Carbon disulfide activates p62-Nrf2-keap1 pathway in rat nerve tissues

Highlights: • The administration of CS₂ activated Nrf2-ARE machinery in rat nerve tissues. • CS₂ enhanced p62-mediated keap1 inactivation. • CS₂ treatment resulted in the activation of calcium-dependent kinase pathway in rat nerve tissues. - Abstract: Oxidative stress is associated with the pathogenesis of carbon disulfide (CS₂) induced polyneuropathy. The nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in protecting cells against oxidative stress. However, whether there exists a Nrf2-mediated antioxidative machinery in CS₂-induced neuropathy has not been elucidated. In the present study, male wistar rats were randomly divided into three experimental groups and one control group. The rats in experimental groups were treated with CS₂ by gavage at dosages of 200, 400 and 600 mg/kg/day respectively, six times per week for 6 weeks. Nrf2-keap1 antioxidative pathway and p62-related kinase signaling in rat nerve tissues was examined by western blotting and real-time PCR. The results demonstrated that CS₂ treatment resulted in Nrf2 translocation from the cytosol to the nucleus in rat spinal cords. In the meantime, the expression of antioxidative enzymes such as NAD(P)H quinone oxidoreductase-1, heme oxygenase-1, and glutamate-cysteine ligase was significantly increased. Furthermore, CS₂ treatment increased the level of p62 and its phosphorylation status, while decreased the level of keap1. In addition, CS₂ also lead to the activation of CAMKK2 and ULK1 kinase signaling in rat spinal cords and sciatic nerves. Taken together, our results indicated that CS₂ intoxication was associated with the activation of Nrf2-ARE antioxidative machinery, which might play a protective role against CS₂-induced neuronal damage.