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Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy
Author(s) -
Stavniichuk Roman,
Shevalye Hanna,
Lupachyk Sergey,
Obrosov Alexander,
Groves John T.,
Obrosova Irina G.,
Yorek Mark A.
Publication year - 2014
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.2549
Subject(s) - peroxynitrite , peripheral neuropathy , peroxynitrous acid , medicine , diabetic neuropathy , nitric oxide , nitration , nitrotyrosine , endocrinology , oxidative stress , pathogenesis , diabetes mellitus , chemistry , pharmacology , nitric oxide synthase , superoxide , biochemistry , enzyme , organic chemistry
Background Peroxynitrite, a product of the reaction of superoxide with nitric oxide, causes oxidative stress with concomitant inactivation of enzymes, poly(ADP‐ribosylation), mitochondrial dysfunction and impaired stress signalling, as well as protein nitration. In this study, we sought to determine the effect of preventing protein nitration or increasing peroxynitrite decomposition on diabetic neuropathy in mice after an extended period of untreated diabetes. Methods C57Bl6/J male control and diabetic mice were treated with the peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS, 10 mg/kg/day) or protein nitration inhibitor (−)‐epicatechin gallate (20 mg/kg/day) for 4 weeks, after an initial 28 weeks of hyperglycaemia. Results Untreated diabetic mice developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and loss of intraepidermal nerve fibres. Both FeTMPS and epicatechin gallate partially corrected sensory nerve conduction slowing and small sensory nerve fibre dysfunction without alleviation of hyperglycaemia. Correction of motor nerve conduction deficit and increase in intraepidermal nerve fibre density were found with FeTMPS treatment only. Conclusions Peroxynitrite injury and protein nitration are implicated in the development of diabetic peripheral neuropathy. The findings indicate that both structural and functional changes of chronic diabetic peripheral neuropathy can be reversed and provide rationale for the development of a new generation of antioxidants and peroxynitrite decomposition catalysts for treatment of diabetic peripheral neuropathy. Published in 2014. This article is a U.S. Government work and is in the public domain in the USA.