Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Obrosova, Irina G.; Drel, Viktor R.; Oltman, Christine L.; Mashtalir, Nazar; Tibrewala, Jyoti; Groves, John T.; Yorek, Mark A.

doi:10.1152/ajpendo.00479.2007

Cited by 108 publications

(104 citation statements)

References 70 publications

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“…Evidence for the important role of the potent oxidant peroxynitrite, a product of superoxide anion radicals and nitric oxide (6,43), in diabetic complications including endothelial dysfunction (44), peripheral (45)(46)(47)(48) and autonomic (49) neuropathy, and retinopathy (50) is emerging. Peroxynitrite causes multiple cytotoxic effects including lipid peroxidation, protein nitration and nitrosylation, DNA breakage and base modification, impairment of cell signaling, depolarization of mitochondrial membrane, PARP and metalloproteinase activation, and, in extreme cases, necrosis and premature apoptosis (6,43).…”

Section: Discussionmentioning

confidence: 99%

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Drel

Pacher²,

Ali³

et al. 2008

Int J Mol Med

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Abstract. This study was aimed at evaluating the potent and specific aldose reductase inhibitor fidarestat, on diabetesassociated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis. Control and streptozotocin-diabetic rats were treated with or without fidarestat (16 mg kg -1 d -1 ) for 10 weeks after an initial 2-week period without treatment. Lens changes were evaluated by indirect ophthalmoscopy and portable slit lamp. Nitrotyrosine, poly(ADP-ribose), and glial fibrillary acidic protein expression were assessed by immunohistochemistry. The rate of apoptosis was quantified in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. To dissect the effects of high glucose exposure in retinal microvascular cells, primary bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without fidarestat (10 μM) for 3-14 days. Apoptosis was assessed by TUNEL assay, nitrotyrosine and poly(ADP-ribose) by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Fidarestat treatment prevented diabetic cataract formation and counteracted retinal nitrosative stress, and poly(ADP-ribose) polymerase activation, as well as glial activation. The number of TUNEL-positive nuclei (mean ± SEM) was increased approximately 4-fold in diabetic rats vs. controls (207±33 vs. 49±4, p<0.01), and this increase was partially prevented by fidarestat (106±34, p<0.05 vs. untreated diabetic group). The apoptotic cell number increased with the prolongation of exposure of both pericytes and endothelial cells to high glucose levels. Fidarestat counteracted nitrotyrosine and poly(ADP-ribose) accumulation and apoptosis in both cell types. Antiapoptotic effect of fidarestat in high glucose-exposed retinal pericytes was not associated with the inhibition of Bax or increase in Bcl-2 expression. In conclusion, the findings, i) support an important role for aldose reductase in diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis, and ii) provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for the prevention and treatment of diabetic ocular complications.

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Section: Discussionmentioning

confidence: 99%

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Drel

Pacher²,

Ali³

et al. 2008

Int J Mol Med

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“…The mechanisms underlying diabetes-induced tactile allodynia have not been studied in detail, although considerable progress has been made in experimental studies performed in the last several years. Tactile allodynia associated with early PDN in STZ-diabetic rats was alleviated by peroxynitrite decomposition catalyst 78 and PARP inhibitor 12,44 treatments, which suggests the involvement of nitrosative stress and PARP activation. The latter is consistent with less severe or absent tactile allodynia in STZ-diabetic inducible nitric oxide synthasedeficient and PARP-deficient mice, compared with the corresponding wild-type mice with STZ-diabetes of similar severity and duration.…”

Section: Diabetes-associated Tactile Allodyniamentioning

confidence: 92%

“…In experimental studies, mechanical withdrawal thresholds in diabetic rat and mouse models are assessed by paw (rats) and tail (mouse) pressure Randall-Selitto test or with a von Frey aesthesiometer and rigid von Frey filaments. Mechanical hyperalgesia has been reported in both STZ-diabetic 20,21,30,77,78 and Zucker diabetic fatty rats, 34,79 in which pressure pain preceded development of type 2 diabetes. In contrast, STZ-diabetic C57Bl/6J mice 13,14,46,47 displayed elevated mechanical withdrawal thresholds.…”

Section: Pathogenesis and Experimental Treatments: Diabetes-associatementioning

confidence: 99%

“…Several hyperglycemia-related mechanisms, i.e., increased AR activity, 77 oxidative-nitrosative stress, 78 and PARP activation, 12,44 as well as impaired insulin signaling 79 have been implicated in pain on pressure in diabetic and prediabetic rat models. Correspondingly, diabetes-induced mechanical hyperalgesia in STZ-diabetic rats was corrected or alleviated by AR inhibitors, 77,80 by antioxidants (␣-lipoic acid, 20 dimethylthiourea, 21 allopurinol, 29 and taurine 30 ), and by a peroxynitrite decomposition catalyst, 78 as well as by PARP inhibitors, 12,44 PARP inhibitor-containing combination therapies, 22 and the Na ϩ /H ϩ -exchanger-1 inhibitor cariporide. 81 Gabapentin (an anticonvulsant agent) and insulin strongly elevated the nociceptive threshold in STZ-diabetic rats, but gabapentin elevated it above normal levels.…”

Section: Pathogenesis and Experimental Treatments: Diabetes-associatementioning

confidence: 99%

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Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

2009

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Summary:Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin-and leptin-receptor-deficient, and highfat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADPribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments. Key Words: Animal models, diabetic insensate neuropathy, diabetic painful neuropathy, formalin-induced hyperalgesia, mechanical hyper-and hypoalgesia, pathogenetic treatments of diabetic neuropathic pain and sensory loss, symptomatic treatments of diabetic pain, tactile allodynia, thermal hyper-and hypoalgesia.

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“…Peroxynitrite and its derivatives are the one species with the strongest oxidation known at present, playing a crucial role in the pathogenesis of diabetes and its complications (12,(30)(31)(32)(33)(34). Peroxynitrite could cause conspicuous nitration to proteins, and NT is believed to be a marker of peroxynitrite-caused damage (12,(31)(32)(33). Our previous study found that peroxynitrite can induce protein nitration in diabetic complications (11,35).…”

Section: S E P T E M B E R -O C T O B E R 0 1 0 N I T R a T I O N Pmentioning

confidence: 99%

Peroxynitrite-induced Nitration of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Promotes Their Binding in Diabetic Angiopathy

Li¹,

Liu

et al. 2010

Mol Med

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Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) play crucial roles in diabetic angiopathy. In vivo, however, the following facts remain unknown: whether COX-2 and iNOS bind, how peroxynitrite-induced nitration of COX-2 and iNOS affects their binding if they do bind and what effects of this mechanism contribute to diabetic angiopathy. This study focused on the issues above. Diabetes was induced in Wistar male rats by intraperitoneal injection of streptozotocin. As a specific scavenger of peroxynitrite, urate was used. After 13 wks of diabetes, the morphological and biochemical changes of the rats showed obvious diabetic angiopathy. There exists in vivo colocalization and binding of COX-2 and iNOS in diabetic angiopathy. The nitration level of total and coimmunoprecipitated COX-2 and iNOS increased significantly, and, simultaneously, their binding and activity increased in the diabetes group. In the diabetes + urate group, the nitration level of COX-2 and iNOS decreased and their binding reduced, consistent with their decreased activity and the attenuated pathological changes in the rat aorta and glomerulus. The results provide in vivo evidence that COX-2 and iNOS can bind in diabetic angiopathy and that peroxynitrite-induced nitration of COX-2 and iNOS promotes their binding, contributing to diabetic angiopathy.

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Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Cited by 108 publications

References 70 publications

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

Peroxynitrite-induced Nitration of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase Promotes Their Binding in Diabetic Angiopathy

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