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

<a>Diabetic peripheral neuropathy</a> (DPN) is a long-term complication of diabetes with a complicated pathogenesis. <a></a><a>AMP-activated protein kinase (</a><a></a><a>AMPK) </a>senses oxidative stress <a></a><a>and </a><a>mitochondrial function</a> playing a central role in the regulation of DPN. Here, we reported that DW14006 <a></a><a></a><a></a><a>(</a><a>2-(3-(7-chloro-6-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinolin-3-yl)phenyl)acetic acid)</a> as a direct AMPKα activator efficiently ameliorated <a>DPN in both</a><a> streptozotocin</a> (STZ)-induced type 1 and BKS <i>db/<a></a><a></a><a>db</a></i> type 2 diabetic mice. <a></a><a></a><a>DW14006 administration highly enhanced neurite outgrowth of dorsal root </a><a>ganglion</a> (DRG) neuron and <a></a><a>improved neurological function</a> in diabetic mice. <a></a><a></a><a>The underlying mechanisms have been intensively investigated. DW14006 treatment improved mitochondrial </a><a></a><a>bioenergetics</a> profiles and <a></a><a>restrained </a>oxidative stress and inflammation in <a>diabetic mice</a> by targeting AMPKa, which has been verified by assay against the STZ-induced diabetic mice injected with <a></a><a>adeno associated virus AAV</a>8-AMPKa-RNAi. <a></a>To our knowledge, our work might be the first report on the amelioration of direct AMPKa activator on DPN by counteracting <a>multiple risk factors</a> including <a>mitochondrial dysfunction, oxidative stress and inflammation</a>, and DW14006 has been highlighted as a potential leading compound in the treatment of DPN.