Mini ReviewOxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: Old perspective with a new angle
Highlights
► Oxidative stress plays a major role in the pathophysiology of diabetic neuropathy. ► Nrf2 is key transcription factor maintaining the antioxidant defense. ► Nrf2 has gained value due to its role in neuroprotection, inflammation and cancer. ► Nrf-2 activators hold a potential for protection of diabetic peripheral nerves.
Introduction
The escalating prevalence of obesity, diabetes and metabolic syndrome at astounding rates in India and worldwide has been raising concern for last two decades. Between 1995 and 2030 the number of adult population affected by the diabetes is projected to grow by 170% [1]. Diabetic neuropathy is one of the most common and assorted complications of long standing diabetes. A detailed definition of DN says “a demonstrable disorder, either clinically evident or subclinical, that occurs in setting of diabetes mellitus without other causes for peripheral neuropathy [2]”.
There are numerous acceptable pathogenetic factors which explain for the various deficits observed in diabetic neuropathy including aldose reductase pathway, advanced glycation end product formation, oxidative/nitrosative/carbonyl stress, increased protein kinase C activity, over-activation of poly ADP-ribose polymerase and inflammation [3], [4], [5], [6], [7], [8]. While many of these pathways overlie and/or intersect with one or other pathways, together they produce a state of disparity between reactive species production and body’s redox homeostasis, resulting in a condition termed as oxidative stress. Oxidative stress plays a major role in diabetes as well as in diabetic neuropathy. Nrf2 pathway has been implicated to play significant role contributing to the antioxidant defense of the body. Excess production of reactive oxygen species (ROS) is considered to cause abnormal axon morphology, altered neuronal membrane permeability along with causing functional modification of various cellular proteins [9], [10], [11]. Nrf2 and heme oxygenase-1 (HO-1, a phase II detoxifying enzyme) has been shown to possess protective effect against STZ induced diabetes and diabetic neuropathy [12]. In the present review, we have presented a contemporary outlook on most talked hypothesis of diabetic complications, oxidative stress and involvement of Nrf2 mediated modulation of antioxidant defense.
Section snippets
Oxidative stress in pathophysiology of DN: Classical perspective
Although hyperglycemia is considered to be a major pathogenic factor in the development of diabetic neuropathy, the mechanisms associated with this are not yet fully understood. Hyperglycemia unleash multiple pathways such as redox imbalances secondary to enhanced aldose reductase activity, increased advanced glycation end products (AGE) and altered protein kinase C (PKC) activity to induce oxidative stress (Fig 1). While specific inhibitors of any of these mechanisms ameliorate various
Transcription factor Nrf2: an emerging concept
Cells possess an array of antioxidant defense machinery to prevent or counterbalance the damage caused by reactive radicals. Important armors of antioxidant defense include superoxide dismutase, catalase, GSH, glutathione peroxidase, polyphenol, flavonoids. In addition to these, there is a family of enzymes which carry out the metabolic detoxification of highly reactive radicals and thus shield cells against excessive oxidative stress. These are phase II detoxifying enzymes which include
Nrf2 and oxidative stress
As discussed earlier, oxidative stress plays a pivotal role in the pathophysiology of diabetic neuropathy and Nrf2 is considered as the axis of defense against oxidative stress, there is a definite correlation between pathogenesis of diabetic neuropathy and Nrf2 pathway. Protective effects of Nrf2 activators have been reported in experimental models for various diseases like diabetes, cerebral ischemia, cancer, neurodegeneration, atherosclerosis and numerous other inflammatory conditions [12],
Antioxidants manipulate transcriptional activity of Nrf2
Treatment/prevention of diabetes related neuropathy hinge primarily upon the glycemic control. Antioxidants are surfacing out to be one of the successful strategies for treatment of diabetic neuropathy. The efficacy of many of the antioxidants has been recognized to be mediated through the induction of detoxifying and antioxidant genes based upon the study of animal model of diabetes. Resveratrol a polyphenolic antioxidant found in grapes proved to reverse the deficits associated with diabetic
Acknowledgments
The authors would like to acknowledge the financial support provided by Council of Scientific and Industrial Research (CSIR, New Delhi, India) and Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India to Dr. S.S. Sharma. Ms Geeta Negi is a recipient of CSIR-NET research fellowship.
References (59)
- et al.
Global estimates of the prevalence of diabetes for 2010 and 2030
Diabetes Res. Clin. Pract.
(2010) - et al.
The role of protein kinase C activation and the vascular complications of diabetes
Pharmacol. Res.
(2007) - et al.
Protective effects of 4-amino1, 8-napthalimide, a poly (ADP-ribose) polymerase inhibitor in experimental diabetic neuropathy
Life Sci.
(2008) Advanced glycation endproducts–role in pathology of diabetic complications
Diabetes Res. Clin. Pract.
(2005)- et al.
Functional and biochemical evidence indicating beneficial effect of Melatonin and Nicotinamide alone and in combination in experimental diabetic neuropathy
Neuropharmacology
(2010) - et al.
Concurrent targeting of nitrosative stress-PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy
Biochem. Biophys. Res. Commun.
(2010) - et al.
Nuclear factor Nrf2 and antioxidant response element regulate NRH:quinone oxidoreductase 2 (NQO2) gene expression and antioxidant induction
Free Radic. Biol. Med.
(2006) - et al.
Nrf2, a cap n collar transcription factor, regulates induction of the heme oxygenase-1 Gene
J. Biol. Chem.
(1999) Nrf2 signaling in coordinated activation of antioxidant gene expression
Free Radic. Biol. Med.
(2004)- et al.
NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector
Arch. Biochem. Biophys.
(2010)
Nrf2:INrf2 (Keap1) signaling in oxidative stress
Free Radic. Biol. Med.
Targeting NRF2 signaling for cancer chemoprevention
Toxicol. Appl. Pharmacol.
Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism
J. Biol. Chem.
Nrf2-mediated haeme oxygenase-1 up-regulation induced by cobalt protoporphyrin has antinociceptive effects against inflammatory pain in the formalin test in mice
Pain
Upregulation of thioredoxin system via Nrf2-antioxidant responsive element pathway in adaptive-retinal neuroprotection in vivo and in vitro
Free Radic. Biol. Med.
Sulforaphane protects against cytokine- and streptozotocin-induced beta-cell damage by suppressing the NF-kappaB pathway
Toxicol. Appl. Pharmacol.
Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes
J. Mol. Cell. Cardiol.
NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy
Biochem. Biophys. Res. Commun.
The role of vitamin E and oxidative stress in diabetes complications
Mech. Ageing. Dev.
Nrf2 regulates curcumin-induced aldose reductase expression indirectly via nuclear factor-kappaB
Pharmacol. Res.
Diabetic Autonomic Neuropathy
Diabetes Care
Pro-inflammatory mechanism in diabetic neuropathy: focus on the nuclear factor kappa b pathway
Curr. Drug Targets
Aldose reductase, still a compelling target for diabetic neuropathy
Curr. Drug Targets
The antioxidant response as a drug target in diabetic neuropathy
Curr. Drug Targets
Role of advanced glycation end products and their receptors in development of diabetic neuropathy
Ann. N. Y. Acad. Sci.
Development of selective axonopathy in adult sensory neurons isolated from diabetic rats: role of glucose-induced oxidative stress
Diabetes
High glucose-induced oxidative stress and mitochondrial dysfunction in neurons
FASEB J.
Mechanisms of disease: the oxidative stress theory of diabetic neuropathy
Rev. Endocr. Metab. Disord.
Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-kappaB and Nrf2 cascades
J. Pineal Res.
Cited by (120)
Chalcogenides-incorporating carbonic anhydrase inhibitors concomitantly reverted oxaliplatin-induced neuropathy and enhanced antiproliferative action
2021, European Journal of Medicinal ChemistrySuppressing BRD4 exhibits protective effects against vincristine-induced peripheral neuropathy by alleviating inflammation and oxidative stress
2020, Biochemical and Biophysical Research Communications