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The Role of Oxidative Stress in Diabetic Neuropathy: Generation of Free Radical Species in the Glycation Reaction and Gene Polymorphisms Encoding Antioxidant Enzymes to Genetic Susceptibility to Diabetic Neuropathy in Population of Type I Diabetic Patients

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Disease is the retribution of outraged Nature.

Hosea Ballou.

Abstract

Diabetic neuropathy (DN) represents the main cause of morbidity and mortality among diabetic patients. Clinical data support the conclusion that the severity of DN is related to the frequency and duration of hyperglycemic periods. The presented experimental and clinical evidences propose that changes in cellular function resulting in oxidative stress act as a leading factor in the development and progression of DN. Hyperglycemia- and dyslipidemia-driven oxidative stress is a major contributor, enhanced by advanced glycation end product (AGE) formation and polyol pathway activation. There are several polymorphous pathways that lead to oxidative stress in the peripheral nervous system in chronic hyperglycemia. This article demonstrates the origin of oxidative stress derived from glycation reactions and genetic variations within the antioxidant genes which could be implicated in the pathogenesis of DN. In the diabetic state, unchecked superoxide accumulation and resultant increases in polyol pathway activity, AGEs accumulation, protein kinase C activity, and hexosamine flux trigger a feed-forward system of progressive cellular dysfunction. In nerve, this confluence of metabolic and vascular disturbances leads to impaired neural function and loss of neurotrophic support, and over the long term, can mediate apoptosis of neurons and Schwann cells, the glial cells of the peripheral nervous system. In this article, we consider AGE-mediated reactive oxygen species (ROS) generation as a pathogenesis factor in the development of DN. It is likely that oxidative modification of proteins and other biomolecules might be the consequence of local generation of superoxide on the interaction of the residues of l-lysine (and probably other amino acids) with α-ketoaldehydes. This phenomenon of non-enzymatic superoxide generation might be an element of autocatalytic intensification of pathophysiological action of carbonyl stress. Glyoxal and methylglyoxal formed during metabolic pathway are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. Genetic variations within the antioxidant genes therefore could be implicated in the pathogenesis of DN. In this work, the supporting data about the association between the −262T > C polymorphism of the catalase (CAT) gene and DN were shown. The −262TT genotype of the CAT gene was significantly associated with higher erythrocyte catalase activity in blood of DN patients compared to the −262CC genotype (17.8 ± 2.7 × 104 IU/g Hb vs. 13.5 ± 3.2 × 104 IU/g Hb, P = 0.0022). The role of these factors in the development of diabetic complications and the prospective prevention of DN by supplementation in formulations of transglycating imidazole-containing peptide-based antioxidants (non-hydrolyzed carnosine, carcinine, n-acetylcarcinine) scavenging ROS in the glycation reaction, modifying the activity of enzymic and non-enzymic antioxidant defenses that participate in metabolic processes with ability of controlling at transcriptional levels the differential expression of several genes encoding antioxidant enzymes inherent to DN in Type I Diabetic patients, now deserve investigation.

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Acknowledgments

This work was planned, organized, and supported by Innovative Vision Products, Inc. (County of New Castle, DE, USA). Innovative Vision Products Inc. is a Pharmaceutical and Nanotechnology Development Company with a focus on innovative chemical entities, drug delivery systems, and unique medical devices to target specific biomedical applications. Over the last decade, IVP has developed a track record in developing these technologies to effectively address the unmet needs of specific diseased populations.

Conflict of interest

The authors report no conflict of interest in this work. The authors bear primary responsibility for accuracy of made statements and employment of the described products and for the content and writing of the paper.

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Authors and Affiliations

  1. Innovative Vision Products, Inc., 3511 Silverside Road, Suite 105, County of New Castle, DE, 19810, USA

    Mark A. Babizhayev

  2. Moscow Helmholtz Research Institute of Eye Diseases, Str. Sadovaya-Chernogryazskaya 14/19, Moscow, 105062, Russian Federation

    Mark A. Babizhayev

  3. Department of Molecular Diagnostics, National Research Centre GosNIIgenetika, Moscow, 113545, Russian Federation

    Valery V. Nosikov

  4. Department of Neurology, I. M. Sechenov Medical Academy, Moscow, 125315, Russia

    Igor A. Strokov

  5. Russian State Medical University, Moscow, 117869, Russian Federation

    Ekaterina L. Savel’yeva & Vladimir F. Sitnikov

  6. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow, 119991, Russian Federation

    Yegor E. Yegorov

  7. Russian Cardiology Research Center, 3-ya Cherepkovskaya ul. 15a, 121552, Moscow, Russia

    Vadim Z. Lankin

  8. Innovative Vision Products, Inc., Moscow Division, Ivanovskaya 20, Suite 74, Moscow, 127434, Russian Federation

    Mark A. Babizhayev

  9. Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, 141700, Russian Federation

    Yegor E. Yegorov

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  1. Mark A. Babizhayev
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Correspondence to Mark A. Babizhayev.

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Babizhayev, M.A., Strokov, I.A., Nosikov, V.V. et al. The Role of Oxidative Stress in Diabetic Neuropathy: Generation of Free Radical Species in the Glycation Reaction and Gene Polymorphisms Encoding Antioxidant Enzymes to Genetic Susceptibility to Diabetic Neuropathy in Population of Type I Diabetic Patients. Cell Biochem Biophys 71, 1425–1443 (2015). https://doi.org/10.1007/s12013-014-0365-y

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