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  • Title: Poly(ADP-ribosyl)ation enhancement in brain cell nuclei is associated with diabetic neuropathy.
    Author: Kuchmerovska T, Shymanskyy I, Donchenko G, Kuchmerovskyy M, Pakirbaieva L, Klimenko A.
    Journal: J Diabetes Complications; 2004; 18(4):198-204. PubMed ID: 15207836.
    Abstract:
    UNLABELLED: The study has been undertaken to evaluate the effect of streptozotocin (STZ)-induced diabetes on rat brain poly(ADP-ribose)polymerase (Parp) activity and assess whether and how a Parp inhibitor, nicotinamide (NAm), may potentially regulate the diabetes-induced changes. Experiments were carried out after 4 weeks of diabetes duration in rats treated with or without NAm (100 or 200 mg kg(-1) day(-1), injected intraperitonally for 2 weeks). Assays were performed in purified brain cell nuclei to determine Parp activity by incorporation of radiolabeled ADP-ribose moieties from nicotinamide adenine dinucleotide (NAD+) into nuclear proteins. NAD+ and ATP levels were measured by enzymatic procedures. DNA damage was detected spectrophotometrically. RESULTS: Parp activity but not NAD-glycohydrolase (NADase) was stimulated by 21% in diabetes vs. control while lowering effects of diabetes on NAD+ and ATP levels were observed. Increase in Parp activity was accompanied by accumulation of malondialdehyde (MDA) and increase in DNA breakage. Treatment with either 100 or 200 mg/kg NAm dose diminished both DNA damage and Parp activity and partially restored the NAD+ and ATP contents, which is probably associated with direct competitive inhibition of Parp as well as with NAm's ability to block diabetes induced oxidative stress. CONCLUSION: Poly(ADP-ribosyl)polymerase overactivation is involved in the development of brain dysfunction in diabetic neuropathy. The mechanism of brain disorders seems to be at least partially connected with a decrease in cellular content and altered subcellular distribution of Parp substrate, NAD+, which, in turn, results in a reduction of ATP level that leads to a total failure of oxidative metabolism. NAm in both doses is effective for the inhibition of poly(ADP-ribosyl)ation.
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