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  3. Antispasmodic Drug Drofenine as an Inhibitor of Kv2.1 Channel Ameliorates Peripheral Neuropathy in Diabetic Mice

Antispasmodic Drug Drofenine as an Inhibitor of Kv2.1 Channel Ameliorates Peripheral Neuropathy in Diabetic Mice

  • iScience. 2020 Sep 28;23(10):101617. doi: 10.1016/j.isci.2020.101617.
Xiaoju Xu 1,  Xu Xu 1,  Yanping Hao 2 3,  Xialin Zhu 1,  Jian Lu 1,  Xingnan Ouyang 1,  Yin Lu 1,  Xi Huang 1,  Yang Li 2 3,  Jiaying Wang 1,  Xu Shen 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 3 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
PMID: 33089105 DOI: 10.1016/j.isci.2020.101617
Abstract

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 in vivo Kv2.1 knockdown through adeno associated virus AAV9-Kv2.1-RNAi. Streptozotocin (STZ) induced type 1 or db/db 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.

Keywords

Human Metabolism; Immunology.

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