RT Journal Article
SR Electronic
T1 DW14006 as a Direct AMPKα Activator Ameliorates Diabetic Peripheral Neuropathy in Mice
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 1974
OP 1988
DO 10.2337/db19-1084
VO 69
IS 9
A1 Xu, Xu
A1 Wang, Wei
A1 Wang, Zhengyu
A1 Lv, Jianlu
A1 Xu, Xiaoju
A1 Xu, Jiawen
A1 Yang, Juanzhen
A1 Zhu, Xialin
A1 Lu, Yin
A1 Duan, Wenhu
A1 Huang, Xi
A1 Wang, Jiaying
A1 Zhou, Jinpei
A1 Shen, Xu
YR 2020
UL http://diabetes.diabetesjournals.org/content/69/9/1974.abstract
AB 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 plays 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 neurons 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 AMPKα, which has been verified by assay against the STZ-induced diabetic mice injected with adeno-associated virus 8–AMPKα–RNAi. To our knowledge, our work might be the first report on the amelioration of the direct AMPKα 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.