Suppression of NF-κB and NF-κB regulated oxidative stress and neuroinflammation by BAY 11-7082 (IκB phosphorylation inhibitor) in experimental diabetic neuropathy.

Abstract

Inflammation is an emerging patho-mechanism of diabetes and its complications. NF-κB pathway is one of the central machinery initiating and propagating inflammatory responses. The present study envisaged the involvement of NF-κB inflammatory cascade in the pathophysiology of diabetic neuropathy using BAY 11-7082, an IκB phosphorylation inhibitor. Streptozotocin was used to induce diabetes in Sprauge Dawley rats. BAY 11-7082 (1 & 3 mg/kg) was administered to diabetic rats for 14 days starting from the end of six weeks post diabetic induction. Diabetic rats developed deficits in nerve functions and altered nociceptive parameters and also showed elevated expression of NF-κB (p65), IκB and p-IκB along with increased levels of IL-6 & TNF-α and inducible enzymes (COX-2 and iNOS). Furthermore, there was an increase in oxidative stress and decrease in Nrf2/HO-1 expression. We observed that BAY 11-7082 alleviated abnormal sensory responses and deficits in nerve functions. BAY 11-7082 also ameliorated the increase in expression of NF-κB, IκB and p-IκB. BAY 11-7082 curbed down the levels of IL-6, TNF-α, COX-2 and iNOS in the sciatic nerve. Lowering of lipid peroxidation and improvement in GSH levels was also seen along with increased expression of Nrf2/HO-1. Thus it can be concluded that NF-κB expression and downstream expression of proinflammatory mediators are prominent features of nerve damage leading to inflammation and oxidative stress and BAY 11-7082 was able to ameliorate experimental diabetic neuropathy by modulating neuroinflammation and improving antioxidant defence.

• Authors: Ashutosh Kumar, Geeta Negi, Shyam S Sharma
• Journal: Biochimie (Biochimie) Vol. 94 Issue 5 Pg. 1158-65 (May 2012) ISSN: 1638-6183 [Electronic] France
• PMID: 22342224 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Interleukin-6
• NF-kappa B
• Nitriles
• Sulfones
• Thiobarbituric Acid Reactive Substances
• Tumor Necrosis Factor-alpha
• Malondialdehyde
• Glutathione

Topics

• Animals
• Blotting, Western
• Diabetic Neuropathies (drug therapy, metabolism)
• Glutathione (metabolism)
• Immunohistochemistry
• Inflammation (drug therapy, metabolism)
• Interleukin-6 (metabolism)
• Male
• Malondialdehyde (metabolism)
• NF-kappa B (metabolism)
• Nitriles (pharmacology)
• Oxidative Stress (drug effects)
• Rats
• Rats, Sprague-Dawley
• Sulfones (pharmacology)
• Thiobarbituric Acid Reactive Substances (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)