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Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase (PARP) Activation in Experimental Diabetic Neuropathy

The Relation Is Revisited

¹ Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
² Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
³ Laboratory of Physiological Studies, National Institutes of Health/National Institute of Alcohol Abuse and Alcoholism, Bethesda, Maryland
⁴ Veteran Affairs Medical Center and Department of Internal Medicine, University of Iowa, Iowa City, Iowa

Poly(ADP-ribose) polymerase (PARP) activation, an important factor in the pathogenesis of diabetes complications, is considered a downstream effector of oxidative-nitrosative stress. However, some recent findings suggest that it is not necessarily the case and that PARP activation may precede and contribute to free radical and oxidant-induced injury. This study evaluated the effect of PARP inhibition on oxidative-nitrosative stress in diabetic peripheral nerve, vasa nervorum, aorta, and high glucose–exposed human Schwann cells. In vivo experiments were performed in control rats and streptozocin (STZ)-induced diabetic rats treated with and without the PARP inhibitor 3-aminobenzamide (ABA) (30 mg · kg^–1 · day^–1 i.p. for 2 weeks after 2 weeks of untreated diabetes). Human Schwann cells (HSC) (passages 7–10; ScienCell Research Labs) were cultured in 5.5 or 30 mmol/l glucose with and without 5 mmol/l ABA. Diabetes-induced increase in peripheral nerve nitrotyrosine immunoreactivity, epineurial vessel superoxide and nitrotyrosine immunoreactivities, and aortic superoxide production was reduced by ABA. PARP-1 (Western blot analysis) was abundantly expressed in HSC, and its expression was not affected by high glucose or ABA treatment. High-glucose–induced superoxide production and overexpression of nitrosylated and poly(ADP-ribosyl)ated protein, chemically reduced amino acid-(4)-hydroxynonenal adducts, and inducible nitric oxide synthase were decreased by ABA. We concluded that PARP activation contributes to superoxide anion radical and peroxynitrite formation in peripheral nerve, vasa nervorum, and aorta of STZ-induced diabetic rats and high- glucose–exposed HSC. The relations between oxidative-nitrosative stress and PARP activation in diabetes are bi- rather than unidirectional, and PARP activation cannot only result from but also lead to free radical and oxidant generation.

Abbreviations: ABA, 3-aminobenzamide; HNE, hydroxynonenal; HSC, human Schwann cells; iNOS, inducible nitric oxide synthase; NAD⁺, nicotinamide adenine dinucleotide; PARP, poly(ADP-ribose) polymerase; PDN, peripheral diabetic neuropathy; STZ, streptozocin

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