Abstract
Background: Previously studies have shown that Nox2 and Nox4, as members of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, Nox), participate in brain damage caused by ischemia-reperfusion (I/R). The aim of this study is to investigate the effects of specific chemical inhibitors of Nox2 and Nox4 on cerebral I/R-induced brain injury in rats.
Methods: At 0.5 h before MCAO surgery, the rats were pretreated with vehicle, Nox2 inhibitor (gp91ds-tat), and Nox4 inhibitor (GKT137831), respectively. After reperfusion for 24 h, the infarct sizes of brain tissues in rats in various groups are determined. The penumbra (ischemic) tissues are collected to measure ROS levels, neuronal apoptosis, and degeneration, as well as the integrity of the blood-brain barrier (BBB) in brain tissues of rats.
Results: gp91ds-tat and GKT137831 pretreatment significantly reduced the infarct sizes in brain tissues of rats, effectively suppressed I/R-induced increase in ROS levels, neuronal apoptosis and degeneration, and obviously alleviated BBB damage.
Conclusion: Under cerebral I/R conditions, Nox2 inhibitor (gp91ds-tat) and Nox4 inhibitor (GKT137831) can effectively play a protective role in the brain tissues of rats.
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References
Andreadou I, Iliodromitis EK, Farmakis D, Kremastinos DT. To prevent, protect and save the ischemic heart: antioxidants revisited. Expert Opin Ther Targets. 2009;13:945–56. https://doi.org/10.1517/14728220903039698.
Ashwal S, Tone B, Tian HR, Cole DJ, Liwnicz BH, Pearce WJ. Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion in the rat pup. Pediatr Res. 1999;46:390–400. https://doi.org/10.1203/00006450-199910000-00006.
Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia—the ischemic penumbra. Stroke. 1981;12:723–5.
Cao G, Ye X, Xu Y, Yin M, Chen H, Kou J, Yu B. YiQiFuMai powder injection ameliorates blood-brain barrier dysfunction and brain edema after focal cerebral ischemia-reperfusion injury in mice. Drug Des Devel Ther. 2016;10:315–25. https://doi.org/10.2147/DDDT.S96818.
Chen H, Kim GS, Okami N, Narasimhan P, Chan PH. NADPH oxidase is involved in post-ischemic brain inflammation. Neurobiol Dis. 2011;42:341–8. https://doi.org/10.1016/j.nbd.2011.01.027.
Chen YH, Du GH, Zhang JT. Salvianolic acid B protects brain against injuries caused by ischemia-reperfusion in rats. Acta Pharmacol Sin. 2000;21:463–6.
De Silva TM, Brait VH, Drummond GR, Sobey CG, Miller AA. Nox2 oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke. PLoS One. 2011;6:e28393. https://doi.org/10.1371/journal.pone.0028393.
Djordjevic VB, Zvezdanovic L, Cosic V. [Oxidative stress in human diseases]. Srp Arh Celok Lek. 2008;136(Suppl 2):158–65.
Green DE, Murphy TC, Kang BY, Kleinhenz JM, Szyndralewiez C, Page P, Sutliff RL, Hart CM. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol. 2012;47:718–26. https://doi.org/10.1165/rcmb.2011-0418OC.
Green SP, Cairns B, Rae J, Errett-Baroncini C, Hongo JA, Erickson RW, Curnutte JT. Induction of gp91-phox, a component of the phagocyte NADPH oxidase, in microglial cells during central nervous system inflammation. J Cereb Blood Flow Metab. 2001;21:374–84. https://doi.org/10.1097/00004647-200104000-00006.
Hafez S, Hoda MN, Guo X, Johnson MH, Fagan SC, Ergul A. Comparative analysis of different methods of ischemia/reperfusion in hyperglycemic stroke outcomes: interaction with tPA. Transl Stroke Res. 2015;6:171–80. https://doi.org/10.1007/s12975-015-0391-0.
Huttemann M, Lee I, Grossman LI, Doan JW, Sanderson TH. Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human disease. Adv Exp Med Biol. 2012;748:237–64. https://doi.org/10.1007/978-1-4614-3573-0_10.
Kahles T, Brandes RP. NADPH oxidases as therapeutic targets in ischemic stroke. Cell Mol Life Sci. 2012;69:2345–63. https://doi.org/10.1007/s00018-012-1011-8.
Kahles T, Brandes RP. Which NADPH oxidase isoform is relevant for ischemic stroke? The case for nox 2. Antioxid Redox Signal. 2013;18:1400–17. https://doi.org/10.1089/ars.2012.4721.
Kahles T, et al. NADPH oxidase Nox1 contributes to ischemic injury in experimental stroke in mice. Neurobiol Dis. 2010;40:185–92. https://doi.org/10.1016/j.nbd.2010.05.023.
Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol. 2014;2:702–14. https://doi.org/10.1016/j.redox.2014.05.006.
Kleikers PW, et al. NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury. J Mol Med. 2012;90:1391–406. https://doi.org/10.1007/s00109-012-0963-3.
Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, Barit D, Schwarz T, Geis C, Kraft P, Barthel K, Schuhmann MK, Herrmann AM, Meuth SG, Stoll G, Meurer S, Schrewe A, Becker L, Gailus-Durner V, Fuchs H, Klopstock T, de Angelis MH, Jandeleit-Dahm K, Shah AM, Weissmann N, Schmidt HH. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol. 2010;8(9). https://doi.org/10.1371/journal.pbio.1000479.
Kochanski R, Peng C, Higashida T, Geng X, Huttemann M, Guthikonda M, Ding Y. Neuroprotection conferred by post-ischemia ethanol therapy in experimental stroke: an inhibitory effect on hyperglycolysis and NADPH oxidase activation. J Neurochem. 2013;126:113–21. https://doi.org/10.1111/jnc.12169.
Kusaka I, Kusaka G, Zhou C, Ishikawa M, Nanda A, Granger DN, Zhang JH, Tang J. Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. Am J Physiol Heart Circ Physiol. 2004;286(6):H2442–51. https://doi.org/10.1152/ajpheart.01169.2003.
Li H, Gao A, Feng D, Wang Y, Zhang L, Cui Y, Li B, Wang Z, Chen G. Evaluation of the protective potential of brain microvascular endothelial cell autophagy on blood-brain barrier integrity during experimental cerebral ischemia-reperfusion injury. Transl Stroke Res. 2014;5(5):618–26. https://doi.org/10.1007/s12975-014-0354-x.
Li H, Wang Y, Feng D, Liu Y, Xu M, Gao A, Tian F, Zhang L, Cui Y, Wang Z, Chen G. Alterations in the time course of expression of the Nox family in the brain in a rat experimental cerebral ischemia and reperfusion model: effects of melatonin. J Pineal Res. 2014;57(1):110–9. https://doi.org/10.1111/jpi.12148.
Liu W, Chen Q, Liu J, Liu KJ. Normobaric hyperoxia protects the blood brain barrier through inhibiting Nox2 containing NADPH oxidase in ischemic stroke. Med Gas Res. 2011;1:22. https://doi.org/10.1186/2045-9912-1-22.
Liu X, et al. Remote ischemic postconditioning alleviates cerebral ischemic injury by attenuating endoplasmic reticulum stress-mediated apoptosis. Transl Stroke Res. 2014;5:692–700. https://doi.org/10.1007/s12975-014-0359-5.
Molina CA. Reperfusion therapies for acute ischemic stroke: current pharmacological and mechanical approaches. Stroke. 2011;42:S16–9. https://doi.org/10.1161/STROKEAHA.110.598763.
Pang T, Wang J, Benicky J, Sanchez-Lemus E, Saavedra JM. Telmisartan directly ameliorates the neuronal inflammatory response to IL-1beta partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation. 2012;9:102. https://doi.org/10.1186/1742-2094-9-102.
Qi Z, et al. Bcl-2 phosphorylation triggers autophagy switch and reduces mitochondrial damage in limb remote ischemic conditioned rats after ischemic stroke. Transl Stroke Res. 2015;6:198–206. https://doi.org/10.1007/s12975-015-0393-y.
Radermacher KA, Wingler K, Kleikers P, Altenhofer S, JR Hermans J, Kleinschnitz C, Hhw Schmidt H. The 1027th target candidate in stroke: will NADPH oxidase hold up? Exp Transl Stroke Med. 2012;4:11. https://doi.org/10.1186/2040-7378-4-11.
Shen J, et al. Interrupted reperfusion reduces the activation of NADPH oxidase after cerebral I/R injury. Free Radic Biol Med. 2011;50:1780–6. https://doi.org/10.1016/j.freeradbiomed.2011.03.028.
Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996;27:1459–66.
Yoshioka H, Niizuma K, Katsu M, Okami N, Sakata H, Kim GS, Narasimhan P, Chan PH. NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia. J Cereb Blood Flow Metab. 2011;31(3):868–80. https://doi.org/10.1038/jcbfm.2010.166.
Zhang L, Li Z, Feng D, Shen H, Tian X, Li H, Wang Z, Chen G. Involvement of Nox2 and Nox4 NADPH oxidases in early brain injury after subarachnoid hemorrhage. Free Radic Res. 2017;51(3):316–28. https://doi.org/10.1080/10715762.2017.1311015.
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Wang, J., Liu, Y., Shen, H., Li, H., Wang, Z., Chen, G. (2020). Nox2 and Nox4 Participate in ROS-Induced Neuronal Apoptosis and Brain Injury During Ischemia-Reperfusion in Rats. In: Martin, R., Boling, W., Chen, G., Zhang, J. (eds) Subarachnoid Hemorrhage. Acta Neurochirurgica Supplement, vol 127. Springer, Cham. https://doi.org/10.1007/978-3-030-04615-6_8
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