The Natural Rotenoid Deguelin Ameliorates Diabetic Neuropathy by Decreasing Oxidative Stress and Plasma Glucose Levels in Rats via the Nrf2 Signalling Pathway

Abstract Background/Aims: Deguelin is a natural rotenoid that shows anti-inflammatory and antimicrobial activities. Rotenoids prevent oxidative damage and potentiate natural antioxidant activity in diabetic conditions, suggesting utility in treating diabetes and its complications. Here, we evaluate the potential efficacy of deguelin against diabetic neuropathy (DN). Methods: DN was induced by streptozotocin followed by daily treatment with deguelin (4, 6 or 8 mg/kg) for 14 days. Blood glucose was measured, neurobehavioral tests for nociception and motor coordination were performed, and neuron conduction velocities were analysed electrophysiologically. We also assessed (Na+-K+) ATPase activity, performed a reactive oxygen species assay, measured the levels of various markers of oxidative stress, and of hydrogen sulphide (H2S) in dorsal root ganglion (DRG) neurons, conducted immunoblotting studies for proteins and ELISA for inflammatory cytokines. Results: Deguelin significantly suppressed mechanical and thermal hyperalgesia, as well as cold allodynia, and partially restored the conduction velocities of neurons in DN rats. Significantly decreased expression levels of capspase-3 in DRG neurons, and increased (Na+-K+) ATPase activity in sciatic nerves, were observed. In addition, deguelin decreased glucose levels, attenuated oxidative stress and neuroinflammation, and elevated levels of H2S, nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1, suggesting a disease-attenuating effect of deguelin in DN rats. To shed light on the underlying mechanism of action of deguelin, insulin- and dimethyl fumarate (BG-12)-treated groups were also included. Insulin suppressed glucose levels and BG-12 produced effects on Nrf2 levels similar to 8 mg/kg deguelin, confirming involvement of the Nrf2 pathway in the beneficial effects of deguelin against DN. Conclusions: Deguelin attenuated DN by decreasing oxidative stress and plasma glucose levels via the Nrf2 signalling pathway.