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DW14006 as a direct AMPKα activator ameliorates diabetic peripheral neuropathy in mice

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posted on 09.07.2020 by Ada Admin, Xu Xu, Wei Wang, Zhengyu Wang, Jianlu Lv, Xiaoju Xu, Jiawen Xu, Juanzhen Yang, Xialin Zhu, Yin Lu, Wenhu Duan, Xi Huang, Jiaying Wang, Jinpei Zhou, Xu Shen
Diabetic peripheral neuropathy (DPN) is a long-term complication of diabetes with a complicated pathogenesis. AMP-activated protein kinase (AMPK) senses oxidative stress and mitochondrial function playing a central role in the regulation of DPN. Here, we reported that DW14006 (2-(3-(7-chloro-6-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinolin-3-yl)phenyl)acetic acid) as a direct AMPKα activator efficiently ameliorated DPN in both streptozotocin (STZ)-induced type 1 and BKS db/db type 2 diabetic mice. DW14006 administration highly enhanced neurite outgrowth of dorsal root ganglion (DRG) neuron and improved neurological function in diabetic mice. The underlying mechanisms have been intensively investigated. DW14006 treatment improved mitochondrial bioenergetics profiles and restrained oxidative stress and inflammation in diabetic mice by targeting AMPKa, which has been verified by assay against the STZ-induced diabetic mice injected with adeno associated virus AAV8-AMPKa-RNAi. To our knowledge, our work might be the first report on the amelioration of direct AMPKa activator on DPN by counteracting multiple risk factors including mitochondrial dysfunction, oxidative stress and inflammation, and DW14006 has been highlighted as a potential leading compound in the treatment of DPN.

Funding

This work was supported by National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (Number:2018ZX09711002), the National Natural Science Foundation for Young Scientists of China (81703806), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_1600), the Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (No. JKLPSE201801) and the Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine).

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