Natural guanine derivatives exert PARP-inhibitory and cytoprotective effects in a model of cardiomyocyte damage under oxidative stress

Abstract

Inhibitors of human poly(ADP-ribose) polymerase (PARP) are considered as promising agents for the treatment of cardiovascular, neurological, and other diseases accompanied by inflammation and oxidative stress. Previously, the ability of the natural compounds 7-methylguanine (7mGua) and 8-hydroxy-7-methylguanine (8h7mGua) to suppress the activity of the recombinant PARP protein was demonstrated. In the present work, we have investigated the possibility of PARP-inhibitory and cytoprotective action of 7mGua and 8h7mGua against rat cardiomyoblast cultures (undifferentiated and differentiated H9c2). It was found that 7mGua and 8h7mGua rapidly penetrate into cells and effectively suppress H2O2-stimulated PARP activation (IC50 = 270 and 55 µM, respectively). The pronounced cytoprotective effects of 7mGua and 8h7mGua were shown in a cellular model of oxidative stress, and 8h7mGua exceeded the classic PARP inhibitor 3-aminobenzamide for effectiveness. The obtained data indicate the prospects for the development of PARP inhibitors based on guanine derivatives and their testing on models of ischemia-reperfusion tissue damage.