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.

Neuroprotective Effect of Salvianolic Acid A against Diabetic Peripheral Neuropathy through Modulation of Nrf2

“…However, if oxidative stress persistently exists, the inflammation will cause the progressive tissue damage. Recent findings showed that Morin and natural rotenoid deguelin exerted neuroprotection in experimental diabetic neuropathy through antioxidative stress and antineuroinflammation [7,25]. Thus, targeting the cellular oxidative stress and inflammation pathway will be likely important therapeutic approaches in the future to reduce the incidence of diabetic neuropathy.…”

<p>Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities of Nesfatin-1: A Review</p>

“…More recently, the neuroprotective effect of nesfatin-1 in PD was further confirmed through in vivo and in vitro experiments, which showed that the antiapoptotic C-Raf-extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway mediates the protective effect of nesfatin-1 on dopaminergic neurons against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)induced neurotoxicity in C57BL/6 mice and 1-methyl-4-phenylpyridillium ion (MPP + )-induced cytotoxicity in MES23.5 cells. 45 Diabetic neuropathy (DN), one of the most debilitating outcomes of diabetes mellitus, is thought to be the consequence of oxidative stress, 46 inflammation, 47 and neural apoptosis. 48 More specifically, increased glucose levels damage the mitochondrial membrane and respiratory chain, resulting in the production of large amounts of ROS, 49 which accelerate the damage of lipids, proteins, and nucleic acids, and eventually lead to inflammation and neural apoptosis.…”

“…Diabetic neuropathy (DN), one of the most debilitating outcomes of diabetes mellitus, is thought to be the consequence of oxidative stress, 46 inflammation, 47 and neural apoptosis. 48 More specifically, increased glucose levels damage the mitochondrial membrane and respiratory chain, resulting in the production of large amounts of ROS, 49 which accelerate the damage of lipids, proteins, and nucleic acids, and eventually lead to inflammation and neural apoptosis.…”

The Coming Age of Flavonoids in the Treatment of Diabetic Complications

“…Catechin, in a model of STZ-diabetic induced rats, was able to reduce the neuronal damage by increasing SOD and CAT, and reducing MDA and lymphocyte infiltration in nerve tissues [93]. Deguelin also ameliorates diabetic neuropathy, attenuated oxidative stress and neuroinflammation through the activation of NRF2 pathway, and partially restored the conduction velocities of neurons in diabetic rats by increasing (Na + -K + ) ATPase activity [94]. A similar neuroprotective effect against oxidative stress and inflammation was reported for phloretin, which either alone or in combination with the anti-neuropathic agent duloxetine promoted nerve fiber regeneration in STZ-induced diabetic rats [95].…”