Inhibition of IκB kinase (IKK) protects against peripheral nerve dysfunction of experimental diabetes

Abstract

Nuclear factor-κB (NF-κB) has been reported as a critical component of signalling mechanisms involved in the pathogenesis of a number of inflammatory conditions. Previous reports have shown that anti-inflammatory agents have a protective role in experimental diabetic neuropathy. Here, we assessed whether the inhibition of NF-κB cascade via IκB kinase (IKK) exerts any neuroprotective effect in experimental diabetic neuropathy. IKK inhibitor SC-514 (1 and 3 mg/kg) was administered daily for 2 weeks starting after 6 weeks of streptozotocin-induced diabetes. Nerve conduction and blood flow were determined by Powerlab and LASER Doppler system, respectively. We evaluated the changes in NF-κB, iNOS, and COX-2 expression by Western blotting in sciatic nerve. We found that IKK inhibition with SC-514 increased nerve blood flow and conduction velocity and improved pain threshold in diabetic animals. SC-514 also reduced the expression of NF-κB and phosphorylation of IKKβ in the sciatic nerve. Treatment with SC-514 reduced the elevated levels of pro-inflammatory cytokines (TNF-α and IL-6), iNOS, and COX-2. SC-514 reduces the expression of NF-κB and its downstream inflammatory components which may be involved in the improvement in nerve functions and pain perception in diabetic neuropathy. From the data of the present study, we suggest that diminution in IKK can be exploited as a drug target to significantly reduce the development of long-term complications of diabetes, particularly neuropathy.