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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 15, 2003; DOI: 10.1124/jpet.103.051342

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Received for publication March 7, 2003.
Revised March 28, 2003.
Accepted for publication May 13, 2003.

L-Selegiline Potentiates the Cellular Poly(ADP-Ribosyl)ation Response to Ionizing Radiation

Christine Brabeck 1, Ragen Pfeiffer 2, Alan Leake 3, Sascha Beneke 4, Ralph Meyer 5, Alexander Bürkle 1*

1 University of Konstanz 2 Cell Control Co. 3 Univ of Newcastle upon Tyne 4 German Cancer Research Center 5 Unversity of Arizona

* Address correspondence to: E-mail: alexander.buerkle{at}uni-konstanz.de

Abstract

DNA strand breaks induced by alkylating agents, oxidants or ionizing radiation trigger the covalent modification of nuclear proteins with poly(ADP-ribose), which is catalysed for the most part by poly(ADP-ribose) polymerase-1 and plays a role in DNA base-excision repair. Poly(ADP-ribosyl)ation capacity of mononuclear blood cells correlates positively with life span of mammalian species. Here we show that L-selegiline, an anti-Parkinson drug with neuroprotective activity and life span-extending effect in laboratory animals, can potentiate gamma-radiation-induced poly(ADP-ribose) formation in intact cells. COR4 hamster cells were incubated with L-selegiline (50 nM) for various time periods, followed by gamma-irradiation (45 Gy). Quantification of cellular poly(ADP-ribose) levels at 10 minutes after starting the irradiation revealed significant increases (up to 1.8-fold) in cells pre-incubated with the drug for 8 hours to 7 days compared to drug-free irradiated controls. There was no selegiline-induced change in poly(ADP-ribose) levels of unirradiated cells nor in basal or radiation-induced DNA strand breaks, respectively. Surprisingly, poly(ADP-ribose) polymerase-1 protein was downregulated by L-selegiline treatment. Addition of L-selegiline to purified poly(ADP-ribose) polymerase-1 did not alter enzymatic activity. In conclusion, the results of the present study identify a novel intervention to potentiate the cellular poly(ADP-ribosyl)ation response. We hypothesize that the effect of L-selegiline is due to modulation of accessory proteins regulating poly(ADP-ribose) polymerase-1 activity and that increased cellular poly(ADP-ribosyl)ation capacity may contribute to the neuroprotective potential and/or life span extension afforded by L-selegiline.


Key words: DNA damage, L-selegiline, Parkinson's disease, life span, neuroprotection, poly(ADP-ribose) polymerase


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