Neuropharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, 160014, India.
National Agri-Food Biotechnology Institute (NABI), Sector-81, SAS Nagar, Mohali, 140306, Punjab, India.
Inflammopharmacology. 2018 Jun;26(3):755-768. doi: 10.1007/s10787-017-0413-5. Epub 2017 Nov 1.
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-α, 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.
已有研究表明，Nrf-2/HO-1 在糖尿病性神经病发病机制中起重要作用。糖尿病性神经病是糖尿病最常见的并发症之一，超过 50%的糖尿病患者会发生糖尿病性神经病。芦丁已被充分证明在各种并发症（如糖尿病性神经病）中具有保护作用。然而，其作用机制尚不完全清楚。本研究旨在探讨芦丁的保护作用及其与 COX-2 抑制剂尼美舒利在糖尿病性神经病中的相互作用。DN（糖尿病性神经病）大鼠给予或不给予芦丁（100 和 200mg/kg）、尼美舒利（5 和 10mg/kg）及其组合治疗 8 周。所有组均测量体重、血清葡萄糖、疼痛评估（机械性痛觉过敏、冷觉过敏、机械性痛觉过敏和热痛觉过敏）和运动神经传导速度（MNCV）。通过生化评估和线粒体 ROS 产生来评估氧化损伤，然后评估炎症和凋亡标志物（TNF-α、caspase-3、Nrf-2、HO-1 和 NF-kBp65）的活性、蛋白和基因表达。通过透射电子显微镜还报告了结构变化。链脲佐菌素（55mg/kg）注射诱导糖尿病导致体重减轻，各种疼痛评估参数的疼痛阈值降低。氧化损伤（增加 MDA，减少 SOD、过氧化氢酶和 GSH 水平）增加线粒体 ROS 产生，随后坐骨神经中炎症标志物表达增加，Nrf-2/HO-1 表达减少。与 DN 对照组大鼠相比，芦丁（100 和 200mg/kg）和尼美舒利（5 和 10mg/kg）治疗可显著减轻这些改变。此外，芦丁（200mg/kg）和尼美舒利（10mg/kg）联合使用可显著增强其保护作用，与链脲佐菌素处理大鼠单独使用相比，其作用更为显著。本研究表明，Nrf-2/HO-1 通路参与了芦丁对链脲佐菌素诱导的糖尿病性神经病的保护作用。
