Inhibitors of Poly(ADP-Ribose)Polymerase-1 as Agents Providing Correction of Brain Dysfunctions Induced by Experimental Diabetes

Abstract

The effects of 1,5-isoquinolinediol (IQD) and nicotinamide (NAm), inhibitors of poly-(ADP-ribose) polymerase-1 (PARP-1), on inflammatory processes and activation of PARP-1 under conditions of the development of experimental diabetic neuropathy, DN (a complication of streptozotocin-induced type-1 diabetes) in rats were studied. The content of IL-4 in blood serum in the case of DN was 50% higher, while that of monocyte-chemotactic protein-1 was 90% higher than those in the control. The content of gamma-interferon also increased, while the content of the granulocyte-macrophage colony-stimulating factor did not change. Against the background of activation of PARP-1 and a decrease in the content of the substrate of this enzyme nicotinamide adenine dinucleotide (NAD) in the brain, fragmentation of PARP-1 was intensified; an increase in the ratio of the contents of a 89 kDa fragment/intact enzyme molecules proved this fact. The mentioned two structurally dissimilar PARP-1 inhibitors partly or entirely normalized the above parameters under DN conditions. These results demonstrate that PARP-1 is one of the main functional targets in realization of the effects of IQD and NAm. At the same time, the spectrum of action of these inhibitors is wider. In particular, they affect the level of proinflammatory cytokines. The ability of the investigated PARP-1 inhibitors to prevent cell death in the brain by suppressing activation and fragmentation of the above-mentioned enzyme shows that other types of action of these agents at the molecular level are possible; these may be the maintenance of the genome integrity in the brain structures under DN conditions and preventing the development of inflammatory processes. Thus, the examined inhibitors can be used in the future in the treatment of brain dysfunctions that are complications of type-1 diabetes mellitus.