File:PMC3757712 gr2 (1).png

English⧼Colon⧽ f0010: Role of NF-κB and Nrf2 in diabetic neuropathy. Hyperglycaemia induced imbalance in Nrf2–NF-κB regulation can contribute to the pathogenesis of diabetic neuropathy. Enhanced NF-κB activity during the hyperglycaemic state is associated with excess production of proinflammatory cytokines such as IL-6, TNF-α, COX-2 and iNOS. These proteins and enzymes are prerequisite mediators for the initiation and amplification of inflammatory processes in neuronal cells [9]. Reduced Nrf2 activity results in impaired antioxidant defence and is characterized by decline in superoxide dismutase (SOD), catalase and glutathione (GSH) levels. Additionally, it decreases the production of detoxifying enzymes such as, haem-oxygenase-1 (HO-I) and NADPH quinone oxidoreductase (NQO1), leading to nitrosative and oxidative stress [14]. Neuroinflammation due to elevated NF-κB can also activate microglia and astrocytes, which further augments the release of proinflammatory mediators, thus develops a vicious cycle of inflammation. Release of algogenic mediators, such as prostaglandins, bradykinins and chemokines due to neuroinflammation, can sensitise the nerve fibres to painful stimulus and end up in sensorimotor alterations [10]. NF-κB mediated neuroinflammation can also result in endoneurial hypoxia due to decreased blood supply to the nervous tissue and ganglion [9]. This neuronal hypoxic condition leads to dysfunction of mitochondrial electron transport chain (etc), decreased efficiency of mitochondria, and results in increased ROS production. Nitrosative and oxidative stress generated in the nerve cells can also lead to increased AGE formation and protein kinase C (PKC) activation [7] and increased peroxynitrite mediated PARP over-activation and apoptosis. The manifestations of neuroinflammation and oxidative stress can cumulatively cause the structural damage which can lead to the functional, sensorimotor and biochemical deficits which are characteristic of diabetic neuropathy.