Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: Old perspective with a new angle

Abstract

Long-standing diabetes and complications thereof particularly, neuropathy stands for one of the major causes of morbidity across the globe. It is postulated that excessive production of reactive oxygen species is a key component in the development and progression of diabetic neuropathy. Oxidative damage is the most common concluding pathway for various pathogenetic mechanisms of neuronal injury in diabetic neuropathy. However despite optimistic preclinical data, it is still very ambiguous that why antioxidants have failed to demonstrate significant neuroprotection in humans. A growing body of evidences now suggests that strategies utilizing a more targeted approach like focusing on Nrf2 (a transcription factor modulating oxidative stress) may provide an enthralling avenue to optimize neuroprotection in diabetes and diabetic neuropathy. This review presents an emerging concept of Nrf2 in diabetic neuropathy; thus looking forward to newer strategies for combating the oxidant induced damage.

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.