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NEUROPHARMACOLOGY

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

Abteilung Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, Germany (C.B., R.P., S.B., R.M., A.B.); and Department of Gerontology, University of Newcastle, Newcastle upon Tyne, UK (R.P., A.L., A.B.)

DNA strand breaks induced by alkylating agents, oxidants, or ionizing radiation trigger the covalent modification of nuclear proteins with poly(ADP-ribose), which is catalyzed 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 -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 -irradiation (45 Gy). Quantification of cellular poly(ADP-ribose) levels at 10 min after starting the irradiation revealed significant increases (up to 1.8-fold) in cells preincubated with the drug for 8 h to 7 days compared with 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 down-regulated 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.

Address correspondence to: Prof. Alexander Bürkle, Department of Biology, University of Konstanz, Box X911, D-78457 Konstanz, Germany. E-mail: alexander.buerkle{at}uni-konstanz.de

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