DW14006 as a Direct AMPKα Activator Ameliorates Diabetic Peripheral Neuropathy in Mice.

Abstract

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.

• Authors: 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
• Journal: Diabetes (Diabetes) Vol. 69 Issue 9 Pg. 1974-1988 (09 2020) ISSN: 1939-327X [Electronic] United States
• PMID: 32647036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by the American Diabetes Association.

Chemical References

• Blood Glucose
• Enzyme Activators
• AMPK alpha1 subunit, mouse
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Blood Glucose
• Diabetes Mellitus, Experimental (metabolism)
• Diabetic Neuropathies (drug therapy, metabolism)
• Enzyme Activators (pharmacology, therapeutic use)
• Ganglia, Spinal (drug effects, metabolism)
• Mice
• Neuronal Outgrowth (drug effects)
• Oxidative Stress (drug effects)