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Modulation of Nrf2 and NF‐κB Counteracts Multiple Manifestations of Experimental Diabetic Neuropathy: Potential of Sulforaphane and Melatonin

In the recent years Nrf2 and NF‐κB have surfaced as two transcription factors orchestrating antioxidant defense and inflammation, respectively. Since oxidative stress and inflammation play a pivotal role in nerve dysfunction and damage in diabetic neuropathy, Nrf2 and NF‐κB could be major players here too. For in vitro experiments neuro2a cells were incubated with sulforaphane and melatonin (both possess dual antioxidant and anti‐inflammatory activities) in the presence of normal (5.5 mM) and high glucose (30 mM). For in vivo studies, sulforaphane and melatonin were administered to rats 6 weeks post diabetes induction for 14 days. Motor nerve conduction velocity, nerve blood flow and pain behavior were improved and malondialdehyde level was reduced by treatment. Antioxidant effect of both agents was derived from Nrf2 as demonstrated by increased expression of Nrf2 and downstream targets HO‐1 and NQO‐1 in neuro2a cells and sciatic nerve of diabetic animals. NF‐κB inhibition may be responsible for their antiinflammatory activity as there was reduction in its expression and IκB kinase (IKK) phosphorylation along with abrogation of proinflammatory mediators. This study supports the defensive role of Nrf2 under conditions of oxidative stress and also suggests that NF‐κB is an important modulator of inflammatory damage in diabetic neuropathy. Funded by Ministry of Chemicals and Fertilizers, Government of India.