SkQ1 regulates expression of Nrf2, ARE-controlled genes encoding antioxidant enzymes, and their activity in cerebral cortex under oxidative stress

The administration of SkQ1 to rats at the dose of 50 nmol/kg for five days significantly increased the mRNA levels of transcription factor Nrf2 and of Nrf2-controlled genes encoding antioxidant enzymes SOD1, SOD2, CAT, and GPx4, whereas changes in the level of mRNA of SOD3 in the cerebral cortex of the rat brain were not significant. This was accompanied by activation of antioxidant enzymes (SOD, CAT, GPx, and GST) and increase in reduced glutathione concentration. Under oxidative stress induced by hyperoxia (0.5 MPa for 90 min), the mRNA level of transcription factor Nrf2 decreased, whereas changes in the transcriptional activity of Nrf2-induced genes (SOD1-3, CAT, GPx4) encoding antioxidant enzymes in the cortex of the rat brain hemispheres were insignificant. Under conditions of hyperoxia, lipid peroxidation intensity was increased, CAT was inhibited, and GST activity was moderately increased, whereas SOD and GPx activities in the rat brain cerebral cortex remained at the stationary level. Pretreatment with SkQ1 before the exposure to hyperbaric oxygenation led to an increase in mRNA level of transcription factor Nrf2 and of Nrf2-induced genes (SOD1-2, CAT, and GPx4) encoding antioxidant enzymes, whereas SOD3 expression in the cerebral cortex of the rat brain under oxidative stress was not changed. Concurrently, we observed an increase in activities of these antioxidant enzymes (SOD, CAT, GPx, and GST) and in level of reduced glutathione. We hypothesize that the protective effect of SkQ1 under hyperoxia-induced oxidative stress could be realized via direct antioxidant activity and through stimulation of the signaling defense system Keap1/Nrf2/ARE.