Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine
ABSTRACTThe anti‐Parkinson drug, rasagiline (N‐propargyl‐(1R)‐aminoindan) promotes neuronal survival, via neuroprotective activity related to its propargyl moiety (propargylamine). We have investigated the neurorescue effects of propargylamine, in a progressive neuronal death model, induced by long‐...
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Veröffentlicht in: | The FASEB journal 2005-11, Vol.19 (13), p.1899-1901 |
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Sprache: | eng |
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Zusammenfassung: | ABSTRACTThe anti‐Parkinson drug, rasagiline (N‐propargyl‐(1R)‐aminoindan) promotes neuronal survival, via neuroprotective activity related to its propargyl moiety (propargylamine). We have investigated the neurorescue effects of propargylamine, in a progressive neuronal death model, induced by long‐term serum deprivation in human SH‐SY5Y neuroblastoma cells. Propargylamine (0.1–10 µM) dose‐dependently reduced the levels of the early apoptosis‐associated phosphorylated protein, H2A‐X (ser 139), as well as decreased the cleavage of caspase‐3 and its substrate poly‐ADP ribose polymerase (PARP). In addition, the compound markedly reversed the apoptotic effects induced by long‐term serum withdrawal, including down‐regulation of the antiapoptotic protein, Bcl‐2, as well as up‐regulation of the proapoptotic proteins, Bax, Bad, and Bim. Real‐time RT‐PCR demonstrated that propargylamine elevated gene expression levels of Bcl‐2, and the neurotrophic factors glial cell line‐derived neurotrophic factor (GDNF) and brain‐derived neurotrophic factor (BDNF) and reduced Bax gene expression. Serum deprivation increased mRNA and protein levels of holo‐amyloid precursor protein (APP), which was markedly decreased by propargylamine. This was accompanied by inducing the release of the nonamyloidogenic α‐secretase form of soluble APP (sAPPα) into the medium. Similar effects on cell survival and APP regulation/processing were demonstrated for rasagiline. These results indicate that both rasagiline and propargylamine possess neurorescue activity, associated with regulation of Bcl‐2 family proteins, neurotrophic factors, and APP metabolism. |
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ISSN: | 0892-6638 1530-6860 |
DOI: | 10.1096/fj.05-3794fje |