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.

The study demonstrated that oxidative stress induced by hyperoxia (0.5 MPa for 90 min) resulted in reduction of mRNA levels of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes (SOD1, CAT, GPx4) in peripheral blood leukocytes of rats. The changes in gene expression profiles under hyperoxia were accompanied by disbalance of activity of antioxidant enzymes in the leukocytes, namely activation of superoxide dismutase and inhibition of catalase, glutathione peroxidase, and glutathione-S-transferase. Pretreatment of rats with SkQ1 (50 nmol/kg for five days) significantly increased mRNA levels of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes SOD2 and GPx4 and normalized the transcriptional activity of the SOD1 and CAT genes in the leukocytes in hyperoxia-induced oxidative stress. At the same time, the activity of catalase and glutathione peroxidase was increased, and the activity of superoxide dismutase and glutathione-S-transferase returned to the control level. It is hypothesized that protective effect of SkQ1 in hyperoxia-induced oxidative stress can be realized via a direct antioxidant property and the stimulation of the Keap1/Nrf2 redox-sensitive signaling system.

This study demonstrated that pretreatment of rats with mitochondria-targeted antioxidant SkQ1 (50 nmol/kg during 5 days) significantly increased the mRNA levels of Nrf2 transcription factor and Nrf2-induced genes encoding antioxidant enzymes SOD1, SOD2, CAT, and GPx4 in rat peripheral blood leukocytes. The increase in expression of these genes with SkQ1 addition was accompanied by increased activities of catalase, glutathione peroxidase, and glutathione-S-transferase in leukocytes. These results indicate that antioxidant properties of SkQ1 might be realized via induction of expression of the genes regulating activity of antioxidant system elements.

No abstract

This study demonstrated that hyperoxia induced (0.5 MPa, 90 min) oxidative stress decreased mRNA level of Nrf2 transcription factor and Nrf2 induced genes encoding antioxidant enzymes (SOD1, CAT, GPx4) in leukocytes of rat blood. The change in gene expression profiles in hyperoxia was accompanied by disbalance of antioxidant enzyme activities in the leukocytes – activation of superoxide dismutase, and inhibition of catalase, glutathione peroxidase. The administration of SkQ1 (50 nmol/kg during 5 days) significantly increased mRNA level of Nrf2 transcription factor and Nrf2 induced genes encoding antioxidant enzymes SOD2 and GPx4 and nor malized the transcriptional activity of the SOD1 and CAT genes in the leukocytes under the hyperoxia induced oxidative stress. Catalase and glutathione peroxidase activity in the leukocytes increased concurrently with reversion of superoxide dismutase activity to the control level. The protective effect of SkQ1 in hyperoxia induced oxidative stress may be realized via direct antioxidant activity and the stimulation of the Keap1/Nrf2/ARE defense system. Administration of SkQ1 in extremely low amounts (50 nmol/kg for 5 days) effectively inhibits the accumulation of lipid peroxidation molecular products, normalizes the structural state of lymphocyte membranes and the level of their apoptosis under the condition of physiological standard and oxidative stress.