Pathophysiology of Ischemic Stroke: Role of Oxidative Stress

Sofía       Orellana-Urzúa; Ignacio       Rojas; Lucas       Líbano; Ramón       Rodrigo
Abstract

Stroke is the second leading cause of mortality and the major cause of adult physical disability worldwide. The currently available treatment to recanalize the blood flow in acute ischemic stroke is intravenous administration of tissue plasminogen activator (t-PA) and endovascular treatment. Nevertheless, those treatments have the disadvantage that reperfusion leads to a highly harmful reactive oxygen species (ROS) production, generating oxidative stress (OS), which is responsible for most of the ischemia-reperfusion injury and thus causing brain tissue damage. In addition, OS can lead brain cells to apoptosis, autophagy and necrosis. The aims of this review are to provide an updated overview of the role of OS in brain IRI, providing some bases for therapeutic interventions based on counteracting the OS-related mechanism of injury and thus suggesting novel possible strategies in the prevention of IRI after stroke.
Keywords: Ischemia-reperfusion, oxidative stress, reactive oxygen species, ischemic stroke, haemorrhagic stroke, antioxidant.
[1] 
GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol  2019; 18(5): 439-58.
[http://dx.doi.org/10.1016/S1474-4422(19)30034-1] [PMID:  30871944] 
[2] 
GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol  2017; 16(11): 877-97.
[http://dx.doi.org/10.1016/S1474-4422(17)30299-5] [PMID:  28931491] 
[3] 
Baldwin K, Orr S, Briand M, Piazza C, Veydt A, McCoy S. Acute ischemic stroke update. Pharmacotherapy  2010; 30(5): 493-514.
[http://dx.doi.org/10.1592/phco.30.5.493] [PMID:  20412000] 
[4] 
Kelly-Hayes M, Beiser A, Kase CS, Scaramucci A, D’Agostino RB, Wolf PA. The influence of gender and age on disability following ischemic stroke: the Framingham study. J Stroke Cerebrovasc Dis  2003; 12(3): 119-26.
[http://dx.doi.org/10.1016/S1052-3057(03)00042-9] [PMID:  17903915] 
[5] 
Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and the GBD Stroke Experts Group. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet  2014; 383(9913): 245-54.
[http://dx.doi.org/10.1016/S0140-6736(13)61953-4] [PMID:  24449944] 
[6] 
Austin V, Crack PJ, Bozinovski S, Miller AA, Vlahos R. COPD and stroke: are systemic inflammation and oxidative stress the missing links? Clin Sci (Lond)  2016; 130(13): 1039-50.
[http://dx.doi.org/10.1042/CS20160043]] [PMID:  27215677] 
[7] 
Chen YW, Sung SF, Chen CH, et al. Intravenous thrombolysis administration 3-4.5 h after acute ischemic stroke: A retrospective, multicenter study. Front Neurol  2019; 10: 1038.
[8] 
Yang Q, Tong X, Schieb L, et al. Vital signs: Recent trends in stroke death rates - United States, 2000-2015. MMWR Morb Mortal Wkly Rep  2017; 66(35): 933-9.
[http://dx.doi.org/10.15585/mmwr.mm6635e1] [PMID:  28880858] 
[9] 
Khatri R, McKinney AM, Swenson B, Janardhan V. Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke. Neurology  2012; 79(13)(Suppl. 1): S52-7.
[http://dx.doi.org/10.1212/WNL.0b013e3182697e70] [PMID:  23008413] 
[10] 
Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke  2009; 4(6): 461-70.
[http://dx.doi.org/10.1111/j.1747-4949.2009.00387.x] [PMID:  19930058] 
[11] 
Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol  2006; 100(2): 739-43.
[http://dx.doi.org/10.1152/japplphysiol.01044.2005] [PMID:  16421281] 
[12] 
Kohen R, Nyska A. Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol  2002; 30(6): 620-50.
[http://dx.doi.org/10.1080/01926230290166724] [PMID:  12512863] 
[13] 
Brandes RP, Weissmann N, Schröder K. Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic Biol Med  2014; 76: 208-26.
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.07.046] [PMID:  25157786] 
[14] 
Halliwell B, Gutteridge JM. Biologically relevant metal iondependent hydroxyl radical generation. An update. FEBS Lett  1992; 307(1): 108-12.
[http://dx.doi.org/10.1016/0014-5793(92)80911-Y] [PMID:  1322323] 
[15] 
Husain K, Hernandez W, Ansari RA, Ferder L. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem  2015; 6(3): 209-17.
[http://dx.doi.org/10.4331/wjbc.v6.i3.209] [PMID:  26322175] 
[16] 
Zhang J, Wang X, Vikash V, et al. ROS and ROS-Mediated Cellular Signaling. Oxid Med Cell Longev  2016; 2016: 4350965.
[http://dx.doi.org/10.1155/2016/4350965] [PMID:  26998193] 
[17] 
Margaill I, Plotkine M, Lerouet D. Antioxidant strategies in the treatment of stroke. Free Radic Biol Med  2005; 39(4): 429-43.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.05.003] [PMID:  16043015] 
[18] 
Alfieri A, Srivastava S, Siow RCM, Modo M, Fraser PA, Mann GE. Targeting the Nrf2-Keap1 antioxidant defence pathway for neurovascular protection in stroke. J Physiol  2011; 589(17): 4125-36.
[http://dx.doi.org/10.1113/jphysiol.2011.210294] [PMID:  21646410] 
[19] 
Zhang C, Shu L, Kong A-NT. MicroRNAs: New players in cancer prevention targeting Nrf2, oxidative stress and inflammatory pathways. Curr Pharmacol Rep  2015; 1(1): 21-30.
[http://dx.doi.org/10.1007/s40495-014-0013-7] [PMID:  26618104] 
[20] 
Shirley R, Ord EN, Work LM. Oxidative stress and the use of antioxidants in stroke. Antioxidants  2014; 3(3): 472-501.
[http://dx.doi.org/10.3390/antiox3030472] [PMID:  26785066] 
[21] 
Ning B, Sun N, Cao R, et al. Ultrasound-aided multi-parametric photoacoustic microscopy of the mouse brain. Sci Rep  2015; 5: 18775.
[http://dx.doi.org/10.1038/srep18775] [PMID:  26688368] 
[22] 
Hu D, Serrano F, Oury TD, Klann E. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J Neurosci  2006; 26(15): 3933-41.
[http://dx.doi.org/10.1523/JNEUROSCI.5566-05.2006] [PMID:  16611809] 
[23] 
Saeed SA, Shad KF, Saleem T, Javed F, Khan MU. Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Exp Brain Res  2007; 182(1): 1-10.
[http://dx.doi.org/10.1007/s00221-007-1050-9] [PMID:  17665180] 
[24] 
Harris RE. Inflammation in the pathogenesis of chronic diseases: The COX-2 controversy. Springer Science & Business Media 2007.
[http://dx.doi.org/10.1007/1-4020-5688-5] 
[25] 
Hewett SJ, Uliasz TF, Vidwans AS, Hewett JA. Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. J Pharmacol Exp Ther  2000; 293(2): 417-25.
[PMID:  10773011] 
[26] 
Figueroa S, Oset-Gasque MJ, Arce C, Martinez-Honduvilla CJ, González MP. Mitochondrial involvement in nitric oxide-induced cellular death in cortical neurons in culture. J Neurosci Res  2006; 83(3): 441-9.
[http://dx.doi.org/10.1002/jnr.20739] [PMID:  16397899] 
[27] 
Thirupathi A, Chang Y-Z. Brain iron metabolism and CNS diseases. Adv Exp Med Biol  2019; 1173: 1-19.
[http://dx.doi.org/10.1007/978-981-13-9589-5_1] [PMID:  31456202] 
[28] 
Herrmann W. The importance of hyperhomocysteinemia as a risk factor for diseases: an overview. Clin Chem Lab Med  2001; 39(8): 666-74.
[http://dx.doi.org/10.1515/CCLM.2001.110] [PMID:  11592431] 
[29] 
Hillered L, Vespa PM, Hovda DA. Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis. J Neurotrauma  2005; 22(1): 3-41.
[http://dx.doi.org/10.1089/neu.2005.22.3] [PMID:  15665601] 
[30] 
Hou ST, MacManus JP. Molecular mechanisms of cerebral ischemia-induced neuronal death. Int Rev Cytol  2002; 221: 93-148.
[http://dx.doi.org/10.1016/S0074-7696(02)21011-6] [PMID:  12455747] 
[31] 
Persson N, Wu J, Zhang Q, et al. Age and sex related differences in subcortical brain iron concentrations among healthy adults. Neuroimage  2015; 122: 385-98.
[http://dx.doi.org/10.1016/j.neuroimage.2015.07.050] [PMID:  26216277] 
[32] 
García-Yébenes I, García-Culebras A, Peña-Martínez C, et al. Iron overload exacerbates the risk of hemorrhagic transformation after tPA (Tissue-Type Plasminogen Activator) administration in thromboembolic stroke mice. Stroke  2018; 49(9): 2163-72.
[http://dx.doi.org/10.1161/STROKEAHA.118.021540] [PMID:  30018160] 
[33] 
Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med  2011; 17(7): 796-808.
[http://dx.doi.org/10.1038/nm.2399] [PMID:  21738161] 
[34] 
Dang J, Brandenburg L-O, Rosen C, et al. Nrf2 expression by neurons, astroglia, and microglia in the cerebral cortical penumbra of ischemic rats. J Mol Neurosci  2012; 46(3): 578-84.
[http://dx.doi.org/10.1007/s12031-011-9645-9] [PMID:  21932039] 
[35] 
Johnson JA, Johnson DA, Kraft AD, et al. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci  2008; 1147: 61-9.
[http://dx.doi.org/10.1196/annals.1427.036] [PMID:  19076431] 
[36] 
Hardingham GE, Lipton SA. Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and disease processes. Antioxid Redox Signal  2011; 14(8): 1421-4.
[http://dx.doi.org/10.1089/ars.2010.3573] [PMID:  20977364] 
[37] 
Coimbra-Costa D, Alva N, Duran M, Carbonell T, Rama R. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol  2017; 12: 216-25.
[http://dx.doi.org/10.1016/j.redox.2017.02.014] [PMID:  28259102] 
[38] 
Yu Y, Han Q, Ding X, et al. Defining core and penumbra in ischemic stroke: A Voxel- and volume-based analysis of whole brain CT perfusion. Sci Rep  2016; 6: 20932.
[http://dx.doi.org/10.1038/srep20932] [PMID:  26860196] 
[39] 
Lo EH, Moskowitz MA, Jacobs TP. Exciting, radical, suicidal: how brain cells die after stroke. Stroke  2005; 36(2): 189-92.
[http://dx.doi.org/10.1161/01.STR.0000153069.96296.fd] [PMID:  15637315] 
[40] 
Murphy TH, Li P, Betts K, Liu R. Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines. J Neurosci  2008; 28(7): 1756-72.
[http://dx.doi.org/10.1523/JNEUROSCI.5128-07.2008] [PMID:  18272696] 
[41] 
Khoshnam SE, Winlow W, Farzaneh M, Farbood Y, Moghaddam HF. Pathogenic mechanisms following ischemic stroke. Neurol Sci  2017; 38(7): 1167-86.
[http://dx.doi.org/10.1007/s10072-017-2938-1] [PMID:  28417216] 
[42] 
Li Y, Yang G-Y. Pathophysiology of ischemic stroke.  Translational Medicine Research 2017; pp. 51-75.
[43] 
Besancon E, Guo S, Lok J, Tymianski M, Lo EH. Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci  2008; 29(5): 268-75.
[http://dx.doi.org/10.1016/j.tips.2008.02.003] [PMID:  18384889] 
[44] 
Rama R, Rodriguez JCG. Excitotoxicity and Oxidative Stress in Acute Ischemic Stroke Acute Ischemic Stroke 2012.
[http://dx.doi.org/10.5772/28300] 
[45] 
Xu L, Emery JF, Ouyang Y-B, Voloboueva LA, Giffard RG. Astrocyte targeted overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia. Glia  2010; 58(9): 1042-9.
[http://dx.doi.org/10.1002/glia.20985] [PMID:  20235222] 
[46] 
Seet RCS, Lee C-YJ, Chan BPL, et al. Oxidative damage in ischemic stroke revealed using multiple biomarkers. Stroke  2011; 42(8): 2326-9.
[http://dx.doi.org/10.1161/STROKEAHA.111.618835] [PMID:  21700941] 
[47] 
Otani H. Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome Antioxidants & Redox Signaling  2011; 1911-26.
[48] 
Suh SW, Shin BS, Ma H, et al. Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol  2008; 64(6): 654-63.
[http://dx.doi.org/10.1002/ana.21511] [PMID:  19107988] 
[49] 
Sun M-S, Jin H, Sun X, et al. Free radical damage in ischemiareperfusion injury: An obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev  2018; 2018: 3804979.
[http://dx.doi.org/10.1155/2018/3804979] [PMID:  29770166] 
[50] 
Zhou D, Fang T, Lu L-Q, Yi L. Neuroprotective potential of cerium oxide nanoparticles for focal cerebral ischemic stroke. J Huazhong Univ Sci Technolog Med Sci  2016; 36(4): 480-6.
[http://dx.doi.org/10.1007/s11596-016-1612-9] [PMID:  27465320] 
[51] 
Ge W-Q, Chen J, Pan H, Chen F, Zhou C-Y. Analysis of risk factors increased hemorrhagic transformation after acute ischemic stroke. J Stroke Cerebrovasc Dis  2018; 27(12): 3587-90.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.08.028] [PMID:  30217636] 
[52] 
Balian NR, Alonzo CB, Zurrú MC, et al. Clinical predictors of hemorrhagic transformation in non lacunar ischemic stroke. Medicina (B Aires)  2017; 77(2): 100-4.
[PMID:  28463214] 
[53] 
Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci  2007; 27(5): 1129-38.
[http://dx.doi.org/10.1523/JNEUROSCI.4468-06.2007] [PMID:  17267568] 
[54] 
Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol  2003; 552(Pt 2): 335-44.
[http://dx.doi.org/10.1113/jphysiol.2003.049478] [PMID:  14561818] 
[55] 
Liu F, Lu J, Manaenko A, Tang J, Hu Q. Mitochondria in ischemic stroke: new insight and implications. Aging Dis  2018; 9(5): 924-37.
[http://dx.doi.org/10.14336/AD.2017.1126] [PMID:  30271667] 
[56] 
Keynes RG, Garthwaite J. Nitric oxide and its role in ischaemic brain injury. Curr Mol Med  2004; 4(2): 179-91.
[http://dx.doi.org/10.2174/1566524043479176] [PMID:  15032712] 
[57] 
Warner DS, Sheng H, Batinić-Haberle I. Oxidants, antioxidants and the ischemic brain. J Exp Biol  2004; 207(Pt 18): 3221-31.
[http://dx.doi.org/10.1242/jeb.01022] [PMID:  15299043] 
[58] 
Selim MH, Ratan RR. The role of iron neurotoxicity in ischemic stroke. Ageing Res Rev  2004; 3(3): 345-53.
[http://dx.doi.org/10.1016/j.arr.2004.04.001] [PMID:  15231241] 
[59] 
Chen ZQ, Mou RT, Feng DX, Wang Z, Chen G. The role of nitric oxide in stroke. Med Gas Res  2017; 7(3): 194-203.
[http://dx.doi.org/10.4103/2045-9912.215750] [PMID:  29152213] 
[60] 
Chen H, Chen X, Luo Y, Shen J. Potential molecular targets of peroxynitrite in mediating blood-brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment. Free Radic Res  2018; 52(11-12): 1220-39.
[http://dx.doi.org/10.1080/10715762.2018.1521519] [PMID:  30468092] 
[61] 
Paspalj D, Nikic P, Savic M, et al. Redox status in acute ischemic stroke: correlation with clinical outcome. Mol Cell Biochem  2015; 406(1-2): 75-81.
[http://dx.doi.org/10.1007/s11010-015-2425-z] [PMID:  25916380] 
[62] 
Kahles T, Brandes RP. Which NADPH oxidase isoform is relevant for ischemic stroke?  The case for Nox 2 Antioxidants & redox Signaling  2013; 1400-7.
[63] 
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(12): e28393.
[http://dx.doi.org/10.1371/journal.pone.0028393] [PMID:  22164282] 
[64] 
Kahles T, Luedike P, Endres M, et al. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke  2007; 38(11): 3000-6.
[http://dx.doi.org/10.1161/STROKEAHA.107.489765] [PMID:  17916764] 
[65] 
Kleinschnitz C, Grund H, Wingler K, et al. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol  2010; 8(9): e1000479.
[http://dx.doi.org/10.1371/journal.pbio.1000479] [PMID:  20877715] 
[66] 
Jackman KA, Miller AA, De Silva TM, Crack PJ, Drummond GR, Sobey CG. Reduction of cerebral infarct volume by apocynin requires pretreatment and is absent in Nox2-deficient mice. Br J Pharmacol  2009; 156(4): 680-8.
[http://dx.doi.org/10.1111/j.1476-5381.2008.00073.x] [PMID:  19175604] 
[67] 
Girouard H, Wang G, Gallo EF, et al. NMDA receptor activation increases free radical production through nitric oxide and NOX2. J Neurosci  2009; 29(8): 2545-52.
[http://dx.doi.org/10.1523/JNEUROSCI.0133-09.2009] [PMID:  19244529] 
[68] 
Brennan AM, Suh SW, Won SJ, et al. NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci  2009; 12(7): 857-63.
[http://dx.doi.org/10.1038/nn.2334] [PMID:  19503084] 
[69] 
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.
[http://dx.doi.org/10.1016/j.redox.2014.05.006] [PMID:  24944913] 
[70] 
Brouns R, De Deyn PP. The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg  2009; 111(6): 483-95.
[http://dx.doi.org/10.1016/j.clineuro.2009.04.001] [PMID:  19446389] 
[71] 
Zhang R, Xu M, Wang Y, Xie F, Zhang G, Qin X. Nrf2-a promising therapeutic target for defensing against oxidative stress in stroke. Mol Neurobiol  2017; 54(8): 6006-17.
[http://dx.doi.org/10.1007/s12035-016-0111-0] [PMID:  27696223] 
[72] 
Tuo Y-H, Liu Z, Chen J-W, et al. NADPH oxidase inhibitor improves outcome of mechanical reperfusion by suppressing hemorrhagic transformation. J Neurointerv Surg  2017; 9(5): 492-8.
[http://dx.doi.org/10.1136/neurintsurg-2016-012377] [PMID:  27075483] 
[73] 
Akinlua I, Asaolu MF, Ojo OC, Oyebanji GO. Evaluation of Oxidative Stress and Antioxidant Level of Stroke Patients in Osun State, South-Western Nigeria. J Biosci Med (Irvine)  2019; 7(5): 189-94.
[http://dx.doi.org/10.4236/jbm.2019.75020] 
[74] 
Gariballa SE, Hutchin TP, Sinclair AJ. Antioxidant capacity after acute ischaemic stroke. QJM  2002; 95(10): 685-90.
[http://dx.doi.org/10.1093/qjmed/95.10.685] [PMID:  12324641] 
[75] 
Lorenzano S, Rost NS, Khan M, et al. Early molecular oxidative stress biomarkers of ischemic penumbra in acute stroke. Neurology  2019; 93(13): e1288-98.
[http://dx.doi.org/10.1212/WNL.0000000000008158] [PMID:  31455665] 
[76] 
Lorenzano S, Rost NS, Khan M, et al. Oxidative stress biomarkers of brain damage: Hyperacute plasma F2-isoprostane predicts infarct growth in stroke. Stroke  2018; 49(3): 630-7.
[http://dx.doi.org/10.1161/STROKEAHA.117.018440] [PMID:  29371434] 
[77] 
Forouzanfar F, Shojapour M, Asgharzade S, Amini E. Causes and consequences of microrna dysregulation following cerebral ischemia-reperfusion injury. CNS Neurol Disord Drug Targets  2019; 18(3): 212-21.
[http://dx.doi.org/10.2174/1871527318666190204104629] [PMID:  30714533] 
[78] 
Fink G. Stress: Physiology, Biochemistry, and Pathology: Handbook of Stress Series. Academic Press 2019.
[79] 
Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci  1990; 13: 171-82.
[http://dx.doi.org/10.1146/annurev.ne.13.030190.001131] [PMID:  1970230] 
[80] 
Pose-Utrilla J, García-Guerra L, Del Puerto A, et al. Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1. Nat Commun  2017; 8(1): 2275.
[http://dx.doi.org/10.1038/s41467-017-02322-5] [PMID:  29273751] 
[81] 
Depp C, Bas-Orth C, Schroeder L, Hellwig A, Bading H. Synaptic activity protects neurons against calcium-mediated oxidation and contraction of mitochondria during excitotoxicity. Antioxid Redox Signal  2018; 29(12): 1109-24.
[http://dx.doi.org/10.1089/ars.2017.7092] [PMID:  28990420] 
[82] 
Rebai O, Belkhir M, Sanchez-Gomez MV, Matute C, Fattouch S, Amri M. Differential molecular targets for neuroprotective effect of chlorogenic acid and its related compounds against glutamate induced excitotoxicity and oxidative stress in rat cortical neurons. Neurochem Res  2017; 42(12): 3559-72.
[http://dx.doi.org/10.1007/s11064-017-2403-9] [PMID:  28948515] 
[83] 
Marosi K, Kim SW, Moehl K, et al. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. J Neurochem  2016; 139(5): 769-81.
[http://dx.doi.org/10.1111/jnc.13868] [PMID:  27739595] 
[84] 
Yilmaz G, Granger DN. Cell adhesion molecules and ischemic stroke. Neurol Res  2008; 30(8): 783-93.
[http://dx.doi.org/10.1179/174313208X341085] [PMID:  18826804] 
[85] 
Kim JY, Park J, Chang JY, Kim S-H, Lee JE. Inflammation after ischemic stroke: The role of leukocytes and glial cells. Exp Neurobiol  2016; 25(5): 241-51.
[http://dx.doi.org/10.5607/en.2016.25.5.241] [PMID:  27790058] 
[86] 
Song YS, Lee Y-S, Narasimhan P, Chan PH. Reduced oxidative stress promotes NF-kappaB-mediated neuroprotective gene expression after transient focal cerebral ischemia: lymphocytotrophic cytokines and antiapoptotic factors. J Cereb Blood Flow Metab  2007; 27(4): 764-75.
[http://dx.doi.org/10.1038/sj.jcbfm.9600379] [PMID:  16868554] 
[87] 
Choi S, Kim JA, Na H-Y, et al. NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia. Free Radic Biol Med  2013; 57: 10-21.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.12.009] [PMID:  23261940] 
[88] 
Song YS, Kim M-S, Kim H-A, et al. Oxidative stress increases phosphorylation of IkappaB kinase-α by enhancing NF-kappaBinducing kinase after transient focal cerebral ischemia. J Cereb Blood Flow Metab  2010; 30(7): 1265-74.
[http://dx.doi.org/10.1038/jcbfm.2010.6] [PMID:  20125184] 
[89] 
Wiesner P, Choi S-H, Almazan F, et al. Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor κ B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia. Circ Res  2010; 107(1): 56-65.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.218420] [PMID:  20489162] 
[90] 
Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surg Neurol  2006; 66(3): 232-45.
[http://dx.doi.org/10.1016/j.surneu.2005.12.028] [PMID:  16935624] 
[91] 
Prakash R, Carmichael ST. Blood-brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury. Curr Opin Neurol  2015; 28(6): 556-64.
[http://dx.doi.org/10.1097/WCO.0000000000000248] [PMID:  26402408] 
[92] 
Rochfort KD, Cummins PM. The blood-brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem Soc Trans  2015; 43(4): 702-6.
[http://dx.doi.org/10.1042/BST20140319] [PMID:  26551716] 
[93] 
Hu X, Li P, Guo Y, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke  2012; 43(11): 3063-70.
[http://dx.doi.org/10.1161/STROKEAHA.112.659656] [PMID:  22933588] 
[94] 
Zhao X, Wang H, Sun G, Zhang J, Edwards NJ, Aronowski J. Neuronal interleukin-4 as a modulator of microglial pathways and ischemic brain damage. J Neurosci  2015; 35(32): 11281-91.
[http://dx.doi.org/10.1523/JNEUROSCI.1685-15.2015] [PMID:  26269636] 
[95] 
Bai J, Lyden PD. Revisiting cerebral postischemic reperfusion injury: new insights in understanding reperfusion failure, hemorrhage, and edema. Int J Stroke  2015; 10(2): 143-52.
[http://dx.doi.org/10.1111/ijs.12434] [PMID:  25598025] 
[96] 
Shi Z-S, Duckwiler GR, Jahan R, et al. Early blood-brain barrier disruption after mechanical thrombectomy in acute ischemic stroke. J Neuroimaging  2018; 28(3): 283-8.
[http://dx.doi.org/10.1111/jon.12504] [PMID:  29484769] 
[97] 
Luby M, Hsia AW, Nadareishvili Z, et al. Frequency of blood-brain barrier disruption post-endovascular therapy and multiple thrombectomy passes in acute ischemic stroke patients. Stroke  2019; 50(8): 2241-4.
[http://dx.doi.org/10.1161/STROKEAHA.119.025914] [PMID:  31238832] 
[98] 
Offner H, Subramanian S, Parker SM, Afentoulis ME, Vandenbark AA, Hurn PD. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab  2006; 26(5): 654-65.
[http://dx.doi.org/10.1038/sj.jcbfm.9600217] [PMID:  16121126] 
[99] 
Liesz A, Zhou W, Mracskó É, et al. Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke. Brain  2011; 134(Pt 3): 704-20.
[http://dx.doi.org/10.1093/brain/awr008] [PMID:  21354973] 
[100] 
Kriz J. Inflammation in ischemic brain injury: Timing is important Critical ReviewsTM in Neurobiology  2006; 145-57.
[101] 
Lucas S-M, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol  2006; 147(Suppl. 1): S232-40.
[http://dx.doi.org/10.1038/sj.bjp.0706400] [PMID:  16402109] 
[102] 
Ridder DA, Schwaninger M. NF-kappaB signaling in cerebral ischemia. Neuroscience  2009; 158(3): 995-1006.
[http://dx.doi.org/10.1016/j.neuroscience.2008.07.007] [PMID:  18675321] 
[103] 
Harari OA, Liao JK. NF-κB and innate immunity in ischemic stroke. Ann N Y Acad Sci  2010; 1207: 32-40.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05735.x] [PMID:  20955423] 
[104] 
McColl BW, Allan SM, Rothwell NJ. Systemic infection, inflammation and acute ischemic stroke. Neuroscience  2009; 158(3): 1049-61.
[http://dx.doi.org/10.1016/j.neuroscience.2008.08.019] [PMID:  18789376] 
[105] 
Pan J, Palmateer J, Schallert T, et al. Novel humanized recombinant T cell receptor ligands protect the female brain after experimental stroke. Transl Stroke Res  2014; 5(5): 577-85.
[http://dx.doi.org/10.1007/s12975-014-0345-y] [PMID:  24838614] 
[106] 
Tokgoz S, Kayrak M, Akpinar Z, Seyithanoğlu A, Güney F, Yürüten B. Neutrophil lymphocyte ratio as a predictor of stroke. J Stroke Cerebrovasc Dis  2013; 22(7): 1169-74.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.01.011] [PMID:  23498372] 
[107] 
Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab  2014; 34(2): 185-99.
[http://dx.doi.org/10.1038/jcbfm.2013.203] [PMID:  24281743] 
[108] 
Turner RJ, Sharp FR. Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci  2016; 10: 56.
[http://dx.doi.org/10.3389/fncel.2016.00056] [PMID:  26973468] 
[109] 
Wang L, Wei C, Deng L, et al. The accuracy of serum matrix metalloproteinase-9 for predicting hemorrhagic transformation after acute ischemic stroke: A systematic review and meta-analysis. J Stroke Cerebrovasc Dis  2018; 27(6): 1653-65.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.01.023] [PMID:  29598905] 
[110] 
Yagi K, Kitazato KT, Uno M, et al. Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator. Stroke  2009; 40(2): 626-31.
[http://dx.doi.org/10.1161/STROKEAHA.108.520262] [PMID:  19095969] 
[111] 
Lapchak PA. Hemorrhagic transformation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep  2002; 2(1): 38-43.
[http://dx.doi.org/10.1007/s11910-002-0051-0] [PMID:  11898581] 
[112] 
Chaturvedi M, Kaczmarek L. Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol Neurobiol  2014; 49(1): 563-73.
[http://dx.doi.org/10.1007/s12035-013-8538-z] [PMID:  24026771] 
[113] 
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol  2010; 11(10): 700-14.
[http://dx.doi.org/10.1038/nrm2970] [PMID:  20823910] 
[114] 
Datta A, Sarmah D, Mounica L, et al. Cell Death Pathways in Ischemic Stroke and Targeted Pharmacotherapy Transl Stroke Res 2020; Online ahead of print 
[http://dx.doi.org/10.1007/s12975-020-00806-z] [PMID:  32219729] 
[115] 
Uzdensky AB. Apoptosis regulation in the penumbra after ischemic stroke: expression of pro- and antiapoptotic proteins. Apoptosis  2019; 24(9-10): 687-702.
[http://dx.doi.org/10.1007/s10495-019-01556-6] [PMID:  31256300] 
[116] 
Seko Y, Fujimura T, Yao T, et al. Secreted tyrosine sulfated-eIF5A mediates oxidative stress-induced apoptosis. Sci Rep  2015; 5: 13737.
[http://dx.doi.org/10.1038/srep13737] [PMID:  26348594] 
[117] 
Kishimoto M, Suenaga J, Takase H, et al. Oxidative stressresponsive apoptosis inducing protein (ORAIP) plays a critical role in cerebral ischemia/reperfusion injury. Sci Rep  2019; 9(1): 13512.
[http://dx.doi.org/10.1038/s41598-019-50073-8] [PMID:  31534168] 
[118] 
Liu N-N, Dong Z-L, Han L-L. MicroRNA-410 inhibition of the TIMP2-dependent MAPK pathway confers neuroprotection against oxidative stress-induced apoptosis after ischemic stroke in mice. Brain Res Bull  2018; 143: 45-57.
[http://dx.doi.org/10.1016/j.brainresbull.2018.09.009] [PMID:  30240841] 
[119] 
Sun X-Z, Liao Y, Li W, Guo L-M. Neuroprotective effects of polysaccharides against oxidative stress-induced neuronal apoptosis. Neural Regen Res  2017; 12: 953-8.
[http://dx.doi.org/10.4103/1673-5374.208590] [PMID:  28761429] 
[120] 
Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2013; 3488-59.
[http://dx.doi.org/10.1016/j.bbamcr.2013.06.001] 
[121] 
Culmsee C, Zhu C, Landshamer S, et al. Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci  2005; 25(44): 10262-72.
[http://dx.doi.org/10.1523/JNEUROSCI.2818-05.2005] [PMID:  16267234] 
[122] 
Broughton BRS, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke  2009; 40(5): e331-9.
[http://dx.doi.org/10.1161/STROKEAHA.108.531632] [PMID:  19182083] 
[123] 
Andrabi SS, Parvez S, Tabassum H. Ischemic stroke and mitochondria: mechanisms and targets. Protoplasma  2020; 257(2): 335-43.
[http://dx.doi.org/10.1007/s00709-019-01439-2] [PMID:  31612315] 
[124] 
Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol  2019; 20(3): 175-93.
[http://dx.doi.org/10.1038/s41580-018-0089-8] [PMID:  30655609] 
[125] 
Moldoveanu T, Czabotar PE. BAX, BAK, and BOK: A coming of age for the BCL-2 family effector proteins. Cold Spring Harb Perspect Biol  2020; 12(4): a036319.
[http://dx.doi.org/10.1101/cshperspect.a036319] [PMID:  31570337] 
[126] 
Ahmad M, Dar NJ, Bhat ZS, et al. Inflammation in ischemic stroke: mechanisms, consequences and possible drug targets. CNS Neurol Disord Drug Targets  2014; 13(8): 1378-96.
[http://dx.doi.org/10.2174/1871527313666141023094720] [PMID:  25345517] 
[127] 
Hüttemann 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.
[http://dx.doi.org/10.1007/978-1-4614-3573-0_10] [PMID:  22729861] 
[128] 
Elkon KB. Review: Cell death, nucleic acids, and immunity: inflammation beyond the grave. Arthritis Rheumatol  2018; 70(6): 805-16.
[http://dx.doi.org/10.1002/art.40452] [PMID:  29439290] 
[129] 
Dostert C, Grusdat M, Letellier E, Brenner D. The TNF family of ligands and receptors: communication modules in the immune system and beyond. Physiol Rev  2019; 99(1): 115-60.
[http://dx.doi.org/10.1152/physrev.00045.2017] [PMID:  30354964] 
[130] 
Hollville E, Romero SE, Deshmukh M. Apoptotic cell death regulation in neurons. FEBS J  2019; 286(17): 3276-98.
[http://dx.doi.org/10.1111/febs.14970] [PMID:  31230407] 
[131] 
Kesavardhana S, Malireddi RKS, Kanneganti T-D. Caspases in Cell Death, Inflammation, and Gasdermin-Induced Pyroptosis. Annu Rev Immunol  2020; 38: 567-95.
[http://dx.doi.org/10.1146/annurev-immunol-073119-095439] [PMID:  32017655] 
[132] 
Deng YH, He HY, Yang LQ, Zhang PY. Dynamic changes in neuronal autophagy and apoptosis in the ischemic penumbra following permanent ischemic stroke. Neural Regen Res  2016; 11(7): 1108-14.
[http://dx.doi.org/10.4103/1673-5374.187045] [PMID:  27630694] 
[133] 
Li Q, Dai Z, Cao Y, Wang L. Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-κB activation. Biochem Biophys Res Commun  2019; 513(2): 479-85.
[http://dx.doi.org/10.1016/j.bbrc.2019.03.202] [PMID:  30979498] 
[134] 
Luan P, Xu J, Ding X, et al. Neuroprotective effect of salvianolate on cerebral ischaemia-reperfusion injury in rats by inhibiting the Caspase-3 signal pathway. Eur J Pharmacol  2020; 872: 172944.
[http://dx.doi.org/10.1016/j.ejphar.2020.172944] [PMID:  31978424] 
[135] 
He F, Zhang N, Lv Y, Sun W, Chen H. Lowdose lipopolysaccharide inhibits neuronal apoptosis induced by cerebral ischemia/reperfusion injury via the PI3K/Akt/FoxO1 signaling pathway in rats. Mol Med Rep  2019; 19(3): 1443-52.
[http://dx.doi.org/10.3892/mmr.2019.9827] [PMID:  30628689] 
[136] 
Wei N, Xiao L, Xue R, et al. MicroRNA-9 mediates the cell apoptosis by targeting Bcl2l11 in ischemic stroke. Mol Neurobiol  2016; 53(10): 6809-17.
[http://dx.doi.org/10.1007/s12035-015-9605-4] [PMID:  26660116] 
[137] 
Hong L-Z, Zhao X-Y, Zhang H-L. p53-mediated neuronal cell death in ischemic brain injury. Neurosci Bull  2010; 26(3): 232-40.
[http://dx.doi.org/10.1007/s12264-010-1111-0] [PMID:  20502500] 
[138] 
Ki Y-W, Lee JE, Park JH, Shin IC, Koh HC. Reactive oxygen species and mitogen-activated protein kinase induce apoptotic death of SH-SY5Y cells in response to fipronil. Toxicol Lett  2012; 211(1): 18-28.
[http://dx.doi.org/10.1016/j.toxlet.2012.02.022] [PMID:  22421270] 
[139] 
Noshita N, Lewén A, Sugawara T, Chan PH. Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab  2001; 21(12): 1442-50.
[http://dx.doi.org/10.1097/00004647-200112000-00009] [PMID:  11740206] 
[140] 
Neumar RW. Molecular mechanisms of ischemic neuronal injury. Ann Emerg Med  2000; 36(5): 483-506.
[http://dx.doi.org/10.1016/S0196-0644(00)82028-4] [PMID:  11054204] 
[141] 
Hunyadi A. The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites. Med Res Rev  2019; 39(6): 2505-33.
[http://dx.doi.org/10.1002/med.21592] [PMID:  31074028] 
[142] 
Komsiiska D. Oxidative stress and stroke: a review of upstream and downstream antioxidant therapeutic options. Comp Clin Pathol  2019; 28: 915-26.
[http://dx.doi.org/10.1007/s00580-019-02940-z] 
[143] 
Zhang A, Qian Y, Qian J. MicroRNA-152-3p protects neurons from oxygen-glucose-deprivation/reoxygenation-induced injury through upregulation of Nrf2/ARE antioxidant signaling by targeting PSD-93. Biochem Biophys Res Commun  2019; 517(1): 69-76.
[http://dx.doi.org/10.1016/j.bbrc.2019.07.012] [PMID:  31326116] 
[144] 
Bao H, Gao M. Overexpression of lemur tyrosine kinase-2 protects neurons from oxygen-glucose deprivation/reoxygenation-induced injury through reinforcement of Nrf2 signaling by modulating GSK-3β phosphorylation. Biochem Biophys Res Commun  2020; 521(4): 964-70.
[http://dx.doi.org/10.1016/j.bbrc.2019.11.002] [PMID:  31722791] 
[145] 
Hoang TT, Johnson DA, Raines RT, Johnson JA. Angiogenin activates the astrocytic Nrf2/antioxidant-response element pathway and thereby protects murine neurons from oxidative stress. J Biol Chem  2019; 294(41): 15095-103.
[http://dx.doi.org/10.1074/jbc.RA119.008491] [PMID:  31431502] 
[146] 
Zhao W, Zhang X, Chen Y, Shao Y, Feng Y. Downregulation of TRIM8 protects neurons from oxygen-glucose deprivation/re-oxygenation-induced injury through reinforcement of the AMPK/Nrf2/ARE antioxidant signaling pathway. Brain Res  2020; 1728: 146590.
[http://dx.doi.org/10.1016/j.brainres.2019.146590] [PMID:  31862654] 
[147] 
Wang M, Li C, Shi W. Stomatin-like protein-2 confers neuroprotection effect in oxygen-glucose deprivation/reoxygenation-injured neurons by regulating AMPK/Nrf2 signalling. J Drug Target  2019; 28(6): 600-8.
[http://dx.doi.org/10.1080/1061186X.2019.1700262] [PMID:  31791154] 
[148] 
He Q, Song N, Jia F, et al. Role of α-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase-1 pathway in iron-induced neurotoxicity. Int J Biochem Cell Biol  2013; 45(6): 1019-30.
[http://dx.doi.org/10.1016/j.biocel.2013.02.012] [PMID:  23454680] 
[149] 
Kobayashi EH, Suzuki T, Funayama R, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun  2016; 7: 11624.
[http://dx.doi.org/10.1038/ncomms11624] [PMID:  27211851] 
[150] 
Li W, Suwanwela NC, Patumraj S. Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R. Microvasc Res  2016; 106: 117-27.
[http://dx.doi.org/10.1016/j.mvr.2015.12.008] [PMID:  26686249] 
[151] 
Ashabi G, Khalaj L, Khodagholi F, Goudarzvand M, Sarkaki A. Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab Brain Dis  2015; 30(3): 747-54.
[http://dx.doi.org/10.1007/s11011-014-9632-2] [PMID:  25413451] 
[152] 
Liu Y, Tang G, Li Y, et al. Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. J Neuroinflammation  2014; 11: 177.
[http://dx.doi.org/10.1186/s12974-014-0177-4] [PMID:  25315906] 
[153] 
Kobayashi A, Ohta T, Yamamoto M. Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying Quinones and Quinone Enzymes, Part A  2004; 273-86.
[http://dx.doi.org/10.1016/S0076-6879(04)78021-0] 
[154] 
Bereczki D Jr, Balla J, Bereczki D. Heme oxygenase-1: Clinical relevance in ischemic stroke. Curr Pharm Des  2018; 24(20): 2229-35.
[http://dx.doi.org/10.2174/1381612824666180717101104] [PMID:  30014798] 
[155] 
Kaiser S, Frase S, Selzner L, et al. Neuroprotection after hemorrhagic stroke depends on cerebral heme oxygenase-1. Antioxidants  2019; 8(10): E496.
[http://dx.doi.org/10.3390/antiox8100496] [PMID:  31635102] 
[156] 
Balla J, Vercellotti GM, Jeney V, et al. Heme, heme oxygenase, and ferritin: How the vascular endothelium survives (and Dies) in an iron-rich environment Antioxidants & Redox Signaling  2007; 2119-38.
[157] 
Cui H-Y, Zhang X-J, Yang Y, et al. Rosmarinic acid elicits neuroprotection in ischemic stroke via Nrf2 and heme oxygenase 1 signaling. Neural Regen Res  2018; 13(12): 2119-28.
[http://dx.doi.org/10.4103/1673-5374.241463] [PMID:  30323140] 
[158] 
McCarty DJ. Treating relapsing multiple sclerosis with dimethyl fumarate. Nurse Pract  2017; 42(7): 8-10.
[http://dx.doi.org/10.1097/01.NPR.0000520421.99157.15] [PMID:  28622251] 
[159] 
Yao Y, Miao W, Liu Z, et al. Dimethyl fumarate and monomethyl fumarate promote post-ischemic recovery in mice. Transl Stroke Res  2016; 7(6): 535-47.
[http://dx.doi.org/10.1007/s12975-016-0496-0] [PMID:  27614618] 
[160] 
Kunze R, Urrutia A, Hoffmann A, et al. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity. Exp Neurol  2015; 266: 99-111.
[http://dx.doi.org/10.1016/j.expneurol.2015.02.022] [PMID:  25725349] 
[161] 
Schrör K, Rauch BH. Aspirin and lipid mediators in the cardiovascular system Prostaglandins Other Lipid Mediat  2015; 121(Pt A): 17-23.
[http://dx.doi.org/10.1016/j.prostaglandins.2015.07.004] [PMID:  26201059] 
[162] 
Shanab AY, Elshaer SL, El-Azab MF, et al. Candesartan stimulates reparative angiogenesis in ischemic retinopathy model: role of hemeoxygenase-1 (HO-1). Angiogenesis  2015; 18(2): 137-50.
[http://dx.doi.org/10.1007/s10456-014-9451-4] [PMID:  25420481] 
[163] 
Yang J, Liu C, Du X, et al. Hypoxia inducible factor 1α plays a key role in remote ischemic preconditioning against stroke by modulating inflammatory responses in rats. J Am Heart Assoc  2018; 7(5): e007589.
[http://dx.doi.org/10.1161/JAHA.117.007589] [PMID:  29478025] 
[164] 
Ogle ME, Gu X, Espinera AR, Wei L. Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor-1α. Neurobiol Dis  2012; 45(2): 733-42.
[http://dx.doi.org/10.1016/j.nbd.2011.10.020] [PMID:  22061780] 
[165] 
Sharp FR, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci  2004; 5(6): 437-48.
[http://dx.doi.org/10.1038/nrn1408] [PMID:  15152194] 
[166] 
Baranova O, Miranda LF, Pichiule P, Dragatsis I, Johnson RS, Chavez JC. Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci  2007; 27(23): 6320-32.
[http://dx.doi.org/10.1523/JNEUROSCI.0449-07.2007] [PMID:  17554006] 
[167] 
Umschweif G, Alexandrovich AG, Trembovler V, Horowitz M, Shohami E. Hypoxia-inducible factor 1 is essential for spontaneous recovery from traumatic brain injury and is a key mediator of heat acclimation induced neuroprotection. J Cereb Blood Flow Metab  2013; 33(4): 524-31.
[http://dx.doi.org/10.1038/jcbfm.2012.193] [PMID:  23281425] 
[168] 
Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK. NAcetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res  2003; 971(1): 1-8.
[http://dx.doi.org/10.1016/S0006-8993(03)02244-3] [PMID:  12691831] 
[169] 
Niu Y-L, Li C, Zhang G-Y. Blocking Daxx trafficking attenuates neuronal cell death following ischemia/reperfusion in rat hippocampus CA1 region. Arch Biochem Biophys  2011; 515(1-2): 89-98.
[http://dx.doi.org/10.1016/j.abb.2011.07.016] [PMID:  21843499] 
[170] 
Knuckey NW, Palm D, Primiano M, Epstein MH, Johanson CE. Nacetylcysteine enhances hippocampal neuronal survival after transient forebrain ischemia in rats. Stroke  1995; 26(2): 305-10.
[http://dx.doi.org/10.1161/01.STR.26.2.305] [PMID:  7831704] 
[171] 
Zhang Q-G, Tian H, Li H-C, Zhang G-Y. Antioxidant N-acetylcysteine inhibits the activation of JNK3 mediated by the GluR6-PSD95-MLK3 signaling module during cerebral ischemia in rat hippocampus. Neurosci Lett  2006; 408(3): 159-64.
[http://dx.doi.org/10.1016/j.neulet.2006.07.007] [PMID:  17030433] 
[172] 
Zhang Z, Yan J, Taheri S, Liu KJ, Shi H. Hypoxia-inducible factor 1 contributes to N-acetylcysteine’s protection in stroke. Free Radic Biol Med  2014; 68: 8-21.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.11.007] [PMID:  24296245] 
[173] 
Dinkova-Kostova AT, Talalay P. Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res  2008; 52(Suppl. 1): S128-38.
[http://dx.doi.org/10.1002/mnfr.200700195] [PMID:  18327872] 
[174] 
Del Rio D, Agnoli C, Pellegrini N, et al. Total antioxidant capacity of the diet is associated with lower risk of ischemic stroke in a large Italian cohort. J Nutr  2011; 141(1): 118-23.
[http://dx.doi.org/10.3945/jn.110.125120] [PMID:  21106923] 
[175] 
Jayedi A, Rashidy-Pour A, Parohan M, Zargar MS, Shab-Bidar S. Dietary and circulating vitamin C, vitamin E, β-carotene and risk of total cardiovascular mortality: a systematic review and doseresponse meta-analysis of prospective observational studies. Public Health Nutr  2019; 22(10): 1872-87.
[http://dx.doi.org/10.1017/S1368980018003725] [PMID:  30630552] 
[176] 
Lee C-H, Chan RSM, Wan HYL, et al. Dietary intake of antioxidant vitamins A, C, and E is inversely associated with adverse cardiovascular outcomes in Chinese-A 22-years population-based prospective study. Nutrients  2018; 10(11): 1664.
[http://dx.doi.org/10.3390/nu10111664] [PMID:  30400367] 
[177] 
Chen G-C, Lu D-B, Pang Z, Liu Q-F. Vitamin C intake, circulating vitamin C and risk of stroke: a meta-analysis of prospective studies. J Am Heart Assoc  2013; 2(6): e000329.
[http://dx.doi.org/10.1161/JAHA.113.000329] [PMID:  24284213] 
[178] 
Dauchet L, Amouyel P, Dallongeville J. Fruit and vegetable consumption and risk of stroke: a meta-analysis of cohort studies. Neurology  2005; 65(8): 1193-7.
[http://dx.doi.org/10.1212/01.wnl.0000180600.09719.53] [PMID:  16247045] 
[179] 
Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med  2004; 140(7): 533-7.
[http://dx.doi.org/10.7326/0003-4819-140-7-200404060-00010] [PMID:  15068981] 
[180] 
Jackson TS, Xu A, Vita JA, Keaney JF Jr. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res  1998; 83(9): 916-22.
[http://dx.doi.org/10.1161/01.RES.83.9.916] [PMID:  9797340] 
[181] 
Lykkesfeldt J, Tveden-Nyborg P. The pharmacokinetics of vitamin C. Nutrients  2019; 11(10): E2412.
[http://dx.doi.org/10.3390/nu11102412] [PMID:  31601028] 
[182] 
Tao X, Su L, Wu J. Current studies on the enzymatic preparation 2-O-α-d-glucopyranosyl-l-ascorbic acid with cyclodextrin glycosyltransferase. Crit Rev Biotechnol  2019; 39(2): 249-57.
[http://dx.doi.org/10.1080/07388551.2018.1531823] [PMID:  30563366] 
[183] 
Han R, Liu L, Li J, Du G, Chen J. Functions, applications and production of 2-O-D-glucopyranosyl-L-ascorbic acid. Appl Microbiol Biotechnol  2012; 95(2): 313-20.
[http://dx.doi.org/10.1007/s00253-012-4150-9] [PMID:  22639144] 
[184] 
Figueroa-Méndez R, Rivas-Arancibia S. Vitamin C in health and disease: Its role in the metabolism of cells and redox state in the brain. Front Physiol  2015; 6: 397.
[http://dx.doi.org/10.3389/fphys.2015.00397] [PMID:  26779027] 
[185] 
Mandl J, Szarka A, Bánhegyi G. Vitamin C: update on physiology and pharmacology. Br J Pharmacol  2009; 157(7): 1097-110.
[http://dx.doi.org/10.1111/j.1476-5381.2009.00282.x] [PMID:  19508394] 
[186] 
de Oliveira BF, Costa DC, Nogueira-Machado JA, Chaves MM. β-Carotene, α-tocopherol and ascorbic acid: differential profile of antioxidant, inflammatory status and regulation of gene expression in human mononuclear cells of diabetic donors. Diabetes Metab Res Rev  2013; 29(8): 636-45.
[http://dx.doi.org/10.1002/dmrr.2439] [PMID:  23861227] 
[187] 
Li L, Li S, Hu C, et al. BKCa channel is a molecular target of vitamin C to protect against ischemic brain stroke. Mol Membr Biol  2019; 35(1): 9-20.
[http://dx.doi.org/10.1080/09687688.2019.1608378] [PMID:  30991005] 
[188] 
Lee P, Ulatowski LM, Vitamin E, Vitamin E. Mechanism of transport and regulation in the CNS. IUBMB Life  2019; 71(4): 424-9.
[http://dx.doi.org/10.1002/iub.1993] [PMID:  30556640] 
[189] 
Ulker S, McKeown PP, Bayraktutan U. Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities. Hypertension  2003; 41(3): 534-9.
[http://dx.doi.org/10.1161/01.HYP.0000057421.28533.37] [PMID:  12623955] 
[190] 
Cheng P, Wang L, Ning S, et al. Vitamin E intake and risk of stroke: a meta-analysis. Br J Nutr  2018; 120(10): 1181-8.
[http://dx.doi.org/10.1017/S0007114518002647] [PMID:  30401005] 
[191] 
Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ  2010; 341: c5702.
[http://dx.doi.org/10.1136/bmj.c5702] [PMID:  21051774] 
[192] 
Bin Q, Hu X, Cao Y, Gao F. The role of vitamin E (tocopherol) supplementation in the prevention of stroke. A meta-analysis of 13 randomised controlled trials. Thromb Haemost  2011; 105(4): 579-85.
[http://dx.doi.org/10.1160/TH10-11-0729] [PMID:  21264448] 
[193] 
Lagowska-Lenard M, Stelmasiak Z, Bartosik-Psujek H. Influence of vitamin C on markers of oxidative stress in the earliest period of ischemic stroke. Pharmacol Rep  2010; 62(4): 751-6.
[http://dx.doi.org/10.1016/S1734-1140(10)70334-0] [PMID:  20885017] 
[194] 
Shahidi F, Ambigaipalan P. Omega-3 polyunsaturated fatty acids and their health benefits. Annu Rev Food Sci Technol  2018; 9: 345-81.
[http://dx.doi.org/10.1146/annurev-food-111317-095850] [PMID:  29350557] 
[195] 
Wiktorowska-Owczarek A, Berezińska M, Nowak JZ. PUFAs: structures, metabolism and functions. Adv Clin Exp Med  2015; 24(6): 931-41.
[http://dx.doi.org/10.17219/acem/31243] [PMID:  26771963] 
[196] 
Rodríguez-Cruz M, Cruz-Guzmán ODR, Almeida-Becerril T, et al. Potential therapeutic impact of omega-3 long chain-polyunsaturated fatty acids on inflammation markers in Duchenne muscular dystrophy: A double-blind, controlled randomized trial. Clin Nutr  2018; 37(6 Pt A): 1840-51.
[http://dx.doi.org/10.1016/j.clnu.2017.09.011] [PMID:  28987470] 
[197] 
Zúñiga J, Cancino M, Medina F, et al. N-3 PUFA supplementation triggers PPAR-α activation and PPAR-α/NF-κB interaction: anti-inflammatory implications in liver ischemia-reperfusion injury. PLoS One  2011; 6(12): e28502.
[http://dx.doi.org/10.1371/journal.pone.0028502] [PMID:  22174823] 
[198] 
Xue B, Yang Z, Wang X, Shi H. Omega-3 polyunsaturated fatty acids antagonize macrophage inflammation via activation of AMPK/SIRT1 pathway. PLoS One  2012; 7(10): e45990.
[http://dx.doi.org/10.1371/journal.pone.0045990] [PMID:  23071533] 
[199] 
Manzi L, Costantini L, Molinari R, Merendino N. Effect of dietary ω-3 polyunsaturated fatty acid dha on glycolytic enzymes and warburg phenotypes in cancer. BioMed Res Int  2015; 2015: 137097.
[http://dx.doi.org/10.1155/2015/137097] [PMID:  26339588] 
[200] 
Venø SK, Bork CS, Jakobsen MU, et al. Marine n-3 polyunsaturated fatty acids and the risk of ischemic stroke. Stroke  2019; 50(2): 274-82.
[http://dx.doi.org/10.1161/STROKEAHA.118.023384] [PMID:  30602356] 
[201] 
Venø SK, Schmidt EB, Bork CS. Polyunsaturated fatty acids and risk of ischemic stroke. Nutrients  2019; 11(7): E1467.
[http://dx.doi.org/10.3390/nu11071467] [PMID:  31252664] 
[202] 
Milanlioglu A, Aslan M, Ozkol H, Çilingir V, Nuri Aydın M, Karadas S. Serum antioxidant enzymes activities and oxidative stress levels in patients with acute ischemic stroke: influence on neurological status and outcome. Wien Klin Wochenschr  2016; 128(5-6): 169-74.
[http://dx.doi.org/10.1007/s00508-015-0742-6] [PMID:  25854910] 
[203] 
Spranger M, Krempien S, Schwab S, Donneberg S, Hacke W. Superoxide dismutase activity in serum of patients with acute cerebral ischemic injury. Correlation with clinical course and infarct size. Stroke  1997; 28(12): 2425-8.
[http://dx.doi.org/10.1161/01.STR.28.12.2425] [PMID:  9412626] 
[204] 
Wang S, Ma F, Huang L, et al. Dl-3-n-Butylphthalide (NBP): A promising therapeutic agent for ischemic stroke. CNS Neurol Disord Drug Targets  2018; 17(5): 338-47.
[http://dx.doi.org/10.2174/1871527317666180612125843] [PMID:  29895257] 
[205] 
Li J, Liu Y, Zhang X, et al. Dl-3-N-butylphthalide alleviates the blood-brain barrier permeability of focal cerebral ischemia reperfusion in mice. Neuroscience  2019; 413: 99-107.
[http://dx.doi.org/10.1016/j.neuroscience.2019.06.020] [PMID:  31247236] 
[206] 
Qin C, Zhou P, Wang L, et al. Dl-3-N-butylphthalide attenuates ischemic reperfusion injury by improving the function of cerebral artery and circulation. J Cereb Blood Flow Metab  2019; 39(10): 2011-21.
[http://dx.doi.org/10.1177/0271678X18776833] [PMID:  29762050] 
[207] 
Xu Z-Q, Zhou Y, Shao B-Z, Zhang J-J, Liu C. A systematic review of neuroprotective efficacy and safety of dl-3-n-butylphthalide in ischemic stroke. Am J Chin Med  2019; 47(3): 507-25.
[http://dx.doi.org/10.1142/S0192415X19500265] [PMID:  30966774] 
[208] 
Kim JY, Lee JE, Yenari MA. Neuroprotection of heat shock proteins (HSPs) in brain ischemia Translational Medicine Research  2017; 383-95.
[http://dx.doi.org/10.1007/978-981-10-5804-2_17] 
[209] 
De Maio A. Extracellular Hsp70: export and function. Curr Protein Pept Sci  2014; 15(3): 225-31.
[http://dx.doi.org/10.2174/1389203715666140331113057] [PMID:  24694368] 
[210] 
Konstantinova EV, Chipigina NS, Shurdumova MH, Kovalenko EI, Sapozhnikov AM. Heat shock protein 70 kDa as a target for diagnostics and therapy of cardiovascular and cerebrovascular diseases. Curr Pharm Des  2019; 25(6): 710-4.
[http://dx.doi.org/10.2174/1381612825666190329123924] [PMID:  30931849] 
[211] 
Mohammadi F, Nezafat N, Negahdaripour M, et al. Neuroprotective effects of heat shock protein70. CNS Neurol Disord Drug Targets  2018; 17(10): 736-42.
[http://dx.doi.org/10.2174/1871527317666180827111152] [PMID:  30147017] 
[212] 
Kim JY, Kim N, Zheng Z, Lee JE, Yenari MA. 70-kDa heat shock protein downregulates dynamin in experimental stroke: A new therapeutic target? Stroke  2016; 47(8): 2103-11.
[http://dx.doi.org/10.1161/STROKEAHA.116.012763] [PMID:  27387989] 
[213] 
Kim JY, Kim JW, Yenari MA. Heat shock protein signaling in brain ischemia and injury. Neurosci Lett  2020; 715: 134642.
[http://dx.doi.org/10.1016/j.neulet.2019.134642] [PMID:  31759081] 
[214] 
Rodrigo R, Fernández-Gajardo R, Gutiérrez R, et al. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets  2013; 12(5): 698-714.
[http://dx.doi.org/10.2174/1871527311312050015] [PMID:  23469845] 
[215] 
An P, Xie J, Qiu S, et al. Hispidulin exhibits neuroprotective activities against cerebral ischemia reperfusion injury through suppressing NLRP3-mediated pyroptosis. Life Sci  2019; 232: 116599.
[http://dx.doi.org/10.1016/j.lfs.2019.116599] [PMID:  31247210] 
[216] 
Cui L, Zhang X, Yang R, et al. Baicalein is neuroprotective in rat MCAO model: role of 12/15-lipoxygenase, mitogen-activated protein kinase and cytosolic phospholipase A2. Pharmacol Biochem Behav  2010; 96(4): 469-75.
[http://dx.doi.org/10.1016/j.pbb.2010.07.007] [PMID:  20637223] 
[217] 
Rodrigo R, Korantzopoulos P, Cereceda M, et al. A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement. J Am Coll Cardiol  2013; 62(16): 1457-65.
[http://dx.doi.org/10.1016/j.jacc.2013.07.014] [PMID:  23916928] 
Cite As
Current Pharmaceutical Design

Pathophysiology of Ischemic Stroke: Role of Oxidative Stress

Abstract
