Abstract
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.
Similar content being viewed by others
Abbreviations
- ARE:
-
antioxidant-responsive element
- HBO:
-
hyperbaric oxygenation
- LPO:
-
lipid peroxidation
- Nrf2:
-
NF-E2-related factor 2
- ROS:
-
reactive oxygen species
References
Suzuki, T., and Yamamoto, M. (2015) Molecular basis of the Keap1–Nrf2 system, Free Radic. Biol. Med., 88, 93–100.
Hybertson, B. M., Gao, B., Bose, S. K., and McCord, J. M. (2011) Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation, Mol. Asp. Med., 32, 234–246.
Holmstrom, K. M., Baird, L., Zhang, Y., Hargreaves, I., Chalasani, A., Land, J. M., Stanyer, L., Yamamoto, M., Dinkova-Kostova, A. T., and Abramov, A. Y. (2013) Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration, Biol. Open, 2, 761–770.
Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., and Hayes, J. D. (2015) Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease, Free Radic. Biol. Med., 88, 108–146.
Sandberg, M., Patil, J., D’Angelo, B., Weber, S. G., and Mallard, C. (2014) NRF2-regulation in brain health and disease: implication of cerebral inflammation, Neuropharmacology, 79, 298–306.
Clark, J. (2008) Oxygen toxicity, in Physiology and Medicine of Hyperbaric Oxygen Therapy (Neuman, T. S., and Thom, S. R., eds.) Philadelphia, PA, Saunders, pp. 527–563.
Skulachev, V. P. (2012) Mitochondria-targeted antioxidants as promising drugs for treatment of age-related brain diseases, J. Alzheimer’s Dis., 28, 283–289.
Isaev, N. K., Novikova, C. V., Stelmashuk, E. V., Barskov, I. V., Silachev, D. N., Khaspekov, L. G., Skulachev, V. P., and Zorov, D. B. (2012) Mitochondria-targeted plastoquinone derivative antioxidant SkQR1 decreases traumainduced neurological deficit in rat, Biochemistry (Moscow), 77, 996–999.
Silachev, D. N., Plotnikov, E. Y., Zorova, L. D., Pevzner, I. B., Sumbatyan, N. V., Korshunova, G. A., Gulyaev, M. V., Pirogov, Y. A., Skulachev, V. P., and Zorov, D. B. (2015) Neuroprotective effects of mitochondria-targeted plastoquinone and thymoquinone in a rat model of brain ischemia/reperfusion injury, Molecules, 20, 14487–14503.
Lukash, A. I., Vnukov, V. V., Ananyan, A. A., Milyutina, N. P., and Kvasha, P. N. (1996) Metal-Containing Compounds of Blood Plasma at Hyperbaric Oxygenation (Experimental and Clinical Aspects) [in Russian], RGU Publishers, Rostov-on-Don.
Chistyakov, V. A., Serezhenkov, V. A., Aleksandrova, A. A., Milyutina, N. P., Prokof’ev, V. N., Mashkina, E. V., Gutnikova, L. V., and Dem’yanenko, S. V. (2010) Effects of plastoquinone derivative 10-(6′-plastoquinonyl)decyltriphenylphosphonium (SkQ1) on contents of steroid hormones and NO level in rats, Biochemistry (Moscow), 75, 1383–1387.
Sirota, T. V. (1999) A new approach in studies on autoxidation of norepinephrine and its use for determination of superoxide dismutase activity, Vopr. Med. Khim., 3, 14–15.
Korolyuk, M. A., Ivanova, L. I., Maiorova, I. G., and Tokarev, V. E. (1988) Method for determination of catalase activity, Lab. Delo, 1, 16–19.
Moin, V. M. (1986) A simple and specific method for determination of glutathione peroxidase activity in erythrocytes, Lab. Delo, 12, 724–727.
Habig, W. H., Pabst, M. J., and Jacoby, W. B. (1974) Glutathione-S-transferase: the first step in mercapturic acid formation, J. Biol. Chem., 249, 7130–7139.
Avis, P. G., Bergel, F., and Bray, R. C. (1955) Cellular constituents. The chemistry of xanthine oxidase, J. Chem. Soc., 1100–1105.
Stalnaya, I. D. (1977) Method of determination of diene conjugation of unsaturated higher fatty acids, in Modern Methods in Biochemistry (Orekhovich, V. N., ed.) [in Russian], Meditsina, Moscow, pp. 63–64.
Stalnaya, I. D., and Garishvili, T. G. (1977) Method of determination of malonic dialdehyde with thiobarbituric acid, in Modern Methods in Biochemistry (Orekhovich, V. N., ed.) [in Russian], Meditsina, Moscow, pp. 66–68.
Bidlack, W. R., and Tappel, A. T. (1973) Fluorescent products of phospholipids during lipid peroxidation, Lipids, 8, 203–209.
Bligh, E., and Dyer, W. (1959) Rapid method of lipids extraction and purification, Can. J. Biochem. Physiol., 37, 911–917.
Vnukov, V. V., Gutsenko, O. I., Milyutina, N. P., Ananyan, A. A., Danilenko, A. O., Panina, S. B., and Kornienko, I. V. (2015) Influence of SkQ1 on expression of Nrf2 transcription factor gene, ARE-controlled genes of antioxidant enzymes and their activity in rat blood leukocytes, Biochemistry (Moscow), 80, 586–591.
Vnukov, V. V., Gutsenko, O. I., Milyutina, N. P., Kornienko, I. V., Ananyan, A. A., Danilenko, A. O., Panina, S. B., Plotnikov, A. A., and Makarenko, M. S. (2015) Influence of SkQ1 on expression of Nrf2 gene, ARE-controlled genes of antioxidant enzymes and their activity in rat blood leukocytes under oxidative stress, Biochemistry (Moscow), 80, 1598–1605.
Forman, H. J., Davies, K. J. A., and Ursini, F. (2014) How do nutritional antioxidants really work: nucleophilic tone and parahormesis versus free radical scavenging in vivo, Free Radic. Biol. Med., 66, 24–35.
Antonenko, Y. N., Avetisyan, A. V., Bakeeva, L. E., Chernyak, B. V., Chertkov, V. A., Domnina, L. V., Ivanova, O. Y., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Muntyan, M. S., Nepryakhina, O. K., Pashkovskaya, A. A., Pletyushkina, O. Y., Pustovidko, A. V., Roginsky, T. I., Rokitskaya, T. I., Ruuge, E. K., Saprunova, V. B., Severina, I. I., Sumonyan, R. A., Skulachev, I. V., Skulachev, M. V., Sumbatyan, N. V., Sviryaeva, I. V., Tashlitsky, V. N., Vasiliev, Y. M., Vyssokikh, M. Y., Yaguzhinsky, L. S., Zamyatnin, A. A., Jr., and Skulachev, V. P. (2008) Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies, Biochemistry (Moscow), 73, 1273–1285.
Kwak, M. K., Itoh, K., Yamamoto, M., and Kensler, T. W. (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter, Mol. Cell Biol., 22, 2883–2892.
Harder, B., Jiang, T., Wu, T., Tao, S., Rojo de la Vega, M., Tian, M., Chapman, E., and Zhang, D. D. (2015) Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention, Biochem. Soc. Trans., 43, 680–686.
Bryan, H. K., Olayanju, A., Goldring, C. E., and Park, B. K. (2013) The Nrf2 cell defense pathway: Keap1-dependent and -independent mechanisms of regulation, Biochem. Pharmacol., 85, 705–717.
Halliwell, B., and Gutteridge, J. (2001) Free Radicals in Biology and Medicine, Oxford University Press, New York, pp. 712–733.
Hulbert, A. J., Pamplona, R., Buffenstein, R., and Buttemer, W. A. (2007) Life and death: metabolic rate, membrane composition, and life span of animals, Physiol. Rev., 87, 1175–1213.
Garbarino, V. R., Orr, M. E., Rodriguez, K. A., and Buffenstein, R. (2015) Mechanisms of oxidative stress resistance in the brain: lessons learned from hypoxia tolerant extremophilic vertebrates, Arch. Biochem. Biophys., 576, 8–16.
Davies, S. S., and Guo, L. (2014) Lipid peroxidation generates biologically active phospholipids including oxidatively N-modified phospholipids, Chem. Phys. Lipids, 181, 1–33.
Cho, H.-Y., Jedlicka, A. E., Reddy, S. P., Zhang, L. Y., Kensler, T. W., and Kleeberger, S. R. (2002) Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene, Am. J. Respir. Cell Mol. Biol., 26, 42–51.
Reddy, S. P. (2008) The antioxidant response element and oxidative stress modifiers in airway diseases, Curr. Mol. Med., 8, 376–383.
He, X., and Ma, Q. (2009) NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation, Mol. Pharmacol., 76, 1265–1278.
Hummler, S. C., Rong, M., Chen, S., Hehre, D., Alapati, D., and Wu, S. (2013) Targeting glycogen synthase kinase-3β to prevent hyperoxia-induced lung injury in neonatal rats, Am. J. Respir. Cell Mol. Biol., 48, 578–588.
Saric, A., Sobocanec, S., Safranko, Z. M., Hadzija, M. P., Bagaric, R., Farkas, V., Svarc, A., Marotti, T., and Balog, T. (2015) Diminished resistance to hyperoxia in brains of reproductively senescent female CBA/H mice, Med. Sci. Monit. Basic Res., 21, 191–199.
Perkowski, S., Sun, J., Singhal, S., Santiago, J., Leikauf, G. D., and Albelda, S. M. (2002) Gene expression profiling of the early pulmonary response to hyperoxia in mice, Am. J. Respir. Cell Mol. Biol., 28, 682–696.
Vnukov, V. V., Danilenko, A. O., Milyutina, N. P., Ananyan, A. A., and Gutsenko, O. I. (2012) SkQ1 as a regulator of free radial oxidation at hyperoxia, Izv. Vuzov Sev. Kavkaz. Region. Ser. Estestv. Nauki, 6, 77–80.
Harrison, R. (2002) Structure and function of xanthine oxidoreductase: where are we now? Free Radic. Biol. Med., 33, 774–797.
Ben-Ari, J., Machoul, I. R., Dorio, R. J., Buckley, S., Warburton, D., and Walker, S. M. (2000) Cytokine response during hyperoxia: sequential production of pulmonary tumor necrosis factor and interleukin-6 in neonate rats, Isr. Med. Assoc. J., 2, 365–369.
Ahmed, S. M. U., Luo, L., Namani, A., Wang, X. J., and Ta, X. (2017) Nrf2 signaling pathway: pivotal roles in inflammation, Biochim. Biophys. Acta, 1863, 585–597.
Plotnikov, E. Y., Chupyrkina, A. A., Jankauskas, S. S., Pevzner, I. B., Silachev, D. N., Skulachev, V. P., and Zorov, D. B. (2011) Mechanisms of nephroprotective effect of mitochondria-targeted antioxidants under rhabdomyolysis and ischemia/reperfusion, Biochim. Biophys. Acta, 1812, 77–86.
Silachev, D. N., Isaev, N. K., Pevzner, I. B., Zorova, L. D., Stelmashook, E. V., Novikova, S. V., Plotnikov, E. Y., Skulachev, V. P., and Zorov, D. B. (2012) The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk, PLoS One, 7, 1–11.
Sifringer, M., Brait, D., Weichelt, U., Zimmerman, G., Endesfelder, S., Brehmer, F., von Haefen, C., Friedman, A., Soreq, H., Bendix, I., Gerstner, B., and Felderhoff-Mueser, U. (2010) Erythropoietin attenuates hyperoxiainduced oxidative stress in the developing rat brain, Brain Behav. Immun., 24, 792–799.
Zhang, D.-X., Zhang, L.-M., Zhao, X.-C., and Sun, W. (2017) Neuroprotective effects of erythropoietin against sevoflurane-induced neuronal apoptosis in primary rat cortical neurons involving the EPOR-Erk1/2-Nrf2/Bach1 signal pathway, Biomed. Pharmacother., 87, 332–341.
Stefanova, N. A., Muraleva, N. A., Maksimova, K. Y., Rudnitskaya, E. A., Kiseleva, E., Telegina, D. V., and Kolosova, N. G. (2016) An antioxidant specifically targeting mitochondria delays progression of Alzheimer’s disease-like pathology, Aging (Albany NY), 8, 2713–2733.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © V. V. Vnukov, O. I. Gutsenko, N. P. Milyutina, I. V. Kornienko, A. A. Ananyan, A. A. Plotnikov, S. B. Panina, 2017, published in Biokhimiya, 2017, Vol. 82, No. 8, pp. 1220-1231.
Rights and permissions
About this article
Cite this article
Vnukov, V.V., Gutsenko, O.I., Milyutina, N.P. et al. SkQ1 regulates expression of Nrf2, ARE-controlled genes encoding antioxidant enzymes, and their activity in cerebral cortex under oxidative stress. Biochemistry Moscow 82, 942–952 (2017). https://doi.org/10.1134/S0006297917080090
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S0006297917080090