Diakun K. Mechanisms of the action of PARP-1 inhibitors under experimental diabetes mellitus

Dissertation is devoted to study of mechanisms of action of PARP-1 inhibitors (1,5-isoquinolinediol and nicotinamide) on processes of poly-ADP-ribosylation in brain of rats in experimental type 1 diabetes mellitus (DM). The corrective effect of the used structurally different PARP-1 inhibitors on the processes of poly-ADP-ribosylation of nuclear proteins in the rat brain at the level of their content, PARP-1 activity and enzyme fragmentation, as well as at the level of Рarp-1 gene expression was revealed. It was found that in type 1 diabetes there was an intensification of oxidative stress, the development of inflammatory processes. Nicotinamide administration led to inhibition of oxidative stress and reduced the level of the interleukin-4. Against the intensification of poly-ADP-ribosylation processes and decrease in NAD+ content in type 1 diabetes, there was an increase in PARP-1 fragmentation and a decrease in NAD-dependent deacetylase SIRT1, which may characterize the degree of neurodegenerative changes in the brain. It was found that pathological disorders of the brain in diabetes occur simultaneously with peripheral diabetic neuropathy. Proof of this is the decrease in collagen content in the tissue of the tibia and fibula, which may be due to both structural rearrangement of collagen and its modifications, as a result of alterations in its amino acid composition and changes in vitamins C, B3 and E in animal serum, vitamins, which are involved and affect collagen synthesis. The use of PARP-1 inhibitors has been shown to improve, at least partially, the studied processes and biochemical parameters which were impaired by type 1 diabetes. The data obtained indicate that in type 1 diabetes there is a relationship between the processes of poly-ADP-ribosylation in the rat brain and other metabolic processes and parameters in the body.