Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Biochem Pharmacol. 2020 Dec;182:114221. doi: 10.1016/j.bcp.2020.114221. Epub 2020 Sep 16.
Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients. Oxidative stress (OS) plays a key role in the pathogenesis of DPN; thus, antioxidant therapy is considered a promising strategy for treating DPN. Diphenyl diselenide (DPDs) is an organic selenium compound with antioxidant pharmacological activities. This study aimed to evaluate its preventive and therapeutic effects on DPN in rats with streptozotocin (STZ)-induced diabetes and explore the underlying mechanisms. In vitro, RSC96 cells were exposed to high glucose (100 mM) and then treated with different concentrations of DPDs (1, 10, 25 and 50 μM). Notably, DPDs markedly suppressed high glucose-induced cytotoxicity and oxidative stress in Schwann cells by decreasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Furthermore, the DPDs treatment effectively activated Nrf2 signaling and inhibited Keap1 expression. An in vivo DPN model was established in Sprague-Dawley (SD) rats injected with STZ (60 mg·kg, ip) and orally administered either different doses of DPDs (5 and 15 mg· kg· d) for 12 weeks or alpha lipoic acid (ALA, 100 mg kg·d) as a positive control. The administration of DPDs significantly increased the motor nerve conduction velocity (MNCV), improved thermal and mechanical hyperalgesia and the sciatic nerve morphology, and ameliorated oxidative stress in the serum and the sciatic nerve of rats with DPN. Mechanistically, DPDs reduced the level of Keap1 and stimulated Nrf2 signaling in the sciatic nerve. Taken together, the results of this study indicate that DPDs ameliorates experimental DPN as an antioxidant by activating the Nrf2/Keap1 signaling pathway. DPDs may represent a new alternative treatment for DPN.
糖尿病周围神经病变（DPN）是 1 型和 2 型糖尿病患者最常见的微血管并发症之一。氧化应激（OS）在 DPN 的发病机制中起关键作用；因此，抗氧化治疗被认为是治疗 DPN 的一种有前途的策略。二苯并二硒醚（DPD）是一种具有抗氧化药理活性的有机硒化合物。本研究旨在评估其对链脲佐菌素（STZ）诱导的糖尿病大鼠 DPN 的预防和治疗作用，并探讨其潜在机制。在体外，将 RSC96 细胞暴露于高葡萄糖（100mM）中，然后用不同浓度的 DPD（1、10、25 和 50μM）处理。值得注意的是，DPD 通过降低活性氧（ROS）和丙二醛（MDA）水平，显著抑制高葡萄糖诱导的施万细胞毒性和氧化应激。此外，DPD 处理有效激活了 Nrf2 信号通路并抑制了 Keap1 的表达。通过向 Sprague-Dawley（SD）大鼠注射 STZ（60mg·kg，ip）建立体内 DPN 模型，并口服给予不同剂量的 DPD（5 和 15mg·kg·d）12 周或作为阳性对照的α-硫辛酸（ALA，100mg·kg·d）。DPD 的给药显著增加了运动神经传导速度（MNCV），改善了热和机械性痛觉过敏以及坐骨神经形态，并改善了 DPN 大鼠血清和坐骨神经中的氧化应激。从机制上讲，DPD 降低了坐骨神经中 Keap1 的水平并刺激了 Nrf2 信号通路。总之，这项研究的结果表明，DPD 通过激活 Nrf2/Keap1 信号通路来改善实验性 DPN 作为抗氧化剂。DPD 可能成为治疗 DPN 的一种新的替代方法。
