Resveratrol Modulates Diabetes-Induced Neuropathic Pain, Apoptosis, and Oxidative Neurotoxicity in Mice Through TRPV4 Channel Inhibition

Diabetic peripheral neuropathy (DPN) is caused by several factors, including reactive free oxygen radicals (ROS)-induced excessive Ca2+ influx. Transient receptor potential (TRP) vanilloid 4 (TRPV4) is a member of the Ca2+-permeable TRP superfamily. Resveratrol (RESV) has been extensively utilized in TRP channel regulation due to its pharmacological properties, which include antioxidant and TRP inhibitory effects. The protective function of RESV and the contribution of TRPV4 to streptozotocin (STZ)-induced neuropathic pain in mice are still unclear. Here, we evaluated the effects of RESV through the modulation of TRPV4 on Ca2+ influx, ROS-mediated pain, apoptosis, and oxidative damage in the mouse dorsal root ganglion (DRGs). From the 32 mice, four groups were induced: control, RESV, STZ, and STZ + RESV. We found that the injection of RESV reduced the changes caused by the STZ-induced stimulation of TRPV4, which in turn increased mechanical/thermal neuropathic pain, cytosolic Ca2+ influx, TRPV4 current density, oxidants (lipid peroxidation, mitochondrial ROS, and cytosolic ROS), and apoptotic markers (caspase-3, -8, and -9). The RESV injection also increased the STZ-mediated reduction of viability of DRG and the amounts of glutathione, glutathione peroxidase, vitamin A, beta-carotene, and vitamin E in the brain, erythrocytes, plasma, liver, and kidney. All of these findings suggest that TRPV4 stimulation generates oxidative neurotoxicity, neuropathic pain, and apoptosis in the STZ-induced diabetic mice. On the other hand, neurotoxicity and apoptosis were reduced due to the downregulation of TRPV4 carried out through the RESV injection.Graphical AbstractAn overview of how resveratrol (RESV) inhibits TRPV4 in mice to modulate the effects of diabetes mellitus-induced diabetic peripheral neuropathy (DPN). Ruthenium red (RuR) inhibits TRPV4, while GSK1016790A (GSK) and reactive free oxygen radicals (ROS) activate it. In the mitochondria of DRGs, the glucose oxidation brought on by diabetes mellitus (STZ) causes an intracellular free Ca2+ and Zn2+ influx excess that is dependent on TRPV4. The administration of STZ leads to the DRG becoming more depolarized (Delta Psi m), which in turn causes an increase in mitochondrial ROS, apoptosis, and caspases (caspase-3, caspase-8, and caspase-9) by downregulating enzymatic (glutathione peroxidase, GSH-Px) and non-enzymatic (glutathione (GSH), vitamin A, and vitamin E) antioxidants. The mice's molecular pathways were diminished by the RESV injections. (Increase (up arrow); diminish (down arrow))