University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India.
Food Funct. 2020 May 1;11(5):4548-4560. doi: 10.1039/c9fo00881k. Epub 2020 May 13.
Diabetes mellitus is a serious debilitating epidemic affecting all social strata, imposing huge health, social and economic burdens. Diabetic neuropathic pain, an important microvascular complication of diabetes mellitus, characterized by allodynia and hyperalgesia, is recognized as one of the most difficult types of pain to treat. The development of tolerance, inadequate relief and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. Reactive oxygen/nitrogen species, cytokines and matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diabetic neuropathy. The present study was designed to explore the effect of naringenin, a citrus flavonoid, on streptozotocin induced diabetic neuropathic pain in Wistar rats. After 8 weeks of diabetes induction, rats developed neuropathy which was evident from marked hyperalgesia and allodynia associated with enhanced oxidative-nitrosative stress, release of inflammatory mediators (TNF-α, TGF-1β), MMP-9 activation and decreased motor nerve conduction velocity. Treatment with naringenin (25, 50, 100 mg kg) for 4 weeks starting from the 5th week of streptozotocin injection significantly attenuated behavioral, biochemical and molecular changes, along with alterations in motor nerve conduction velocity in a dose-dependent manner. Moreover, diabetic rats treated with insulin-naringenin combination produced a more pronounced effect as compared to individual drugs. The major finding of the study is that insulin alone corrected the hyperglycemia and partially reversed the pain response in diabetic rats. However, combination with naringenin not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory cytokine release and MMP inhibition in the diabetic rats. Modulation of MMP-9 by a natural flavonoid like naringenin seems to be a novel approach to target diabetic neuropathic pain.
糖尿病是一种严重的衰弱性流行病，影响所有社会阶层，给健康、社会和经济带来巨大负担。糖尿病性神经病理性疼痛是糖尿病的一种重要微血管并发症，其特征为感觉异常和痛觉过敏，被认为是最难治疗的疼痛类型之一。经典镇痛剂的耐受性发展、缓解不足和潜在毒性，促使人们研究新的药物来缓解这种疼痛。活性氧/氮物种、细胞因子和基质金属蛋白酶 (MMPs) 参与了糖尿病神经病变的发病机制。本研究旨在探讨柚皮素（一种柑橘类黄酮）对链脲佐菌素诱导的 Wistar 大鼠糖尿病性神经病理性疼痛的影响。在糖尿病诱导 8 周后，大鼠出现了神经病，表现为明显的痛觉过敏和感觉异常，伴有氧化-硝化应激增强、炎症介质（TNF-α、TGF-β1）释放、MMP-9 激活和运动神经传导速度降低。从链脲佐菌素注射后的第 5 周开始，用柚皮素（25、50、100mg/kg）治疗 4 周，可显著减轻行为、生化和分子变化，并以剂量依赖性方式改变运动神经传导速度。此外，与单独使用药物相比，用胰岛素-柚皮素联合治疗的糖尿病大鼠产生了更明显的效果。研究的主要发现是，胰岛素单独纠正了高血糖，并部分逆转了糖尿病大鼠的疼痛反应。然而，与柚皮素联合使用不仅减轻了糖尿病状况，而且通过调节氧化-硝化应激、炎症细胞因子释放和 MMP 抑制，逆转了糖尿病大鼠的神经病理性疼痛。天然黄酮类化合物如柚皮素对 MMP-9 的调节似乎是一种针对糖尿病性神经病理性疼痛的新方法。
