Xu Xiaoju, Xu Xu, Hao Yanping, Zhu Xialin, Lu Jian, Ouyang Xingnan, Lu Yin, Huang Xi, Li Yang, Wang Jiaying, Shen Xu
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
iScience. 2020 Sep 28;23(10):101617. doi: 10.1016/j.isci.2020.101617. eCollection 2020 Oct 23.
Diabetic peripheral neuropathy (DPN) is a common diabetic complication and has yet no efficient medication. Here, we report that antispasmodic drug drofenine (Dfe) blocks Kv2.1 and ameliorates DPN-like pathology in diabetic mice. The underlying mechanisms are investigated against the DPN mice with Kv2.1 knockdown through adeno associated virus AAV9-Kv2.1-RNAi. Streptozotocin (STZ) induced type 1 or type 2 diabetic mice with DPN exhibited a high level of Kv2.1 protein in dorsal root ganglion (DRG) tissue and a suppressed neurite outgrowth in DRG neuron. Dfe promoted neurite outgrowth by inhibiting Kv2.1 channel and/or Kv2.1 mRNA and protein expression level. Moreover, it suppressed inflammation by repressing IκBα/NF-κB signaling, inhibited apoptosis by regulating Kv2.1-mediated Bcl-2 family proteins and Caspase-3 and ameliorated mitochondrial dysfunction through Kv2.1/CaMKKβ/AMPK/PGC1α pathway. Our work supports that Kv2.1 inhibition is a promisingly therapeutic strategy for DPN and highlights the potential of Dfe in treating this disease.
糖尿病周围神经病变（DPN）是一种常见的糖尿病并发症，目前尚无有效的治疗药物。在此，我们报告解痉药曲马多（Dfe）可阻断Kv2.1，并改善糖尿病小鼠的DPN样病理变化。通过腺相关病毒AAV9-Kv2.1-RNAi敲低Kv2.1，对DPN小鼠的潜在机制进行了研究。链脲佐菌素（STZ）诱导的1型或2型糖尿病伴DPN小鼠的背根神经节（DRG）组织中Kv2.1蛋白水平较高，DRG神经元的神经突生长受到抑制。Dfe通过抑制Kv2.1通道和/或Kv2.1 mRNA及蛋白表达水平来促进神经突生长。此外，它通过抑制IκBα/NF-κB信号通路来抑制炎症，通过调节Kv2.1介导的Bcl-2家族蛋白和半胱天冬酶-3来抑制细胞凋亡，并通过Kv2.1/CaMKKβ/AMPK/PGC1α途径改善线粒体功能障碍。我们的研究支持抑制Kv2.1是一种有前景的DPN治疗策略，并突出了Dfe治疗该疾病的潜力。
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