JSH-23 targets nuclear factor-kappa B and reverses various deficits in experimental diabetic neuropathy: effect on neuroinflammation and antioxidant defence

Aim: Nuclear factor-kappa B (NF-κB) being reported to play an important role in the pathogenesis of diabetic neuropathy is believed to be a central mechanism involved in the genesis and promulgation of inflammatory insult. Here we have targeted the nuclear translocation of NF-κB using JSH-23 to elucidate its role in diabetic neuropathy.

Methods: JSH-23 (1 and 3 mg/kg) was administered for 2 weeks in diabetic rats, after 6 weeks of diabetes induction using streptozotocin (55 mg/kg) as diabetogenic agent. Functional (motor nerve conduction velocity and blood flow), behavioural (mechanical hyperalgesia), biochemical [malondialdehyde, glutathione, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels] and NF-κB translocation studies (western blot technique) were then undertaken.

Results: JSH-23 treatment significantly reversed the nerve conduction and nerve blood flow deficits seen in diabetic Animals. Reduction in mechanical pain threshold was also partially corrected by the treatment. Protein expression studies showed that nuclear translocation of p65/p50 subunit was inhibited by JSH-23 treatment in the sciatic nerve. The treatment also lowered the elevated IL-6, TNF-α, cyclo-oxygenase (COX-2) and inducible nitric oxide synthase (iNOS) levels/expression, indicating reduction in the inflammatory damage of the sciatic nerve. Apart from these effects, JSH-23 also increased Nrf2 and hemeoxygenase-1 (HO-1) levels which could imply its potential in increasing the strength of antioxidant defence.

Conclusion: We observed that NF-κB inhibition partially reversed functional, behavioural and biochemical deficits with JSH-23 treatment. This study substantiates the role of NF-κB activation in the aetiology of diabetic neuropathy and protection afforded by inhibition of NF-κB by JSH-23, which can be attributed to its effect on neuroinflammation and oxidative stress.