Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine.

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Bar-Am O, Weinreb O, Amit T, Youdim MB

Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine.

FASEB J. 2005 Nov;19(13):1899-901. Epub 2005 Sep 7.

PubMed ID

16148027 [ View in PubMed

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Abstract

The 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 microM) 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 alpha-secretase form of soluble APP (sAPPalpha) 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Rasagiline	Apoptosis regulator Bcl-2	Protein	Humans	Yes	Activator	Details