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DW14006 as a direct AMPKα activator ameliorates diabetic peripheral neuropathy in mice
figure
posted on 2020-07-09, 13:47 authored by Ada AdminAda 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 ShenDiabetic 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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