L-Selegiline Potentiates the Cellular Poly(ADP-Ribosyl)ation Response to Ionizing Radiation
by
Brabeck C, Pfeiffer R, Leake A,
Beneke S, Meyer R, Burkle A.
University of Konstanz.
Pharmacol Exp Ther 2003 May 15

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.

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