Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain


METABOLIC BRAIN DISEASE, vol.31, no.2, pp.385-393, 2016 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 31 Issue: 2
  • Publication Date: 2016
  • Doi Number: 10.1007/s11011-015-9769-7
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.385-393
  • Süleyman Demirel University Affiliated: Yes


N-acetylcysteine (NAC) is a sulfhydryl donor antioxidant that contributes to the regeneration of glutathione (GSH) and also scavengers via a direct reaction with free oxygen radicals. Recently, we observed a modulatory role of NAC on GSH-depleted dorsal root ganglion (DRG) cells in rats. NAC may have a protective role on oxidative stress and calcium influx through regulation of the TRPM2 channel in diabetic neurons. Therefore, we investigated the effects of NAC on DRG TRPM2 channel currents and brain oxidative stress in streptozotocin (STZ)-induced diabetic rats. Thirty-six rats divided into four groups: control, STZ, NAC and STZ + NAC. Diabetes was induced in the STZ and STZ + NAC groups by intraperitoneal STZ (65 mg/kg) administration. After the induction of diabetes, rats in the NAC and STZ + NAC groups received NAC (150 mg/kg) via gastric gavage. After 2 weeks, DRG neurons and the brain cortex were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM2 currents in the DRG following diabetes induction with STZ were gated by H2O2. TRPM2 channel current densities in the DRG and lipid peroxidation levels in the DRG and brain were higher in the STZ groups than in controls; however, brain GSH, GSH peroxidase (GSH-Px), vitamin C and vitamin E concentrations and DRG GSH-Px activity were decreased by diabetes. STZ + H2O2-induced TRPM2 gating was totally inhibited by NAC and partially inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2-APB). GSH-Px activity and lipid peroxidation levels were also attenuated by NAC treatment. In conclusion, we observed a modulatory role of NAC on oxidative stress and Ca2+ entry through the TRPM2 channel in the diabetic DRG and brain. Since excessive oxidative stress and overload Ca2+ entry are common features of neuropathic pain, our findings are relevant to the etiology and treatment of pain neuropathology in DRG neurons.