeer
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PL
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000201:enzymology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D009498:Neurotoxins / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012642:Selegiline / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D008996:Monoamine Oxidase Inhibitors; D009498:Neurotoxins; D012333:RNA, Messenger; D012642:Selegiline; D008995:Monoamine Oxidase