Redox and bioenergetic modulation by eupatilin attenuated neuropathic allodynia in mice with diet-induced diabetes

<b>Objectives</b>: Painful diabetic neuropathy poses a devastating health burden, with one-third of diabetic patients being afflicted. Currently, most of the neuropathic pain drugs have shown insufficient efficacy, significant adverse reactions and poor patient compliance. Striving for improved neuropathic pain therapies is necessary in diabetic patients. This study aimed to investigate the potential antinociceptive effect of eupatilin, a natural flavonoid, against persistent neuropathic pain associated with diet-induced type 2 diabetes, and probe mechanism(s).<b>Methods:</b> C57BL6J male mice were fed with a high-fat diet for 8 weeks to induce type 2 diabetes. The von Frey test and the acetone test were used to assess pain-like behaviors, shown as neuropathic allodynia to mechanical and cold stimuli, respectively. Redox and bioenergetics-related mechanisms were investigated in vivo and in vitro.<b>Results:</b> Chronic eupatilin therapy not only ameliorated the established symptoms of mechanical and cold allodynia in mice with type 2 diabetes, but also decelerated pain development given preemptively at low doses. Although eupatilin did not impact metabolic features (body weight, food intake, blood glucose, glucose tolerance, glycosylated haemoglobin and insulin) in diabetic mice, it improved mitochondrial bioenergetics in dorsal root ganglion neurons, alleviated exacerbated oxidative stress in pain-associated tissues, and restored nerve conduction velocity and blood flow in sciatic nerves. Notably, the pain-alleviating actions of eupatilin were modified by pharmacologically manipulating mitochondrial bioenergetics and redox status.<b>Discussion:</b> These findings uncover the analgesic activity of eupatilin, an effect that suggests a causal association with its bioenergetics-enhancing and antioxidant effects, in mice with diet-induced type 2 diabetes.