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

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.