Enhanced inflammatory response via activation of NF-κB in acute experimental diabetic neuropathy subjected to ischemia–reperfusion injury

Wang, Yanping; Schmeichel, Ann M.; Iida, Haruyasu; Schmelzer, James D.; Low, Phillip A.

doi:10.1016/j.jns.2006.03.011

Cited by 85 publications

(44 citation statements)

References 35 publications

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“…The role of NF-B is complex and depends on age and on injury type and timing (47,48). When diabetic peripheral nerve is exposed to ischemia followed by reperfusion, NF-B expression in Schwann cells of diabetic peripheral nerve rises (49). In human Schwann cell cultures, tumor necrosis factor-␣ contributes to the transient activation of NF-B in the absence of apoptosis (50).…”

Section: Discussionmentioning

confidence: 99%

Receptor for Advanced Glycation End Products (RAGEs) and Experimental Diabetic Neuropathy

et al. 2008

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OBJECTIVE-Heightened expression of the receptor for advanced glycation end products (RAGE) contributes to development of systemic diabetic complications, but its contribution to diabetic neuropathy is uncertain. We studied experimental diabetic neuropathy and its relationship with RAGE expression using streptozotocin-induced diabetic mice including a RAGE Ϫ/Ϫ cohort exposed to long-term diabetes compared with littermates without diabetes.RESEARCH DESIGN AND METHODS-Structural indexes of neuropathy were addressed with serial (1, 3, 5, and 9 months of experimental diabetes) electrophysiological and quantitative morphometric analysis of dorsal root ganglia (DRG), peripheral nerve, and epidermal innervation. RAGE protein and mRNA levels in DRG, peripheral nerve, and epidermal terminals were assessed in WT and RAGE Ϫ/Ϫ mice, with and without diabetes. The correlation of RAGE activation with nuclear factor (NF)-B and protein kinase C ␤II (PKC␤II) protein and mRNA expression was also determined. RESULTS-Diabetic peripheral epidermal axons, sural axons,Schwann cells, and sensory neurons within ganglia developed dramatic and cumulative rises in RAGE mRNA and protein along with progressive electrophysiological and structural abnormalities. RAGE Ϫ/Ϫ mice had attenuated structural features of neuropathy after 5 months of diabetes. RAGE-mediated signaling pathway activation for NF-B and PKC␤II pathways was most evident among Schwann cells in the DRG and peripheral nerve.CONCLUSIONS-In a long-term model of experimental diabetes resembling human diabetic peripheral neuropathy, RAGE expression in the peripheral nervous system rises cumulatively and relates to progressive pathological changes. Mice lacking RAGE have attenuated features of neuropathy and limited activation of potentially detrimental signaling pathways. Diabetes

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Section: Discussionmentioning

confidence: 99%

Receptor for Advanced Glycation End Products (RAGEs) and Experimental Diabetic Neuropathy

et al. 2008

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“…Chronic NF-κB activation appears to render neurons and blood vessels more susceptible to ischemia-reperfusion injury [139]. The subsequent extensive infiltration of macrophages is further intensified by NF-κB-stimulated release of cytokines from endothelial cells, Schwann cells and neurons [140].…”

Section: The Intersection Of Ros/rns and Other Metabolic Pathwaysmentioning

confidence: 99%

Mechanisms of disease: The oxidative stress theory of diabetic neuropathy

Figueroa‐Romero

Sadidi

Feldman

2008

Rev Endocr Metab Disord

233

175

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Diabetic neuropathy is the most common complication of diabetes, affecting 50% of diabetic patients. Currently, the only treatment for diabetic neuropathy is glucose control and careful foot care. In this review, we discuss the idea that excess glucose overloads the electron transport chain, leading to the production of superoxides and subsequent mitochondrial and cytosolic oxidative stress. Defects in metabolic and vascular pathways intersect with oxidative stress to produce the onset and progression of nerve injury present in diabetic neuropathy. These pathways include the production of advanced glycation end products, alterations in the sorbitol, hexosamine and protein kinase C pathways and activation of Poly-ADP ribose polymerase. New bioinformatics approaches can augment current research and lead to new discoveries to understand the pathogenesis of diabetic neuropathy and to identify more effective molecular therapeutic targets.

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“…Unfortunately, all monotherapies for DPN studied so far, including AR and protein kinase C inhibitors, acetyl carnitine, nerve growth factor, and the antioxidant α–lipoic acid, showed modest efficacy in clinical trials, or have been abandoned due to adverse side effects (Tesfaye et al, 2010). The continued drug discovery for DPN is currently focused on 1) invention and development of new inhibitors of previously characterized pathogenetic mechanisms e.g., new AR (Bril et al, 2009) and non-enzymatic glycation (Wada et al, 2001) inhibitors, as well as potent superoxide dismutase mimetics (Coppey et al, 2001a) and peroxynitrite decomposition catalysts (Drel et al, 2007a; Obrosova et al, 2007a) to combat oxidative-nitrosative stress; 2) identification of new pathogenetic mechanisms and drug targets e.g., poly(ADP-ribose) polymerase (Drel et al, 2010; Obrosova et al, 2004; Obrosova et al, 2008; Szabo et al, 2004), low-grade inflammation (Dopius et al, 2009; Wang et al, 2006; Wang et al, 2008) likely to be associated with cyclooxygenase-2 (Kellogg et al, 2007), 12/15-lipoxygenase (Obrosova et al, 2010; Stavniichuk et al, 2010), and nuclear factor-κB (Cameron and Cotter, 2009) activation, disrupted neuregulin/caveolin-1 signaling (McGuire et al, 2009) and molecular chaperone activity (Urban et al, 2010), and activation of neutral endopeptidase, a protease that degrades vaso- and neuro-active peptides (Coppey et al, 2010); 3) studies of combination therapies (Cotter et al, 2001; Li et al, 2005) and mono-drugs targeting several pathogenetic mechanisms (Kumar and Sharma, 2010). …”

Section: Introductionmentioning

confidence: 99%

Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative–nitrosative stress and p38 MAPK activation

Stavniichuk

Drel

Shevalye

et al. 2011

Experimental Neurology

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With consideration of multifactorial etiology of diabetic peripheral neuropathy, an ideal drug or drug combination should target at least several key pathogenetic mechanisms. The flavonoid baicalein (5,6,7-trihydroxyflavone) has been reported to counteract sorbitol accumulation, activation of 12/15-lipoxygenase, oxidative-nitrosative stress, inflammation, and impaired signaling in models of chronic disease. This study evaluated baicalein on diabetic peripheral neuropathy. Control and streptozotocin-diabetic C57Bl6/J mice were maintained with or without baicalein treatment (30 mgkg−1d−1, i.p., for 4 weeks after 12 weeks without treatment). Neuropathy was evaluated by sciatic motor and hind-limb digital sensory nerve conduction velocities, thermal algesia (Hargreaves test), tactile response threshold (flexible von Frey filament test), and intraepidermal nerve fiber density (fluorescent immunohistochemistry with confocal microscopy). Sciatic nerve and spinal cord 12/15-lipoxygenase and total and phosphorylated p38 mitogen-activated protein kinase expression and nitrated protein levels were evaluated by Western blot analysis, 12(S)hydroxyeicosatetraenoic acid concentration (a measure of 12/15-lipoxygenase activity) by ELISA, and glucose and sorbitol pathway intermediate concentrations by enzymatic spectrofluorometric assays. Baicalein did not affect diabetic hyperglycemia, and alleviated nerve conduction deficit and small sensory nerve fiber dysfunction, but not intraepidermal nerve fiber loss. It counteracted diabetes-associated p38 mitogen-activated protein kinase phosphorylation, oxidative-nitrosative stress, and 12/15-lipoxygenase overexpression and activation, but not glucose or sorbitol pathway intermediate accumulation. In conclusion, baicalein targets several mechanisms implicated in diabetic peripheral neuropathy. The findings provide rationale for studying hydroxyflavones with improved pharmacological profile as potential treatments for diabetic neuropathy and other diabetic complications.

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Enhanced inflammatory response via activation of NF-κB in acute experimental diabetic neuropathy subjected to ischemia–reperfusion injury

Cited by 85 publications

References 35 publications

Receptor for Advanced Glycation End Products (RAGEs) and Experimental Diabetic Neuropathy

Receptor for Advanced Glycation End Products (RAGEs) and Experimental Diabetic Neuropathy

Mechanisms of disease: The oxidative stress theory of diabetic neuropathy

Baicalein alleviates diabetic peripheral neuropathy through inhibition of oxidative–nitrosative stress and p38 MAPK activation

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