Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway

Emerging role of Nrf-2/HO-1 in pathogenesis of diabetic neuropathy has been suggested. Diabetic neuropathy is one of the most common complications of diabetes and more than 50% patients of diabetes develop diabetic neuropathy. Rutin has been well documented to show protective effect in various complications, e.g., diabetic neuropathy. However, its mechanistic insight is still not completely understood. The present study has been designed to explore the protective effect of rutin and its interaction with COX-2 inhibitor, nimesulide in diabetic neuropathy. DN (diabetic neuropathy) rats were maintained with or without rutin (100 and 200 mg/kg), nimesulide (5 and 10 mg/kg), and their combinations for 8 weeks. Body weight, serum glucose, pain assessment (mechanical allodynia, cold allodynia, mechanical hyperalgesia, and thermal hyperalgesia), and motor nerve conduction velocity (MNCV) were measured in all groups. Oxidative damage was assessed through biochemical estimation and mitochondrial ROS production, followed by inflammatory and apoptotic markers (TNF-alpha, caspase-3, Nrf-2, HO-1, and NF-kBp65) for their activity, protein, and gene expression. The structural changes were also reported through transmission electron microscope. Streptozotocin injection (55 mg/kg) induced diabetes reduced body weight, reduced the threshold for pain in various pain assessment parameters. Oxidative damage (increased MDA, decreased SOD, catalase, and GSH levels) increased mitochondrial ROS production followed by increased expression of inflammatory markers and decreased expression of Nrf-2/HO-1 in sciatic nerve. Treatment with rutin (100 and 200 mg/kg) and nimesulide (5 and 10 mg/kg) significantly attenuates these alterations as compared to DN control rats. Furthermore, combination of rutin (200 mg/kg) and nimesulide (10 mg/kg) significantly potentiated their protective effect which was significant as compared to their effect alone in streptozotocin-treated rats. The present study suggests the involvement of Nrf-2/HO-1 pathway in the protective effect of rutin against streptozotocin-induced diabetic neuropathy.