Diphenyl diselenide alleviates diabetic peripheral neuropathy in rats with streptozotocin-induced diabetes by modulating oxidative stress.
Diphenyl diselenide alleviates diabetic peripheral neuropathy in rats with streptozotocin-induced diabetes by modulating oxidative stress.
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DOI：
10.1016/j.bcp.2020.114221
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发表时间：
2020-09
影响因子：
5.8
通讯作者：
Xing Wang;Yi Huan;Cai-na Li;Hui Cao;Su-juan Sun;Lei Lei-Lei;Quan Liu;Shuainan Liu;Wenming Ji;Hongmei Liu;Kaixun Huang;Jun Zhou;Z. Shen
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文献类型：
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作者：
Xing Wang;Yi Huan;Cai-na Li;Hui Cao;Su-juan Sun;Lei Lei-Lei;Quan Liu;Shuainan Liu;Wenming Ji;Hongmei Liu;Kaixun Huang;Jun Zhou;Z. Shen
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的一种很有前途的策略。二苯二硒是一种具有抗氧化药理活性的有机硒化合物。本研究旨在评价其对链脲佐菌素（STZ）诱导的糖尿病大鼠DPN的预防和治疗作用，并探讨其机制。在体外，RSC96细胞先暴露于高糖环境（100 mM），然后用不同浓度的DPDs（1、10、25和50 μM）处理。值得注意的是，DPDs通过降低活性氧（ROS）和丙二醛（MDA）水平，显著抑制高糖诱导的雪旺细胞毒性和氧化应激。此外，DPDs处理有效激活Nrf2信号，抑制Keap1表达。在Sprague-Dawley （SD）大鼠体内建立DPN模型，小鼠注射STZ (60 mg·kg - 1, ip)，并口服不同剂量的DPDs(5和15 mg·kg - 1·d - 1) 12周，或α硫辛酸（ALA, 100 mg kg - 1·d - 1）作为阳性对照。DPDs可显著提高DPN大鼠运动神经传导速度（MNCV），改善热、机械痛觉过敏和坐骨神经形态，改善血清和坐骨神经氧化应激。在机制上，DPDs降低了Keap1的水平，刺激了坐骨神经中的Nrf2信号。综上所述，本研究结果表明，DPDs通过激活Nrf2/Keap1信号通路来改善实验性DPN。DPDs可能是DPN的一种新的替代治疗方法。
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−1, ip) and orally administered either different doses of DPDs (5 and 15 mg· kg−1· d−1) for 12 weeks or alpha lipoic acid (ALA, 100 mg kg−1·d−1) 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.