Neuroinflammation and Oxidative Stress in Diabetic Neuropathy: Futuristic Strategies Based on These Targets

Figure 2

Crosstalk between oxidative stress and inflammation. Hyperglycemia mediated oxidative stress and inflammatory pathways are known to interact with each other at various levels. ROS activates nuclear factor (erythroid-1) related factor (Nrf2) by directly oxidising the thiol residues on kelch-like ECF associated protein (Keap-1). Nrf2 then migrates into the nucleus to activate antioxidant response elements (ARE) of genome. However, this Nrf2 activation by hyperglycemia is inhibited through extracellular related kinase activation (ERK). ROS also activates inhibitory kappa B kinase (IKK), which then phosphorylates the inhibitory kappa B protein (IκB); the latter combines with cytosolic NF-κB complex ant thus preventing its transcription. Phosphorylation of IκB labels it for ubiquitination and proteasomal degradation and, hence, releases NF-κB complex to enter into nucleus, which then expresses several proinflammatory mediators. Similarly, oxidative stress mediated c-JUN N terminal kinases (JNK) activation mediates the c-JUN component of activator protein-1 (AP-1) activation, which then combines with c-FOS subunit. The resulting AP-1 heterodimer binds with genome and increases production of various vascular inflammatory mediators. Oxidative stress mediated PARP activation also leads to inflammation through necrotic cell death. Nrf2 inhibits IκB degradation and thus prevents NF-κB mediated inflammation. NF-κB also prevents the Nrf2 signalling through histone deacetylases (HDAC3) recruitment (ASK-1-apoptosis signalling related kinase-1 and MCP-1-monocyte chemoattractant protein-1).