{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:02:59Z","timestamp":1785416579185,"version":"3.56.0"},"reference-count":157,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Global brain ischemia-reperfusion (I\/R) injury manifests as selective neuronal vulnerability rather than uniform tissue damage. Specific neuroanatomical regions\u2014most notably the hippocampal cornu ammonis 1 (CA1) subfield, striatum, and cerebellum\u2014exhibit a heightened susceptibility to oxidative stress\u2013induced degeneration. This review consolidates current understanding regarding the region- and cell-specific vulnerability to reactive oxygen species (ROS) following global I\/R, highlighting the molecular and cellular determinants that drive this selectivity. We examine the spatial distribution of ROS-generating systems, including NADPH oxidases (NOX2\/NOX4) and mitochondrial complexes, alongside the divergent expression of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase. Inherent neuronal properties, such as elevated synaptic activity, calcium permeability, and rigorous metabolic demands, further exacerbate oxidative injury. Additionally, we evaluate how astrocyte\u2013neuron interactions and regional variations in blood\u2013brain barrier (BBB) integrity modulate the severity and progression of ROS-induced damage. The roles of astrocytic endfoot polarization, aquaporin-4 (AQP4) localization, and Kir4.1-mediated potassium buffering in post-ischemic outcomes are also discussed. Furthermore, this review surveys emerging antioxidant-based therapies\u2014ranging from edaravone and melatonin to selenium nanoparticles and miRNA-based interventions\u2014while addressing translational hurdles like narrow therapeutic windows and inter-individual variability. By synthesizing experimental and translational evidence, this work provides a comprehensive framework for understanding oxidative stress\u2013related vulnerability in I\/R injury. Ultimately, it underscores the necessity for precision antioxidant strategies tailored to brain-region specificity, pathophysiological timing, and patient-specific factors to improve clinical outcomes.<\/jats:p>","DOI":"10.31083\/fbl48324","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:17:49Z","timestamp":1785413869000},"source":"Crossref","is-referenced-by-count":0,"title":["Region- and Cell-Specific Vulnerability to ROS After Global Brain Ischemia-Reperfusion Injury: Molecular and Cellular Mechanisms"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2283-6066","authenticated-orcid":true,"given":"Bo Hyun","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Anatomy, College of Dentistry and Research Institute for Dental Engineering, Kangwon National University, 25457 Gangneung, Gangwon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0575-275X","authenticated-orcid":true,"given":"Ki-Yeon","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Anatomy, College of Dentistry and Research Institute for Dental Engineering, Kangwon National University, 25457 Gangneung, Gangwon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia\/reperfusion injury. International Review of Cell and Molecular Biology. 2012; 298: 229\u2013317.","DOI":"10.1016\/B978-0-12-394309-5.00006-7"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Candelario-Jalil E, Paul S. Impact of aging and comorbidities on ischemic stroke outcomes in preclinical animal models: A translational perspective. Experimental Neurology. 2021; 335: 113494.","DOI":"10.1016\/j.expneurol.2020.113494"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Pulsinelli WA, Brierley JB. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke. 1979; 10: 267\u2013272.","DOI":"10.1161\/01.str.10.3.267"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Research. 1982; 239: 57\u201369.","DOI":"10.1016\/0006-8993(82)90833-2"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Cho JH, Tae HJ, Kim IS, Song M, Kim H, Lee TK, et al. Melatonin alleviates asphyxial cardiac arrest-induced cerebellar Purkinje cell death by attenuation of oxidative stress. Experimental Neurology. 2019; 320: 112983.","DOI":"10.1016\/j.expneurol.2019.112983"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Lee CH, Ahn JH, Won MH. Factors Contributing to Resistance to Ischemia-Reperfusion Injury in Olfactory Mitral Cells. International Journal of Molecular Sciences. 2025; 26: 5079.","DOI":"10.3390\/ijms26115079"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Tarafdar A, Pula G. The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders. International Journal of Molecular Sciences. 2018; 19: 3824.","DOI":"10.3390\/ijms19123824"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Norat P, Soldozy S, Sokolowski JD, Gorick CM, Kumar JS, Chae Y, et al. Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation. NPJ Regenerative Medicine. 2020; 5: 22.","DOI":"10.1038\/s41536-020-00107-x"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Fang J, Sheng R, Qin ZH. NADPH Oxidases in the Central Nervous System: Regional and Cellular Localization and the Possible Link to Brain Diseases. Antioxidants & Redox Signaling. 2021; 35: 951\u2013973.","DOI":"10.1089\/ars.2021.0040"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Szu JI, Binder DK. Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy. Frontiers in Cellular Neuroscience. 2022; 16: 900588.","DOI":"10.3389\/fncel.2022.900588"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Tyurikova O, Kopach O, Zheng K, Rathore D, Codadu N, Wu SY, et al. Astrocyte Kir4.1 expression level territorially controls excitatory transmission in the brain. Cell Reports. 2025; 44: 115299.","DOI":"10.1016\/j.celrep.2025.115299"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Liu H, Tan AYS, Mehrabi NF, Turner CP, Curtis MA, Faull RLM, et al. Astrocytic proteins involved in regulation of the extracellular environment are increased in the Alzheimer's disease middle temporal gyrus. Neurobiology of Disease. 2025; 204: 106749.","DOI":"10.1016\/j.nbd.2024.106749"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Sies H, Belousov VV, Chandel NS, Davies MJ, Jones DP, Mann GE, et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nature reviews Molecular cell biology. 2022; 23: 499\u2013515.","DOI":"10.1038\/s41580-022-00456-z"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Salaudeen MA, Bello N, Danraka RN, Ammani ML. Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones. Biomolecules. 2024; 14: 305.","DOI":"10.3390\/biom14030305"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Mu Q, Xue Y, Lu Y, Zhang Y, Cheng Q, Wan J, et al. Advances in the therapy of cerebral ischemia-reperfusion injury with natural product-based nanoparticles. Nano TransMed. 2022; 1: e9130009.","DOI":"10.26599\/NTM.2022.9130009"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Chen C, Ma J, Duan S, Xue M, Yang Z, Ma Z, et al. Mitigation of ischemia\/reperfusion injury via selenium nanoparticles: Suppression of STAT1 to inhibit cardiomyocyte oxidative stress and inflammation. Biomaterials. 2025; 318: 123119.","DOI":"10.1016\/j.biomaterials.2025.123119"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Yang M, Liu B, Chen B, Shen Y, Liu G. Cerebral ischemia-reperfusion injury: mechanisms and promising therapies. Frontiers in Pharmacology. 2025; 16: 1613464.","DOI":"10.3389\/fphar.2025.1613464"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Yang C, Jia X, Wang Y, Fan J, Zhao C, Yang Y, et al. Association between Dietary Total Antioxidant Capacity of Antioxidant Vitamins and the Risk of Stroke among US Adults. Antioxidants (Basel, Switzerland). 2022; 11: 2252.","DOI":"10.3390\/antiox11112252"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Huang Y, Ni Y, Yu L, Shu L, Zhu Q, He X. Dietary total antioxidant capacity and risk of stroke: a systematic review and dose-response meta-analysis of observational studies. Frontiers in Nutrition. 2024; 11: 1451386.","DOI":"10.3389\/fnut.2024.1451386"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Tkaczenko H, Kurhaluk N. Antioxidant-Rich Functional Foods and Exercise: Unlocking Metabolic Health Through Nrf2 and Related Pathways. International Journal of Molecular Sciences. 2025; 26: 1098.","DOI":"10.3390\/ijms26031098"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Savitz SI, Baron JC, Yenari MA, Sanossian N, Fisher M. Reconsidering Neuroprotection in the Reperfusion Era. Stroke. 2017; 48: 3413\u20133419.","DOI":"10.1161\/STROKEAHA.117.017283"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Muir KW. Heterogeneity of stroke pathophysiology and neuroprotective clinical trial design. Stroke. 2002; 33: 1545\u20131550.","DOI":"10.1161\/01.str.0000018684.86293.ab"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Bonkhoff AK, Grefkes C. Precision medicine in stroke: towards personalized outcome predictions using artificial intelligence. Brain : a Journal of Neurology. 2022; 145: 457\u2013475.","DOI":"10.1093\/brain\/awab439"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2001; 21: 2\u201314.","DOI":"10.1097\/00004647-200101000-00002"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxidants & Redox Signaling. 2011; 14: 1505\u20131517.","DOI":"10.1089\/ars.2010.3576"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox Biology. 2015; 6: 524\u2013551.","DOI":"10.1016\/j.redox.2015.08.020"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Candelario-Jalil E, Mhadu NH, Al-Dalain SM, Mart\u00ednez G, Le\u00f3n OS. Time course of oxidative damage in different brain regions following transient cerebral ischemia in gerbils. Neuroscience Research. 2001; 41: 233\u2013241.","DOI":"10.1016\/s0168-0102(01)00282-6"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Rodrigo R, Fern\u00e1ndez-Gajardo R, Guti\u00e9rrez R, Matamala JM, Carrasco R, Miranda-Merchak A, et al. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS & Neurological Disorders Drug Targets. 2013; 12: 698\u2013714.","DOI":"10.2174\/1871527311312050015"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Pawluk H, Tafelska-Kaczmarek A, Sopo\u0144ska M, Porzych M, Modrzejewska M, Pawluk M, et al. The Influence of Oxidative Stress Markers in Patients with Ischemic Stroke. Biomolecules. 2024; 14: 1130.","DOI":"10.3390\/biom14091130"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Angelova PR, Abramov AY. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS Letters. 2018; 592: 692\u2013702.","DOI":"10.1002\/1873-3468.12964"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Medvedeva YV, Ji SG, Yin HZ, Weiss JH. Differential Vulnerability of CA1 versus CA3 Pyramidal Neurons After Ischemia: Possible Relationship to Sources of Zn2+ Accumulation and Its Entry into and Prolonged Effects on Mitochondria. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2017; 37: 726\u2013737.","DOI":"10.1523\/JNEUROSCI.3270-16.2016"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Medvedeva YV, Sharman E, Weiss JH. Mechanisms of delayed ischemia\/reperfusion evoked ROS generation in the hippocampal CA1 zone of adult mouse brain slices. Scientific Reports. 2025; 15: 23439.","DOI":"10.1038\/s41598-025-07070-x"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Orellana-Urz\u00faa S, Rojas I, L\u00edbano L, Rodrigo R. Pathophysiology of Ischemic Stroke: Role of Oxidative Stress. Current Pharmaceutical Design. 2020; 26: 4246\u20134260.","DOI":"10.2174\/1381612826666200708133912"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Kahles T, Brandes RP. NADPH oxidases as therapeutic targets in ischemic stroke. Cellular and Molecular Life Sciences : CMLS. 2012; 69: 2345\u20132363.","DOI":"10.1007\/s00018-012-1011-8"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Yang Q, Huang Q, Hu Z, Tang X. Potential Neuroprotective Treatment of Stroke: Targeting Excitotoxicity, Oxidative Stress, and Inflammation. Frontiers in Neuroscience. 2019; 13: 1036.","DOI":"10.3389\/fnins.2019.01036"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Ren JX, Li C, Yan XL, Qu Y, Yang Y, Guo ZN. Crosstalk between Oxidative Stress and Ferroptosis\/Oxytosis in Ischemic Stroke: Possible Targets and Molecular Mechanisms. Oxidative Medicine and Cellular Longevity. 2021; 2021: 6643382.","DOI":"10.1155\/2021\/6643382"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Wilde GJ, Pringle AK, Wright P, Iannotti F. Differential vulnerability of the CA1 and CA3 subfields of the hippocampus to superoxide and hydroxyl radicals in vitro. Journal of Neurochemistry. 1997; 69: 883\u2013886.","DOI":"10.1046\/j.1471-4159.1997.69020883.x"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Einenkel AM, Salameh A. Selective vulnerability of hippocampal CA1 and CA3 pyramidal cells: What are possible pathomechanisms and should more attention be paid to the CA3 region in future studies? Journal of Neuroscience Research. 2024; 102: e25276.","DOI":"10.1002\/jnr.25276"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Vinokurov AY, Stelmashuk OA, Ukolova PA, Zherebtsov EA, Abramov AY. Brain region specificity in reactive oxygen species production and maintenance of redox balance. Free Radical Biology & Medicine. 2021; 174: 195\u2013201.","DOI":"10.1016\/j.freeradbiomed.2021.08.014"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"Shiino A, Matsuda M, Handa J, Chance B. Poor recovery of mitochondrial redox state in CA1 after transient forebrain ischemia in gerbils. Stroke. 1998; 29: 2421\u20134; discussion 2425.","DOI":"10.1161\/01.str.29.11.2421"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"Yin B, Barrionuevo G, Batinic-Haberle I, Sandberg M, Weber SG. Differences in Reperfusion-Induced Mitochondrial Oxidative Stress and Cell Death Between Hippocampal CA1 and CA3 Subfields Are Due to the Mitochondrial Thioredoxin System. Antioxidants & Redox Signaling. 2017; 27: 534\u2013549.","DOI":"10.1089\/ars.2016.6706"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Sun C, Fukushi Y, Wang Y, Yamamoto S. Astrocytes Protect Neurons in the Hippocampal CA3 Against Ischemia by Suppressing the Intracellular Ca2+ Overload. Frontiers in Cellular Neuroscience. 2018; 12: 280.","DOI":"10.3389\/fncel.2018.00280"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Lewczuk A, Zablocka B, Beresewicz-Haller M. Is Nrf2 Behind Endogenous Neuroprotection of the Hippocampal CA2-4,DG Region? Molecular Neurobiology. 2023; 60: 1645\u20131658.","DOI":"10.1007\/s12035-022-03166-x"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"Andrade-Talavera Y, Rodr\u00edguez-Moreno A. Kainate receptors in the CA2 region of the hippocampus. Neural Regeneration Research. 2023; 18: 320\u2013321.","DOI":"10.4103\/1673-5374.343912"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews. Neuroscience. 2007; 8: 57\u201369.","DOI":"10.1038\/nrn2038"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nature Reviews. Immunology. 2004; 4: 181\u2013189.","DOI":"10.1038\/nri1312"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007; 55: 453\u2013462.","DOI":"10.1002\/glia.20467"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Fan W, Chen H, Li M, Fan X, Jiang F, Xu C, et al. NRF2 activation ameliorates blood-brain barrier injury after cerebral ischemic stroke by regulating ferroptosis and inflammation. Scientific Reports. 2024; 14: 5300.","DOI":"10.1038\/s41598-024-53836-0"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Li D, Huo X, Shen L, Qian M, Wang J, Mao S, et al. Astrocyte heterogeneity in ischemic stroke: Molecular mechanisms and therapeutic targets. Neurobiology of Disease. 2025; 209: 106885.","DOI":"10.1016\/j.nbd.2025.106885"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Ma Q. Role of nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology. 2013; 53: 401\u2013426.","DOI":"10.1146\/annurev-pharmtox-011112-140320"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Loor G, Kondapalli J, Iwase H, Chandel NS, Waypa GB, Guzy RD, et al. Mitochondrial oxidant stress triggers cell death in simulated ischemia-reperfusion. Biochimica et Biophysica Acta. 2011; 1813: 1382\u20131394.","DOI":"10.1016\/j.bbamcr.2010.12.008"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Lipton SA. Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx : the Journal of the American Society for Experimental NeuroTherapeutics. 2004; 1: 101\u2013110.","DOI":"10.1602\/neurorx.1.1.101"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Himeda T, Hayakawa N, Tounai H, Sakuma M, Kato H, Araki T. Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2005; 30: 2014\u20132025.","DOI":"10.1038\/sj.npp.1300798"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Bidmon HJ, Emde B, Kowalski T, Schmitt M, Mayer B, Kato K, et al. Nitric oxide synthase-I containing cortical interneurons co-express antioxidative enzymes and anti-apoptotic Bcl-2 following focal ischemia: evidence for direct and indirect mechanisms towards their resistance to neuropathology. Journal of Chemical Neuroanatomy. 2001; 22: 167\u2013184.","DOI":"10.1016\/s0891-0618(01)00126-0"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Kumar P, Goettemoeller AM, Espinosa-Garcia C, Tobin BR, Tfaily A, Nelson RS, et al. Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer's pathology. Nature Communications. 2024; 15: 2823.","DOI":"10.1038\/s41467-024-47028-7"},{"key":"ref56","doi-asserted-by":"publisher","unstructured":"Dringen R. Metabolism and functions of glutathione in brain. Progress in Neurobiology. 2000; 62: 649\u2013671.","DOI":"10.1016\/s0301-0082(99)00060-x"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Liu G, Hosomi N, Hitomi H, Pelisch N, Fu H, Masugata H, et al. Angiotensin II induces human astrocyte senescence through reactive oxygen species production. Hypertension Research : Official Journal of the Japanese Society of Hypertension. 2011; 34: 479\u2013483.","DOI":"10.1038\/hr.2010.269"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Park JE, Leem YH, Park JS, Kim SE, Kim HS. Astrocytic Nrf2 Mediates the Neuroprotective and Anti-Inflammatory Effects of Nootkatone in an MPTP-Induced Parkinson's Disease Mouse Model. Antioxidants (Basel, Switzerland). 2023; 12: 1999.","DOI":"10.3390\/antiox12111999"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ. Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1998; 18: 6241\u20136253.","DOI":"10.1523\/JNEUROSCI.18-16-06241.1998"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Back SA, Luo NL, Mallinson RA, O'Malley JP, Wallen LD, Frei B, et al. Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Annals of Neurology. 2005; 58: 108\u2013120.","DOI":"10.1002\/ana.20530"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Pitt D, Nagelmeier IE, Wilson HC, Raine CS. Glutamate uptake by oligodendrocytes: Implications for excitotoxicity in multiple sclerosis. Neurology. 2003; 61: 1113\u20131120.","DOI":"10.1212\/01.wnl.0000090564.88719.37"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Spaas J, van Veggel L, Schepers M, Tiane A, van Horssen J, Wilson DM, et al. Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders. Cellular and Molecular Life Sciences : CMLS. 2021; 78: 4615\u20134637.","DOI":"10.1007\/s00018-021-03802-0"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Huang S, Ren C, Luo Y, Ding Y, Ji X, Li S. New insights into the roles of oligodendrocytes regulation in ischemic stroke recovery. Neurobiology of Disease. 2023; 184: 106200.","DOI":"10.1016\/j.nbd.2023.106200"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Li X, Yang X, Lu H, Wang W, Cai L, Chen J, et al. Calycosin attenuates the inflammatory damage of microglia induced by oxygen and glucose deprivation through the HMGB1\/TLR4\/NF-\u03baB signaling pathway. Acta Biochimica et Biophysica Sinica. 2023; 55: 1415\u20131424.","DOI":"10.3724\/abbs.2023125"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Zhao H, Yenari MA, Cheng D, Sapolsky RM, Steinberg GK. Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. Journal of Neurochemistry. 2003; 85: 1026\u20131036.","DOI":"10.1046\/j.1471-4159.2003.01756.x"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Zhang Q, Jia M, Wang Y, Wang Q, Wu J. Cell Death Mechanisms in Cerebral Ischemia-Reperfusion Injury. Neurochemical Research. 2022; 47: 3525\u20133542.","DOI":"10.1007\/s11064-022-03697-8"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Page AB, Owen CR, Kumar R, Miller JM, Rafols JA, White BC, et al. Persistent eIF2alpha(P) is colocalized with cytoplasmic cytochrome c in vulnerable hippocampal neurons after 4 hours of reperfusion following 10-minute complete brain ischemia. Acta Neuropathologica. 2003; 106: 8\u201316.","DOI":"10.1007\/s00401-003-0693-2"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Sugawara T, Fujimura M, Noshita N, Kim GW, Saito A, Hayashi T, et al. Neuronal death\/survival signaling pathways in cerebral ischemia. NeuroRx : the Journal of the American Society for Experimental NeuroTherapeutics. 2004; 1: 17\u201325.","DOI":"10.1602\/neurorx.1.1.17"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Ullah I, Chung K, Oh J, Beloor J, Bae S, Lee SC, et al. Intranasal delivery of a Fas-blocking peptide attenuates Fas-mediated apoptosis in brain ischemia. Scientific Reports. 2018; 8: 15041.","DOI":"10.1038\/s41598-018-33296-z"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J, et al. CD95 ligand (Fas-L\/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1999; 19: 3809\u20133817.","DOI":"10.1523\/JNEUROSCI.19-10-03809.1999"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149: 1060\u20131072.","DOI":"10.1016\/j.cell.2012.03.042"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Fu C, Wu Y, Liu S, Luo C, Lu Y, Liu M, et al. Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K\/AKT\/Nrf2 and SLC7A11\/GPX4 signaling pathway after ischemia. Journal of Ethnopharmacology. 2022; 289: 115021.","DOI":"10.1016\/j.jep.2022.115021"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Shen L, Lin D, Li X, Wu H, Lenahan C, Pan Y, et al. Ferroptosis in Acute Central Nervous System Injuries: The Future Direction? Frontiers in Cell and Developmental Biology. 2020; 8: 594.","DOI":"10.3389\/fcell.2020.00594"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Tuo QZ, Liu Y, Xiang Z, Yan HF, Zou T, Shu Y, et al. Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia\/reperfusion. Signal Transduction and Targeted Therapy. 2022; 7: 59.","DOI":"10.1038\/s41392-022-00917-z"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, et al. Poly(ADP-ribose) (PAR) polymer is a death signal. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103: 18308\u201318313.","DOI":"10.1073\/pnas.0606526103"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Narne P, Pandey V, Simhadri PK, Phanithi PB. Poly(ADP-ribose)polymerase-1 hyperactivation in neurodegenerative diseases: The death knell tolls for neurons. Seminars in Cell & Developmental Biology. 2017; 63: 154\u2013166.","DOI":"10.1016\/j.semcdb.2016.11.007"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Liu S, Luo W, Wang Y. Emerging role of PARP-1 and PARthanatos in ischemic stroke. Journal of Neurochemistry. 2022; 160: 74\u201387.","DOI":"10.1111\/jnc.15464"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Hamby AM, Suh SW, Kauppinen TM, Swanson RA. Use of a poly(ADP-ribose) polymerase inhibitor to suppress inflammation and neuronal death after cerebral ischemia-reperfusion. Stroke. 2007; 38: 632\u2013636.","DOI":"10.1161\/01.STR.0000250742.61241.79"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Greco R, Tassorelli C, Mangione AS, Levandis G, Certo M, Nappi G, et al. Neuroprotection by the PARP inhibitor PJ34 modulates cerebral and circulating RAGE levels in rats exposed to focal brain ischemia. European Journal of Pharmacology. 2014; 744: 91\u201397.","DOI":"10.1016\/j.ejphar.2014.10.006"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"Mehrabadi AR, Korolainen MA, Odero G, Miller DW, Kauppinen TM. Poly(ADP-ribose) polymerase-1 regulates microglia mediated decrease of endothelial tight junction integrity. Neurochemistry International. 2017; 108: 266\u2013271.","DOI":"10.1016\/j.neuint.2017.04.014"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Fatokun AA, Dawson VL, Dawson TM. Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. British Journal of Pharmacology. 2014; 171: 2000\u20132016.","DOI":"10.1111\/bph.12416"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"Choi ME, Price DR, Ryter SW, Choi AMK. Necroptosis: a crucial pathogenic mediator of human disease. JCI Insight. 2019; 4: e128834.","DOI":"10.1172\/jci.insight.128834"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"Chaouhan HS, Vinod C, Mahapatra N, Yu SH, Wang IK, Chen KB, et al. Necroptosis: A Pathogenic Negotiator in Human Diseases. International Journal of Molecular Sciences. 2022; 23: 12714.","DOI":"10.3390\/ijms232112714"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"Zhang S, Tang MB, Luo HY, Shi CH, Xu YM. Necroptosis in neurodegenerative diseases: a potential therapeutic target. Cell Death & Disease. 2017; 8: e2905.","DOI":"10.1038\/cddis.2017.286"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology. 2005; 1: 112\u2013119.","DOI":"10.1038\/nchembio711"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"Chen Y, Zhang L, Yu H, Song K, Shi J, Chen L, et al. Necrostatin-1 Improves Long-term Functional Recovery Through Protecting Oligodendrocyte Precursor Cells After Transient Focal Cerebral Ischemia in Mice. Neuroscience. 2018; 371: 229\u2013241.","DOI":"10.1016\/j.neuroscience.2017.12.007"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal Cell Death. Physiological Reviews. 2018; 98: 813\u2013880.","DOI":"10.1152\/physrev.00011.2017"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 2013; 9: 1321\u20131333.","DOI":"10.4161\/auto.25132"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Hou W, Hao Y, Sun L, Zhao Y, Zheng X, Song L. The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke. Molecular Brain. 2022; 15: 14.","DOI":"10.1186\/s13041-022-00899-7"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Mao L, Wu DH, Hu GH, Fan JH. TLR4 Enhances Cerebral Ischemia\/Reperfusion Injury via Regulating NLRP3 Inflammasome and Autophagy. Mediators of Inflammation. 2023; 2023: 9335166.","DOI":"10.1155\/2023\/9335166"},{"key":"ref91","doi-asserted-by":"publisher","unstructured":"Mo Y, Sun YY, Liu KY. Autophagy and inflammation in ischemic stroke. Neural Regeneration Research. 2020; 15: 1388\u20131396.","DOI":"10.4103\/1673-5374.274331"},{"key":"ref92","doi-asserted-by":"publisher","unstructured":"Zhang Y, Li H. Inhibition of Autophagy Attenuated Cell Damage after OGD\/R in SH-SY5Y Cells by Down-Regulating AMPK-Mediated Autophagy Signaling Pathway. Open Access Library Journal. 2019; 6: 1\u201312.","DOI":"10.4236\/oalib.1105240"},{"key":"ref93","doi-asserted-by":"publisher","unstructured":"Zheng J, Li Y, Zhang T, Fu Y, Long P, Gao X, et al. Endoplasmic reticulum stress and autophagy in cerebral ischemia\/reperfusion injury: PERK as a potential target for intervention. Neural Regeneration Research. 2025; 20: 1455\u20131466.","DOI":"10.4103\/NRR.NRR-D-23-00794"},{"key":"ref94","doi-asserted-by":"publisher","unstructured":"Yuan ZL, Mo YZ, Li DL, Xie L, Chen MH. Inhibition of ERK downregulates autophagy via mitigating mitochondrial fragmentation to protect SH-SY5Y cells from OGD\/R injury. Cell Communication and Signaling : CCS. 2023; 21: 204.","DOI":"10.1186\/s12964-023-01211-3"},{"key":"ref95","doi-asserted-by":"publisher","unstructured":"Xu M, Zhang HL. Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy. Acta Pharmacologica Sinica. 2011; 32: 1089\u20131099.","DOI":"10.1038\/aps.2011.50"},{"key":"ref96","doi-asserted-by":"publisher","unstructured":"Ni Y, Gu WW, Liu ZH, Zhu YM, Rong JG, Kent TA, et al. RIP1K Contributes to Neuronal and Astrocytic Cell Death in Ischemic Stroke via Activating Autophagic-lysosomal Pathway. Neuroscience. 2018; 371: 60\u201374.","DOI":"10.1016\/j.neuroscience.2017.10.038"},{"key":"ref97","doi-asserted-by":"publisher","unstructured":"Potokar M, Jorga\u010devski J. Targeting autophagy in astrocytes: a potential for neurodegenerative disease intervention. Frontiers in Cellular Neuroscience. 2025; 19: 1584767.","DOI":"10.3389\/fncel.2025.1584767"},{"key":"ref98","doi-asserted-by":"publisher","unstructured":"Bussi C, Peralta Ramos JM, Arroyo DS, Gaviglio EA, Gallea JI, Wang JM, et al. Autophagy down regulates pro-inflammatory mediators in BV2 microglial cells and rescues both LPS and alpha-synuclein induced neuronal cell death. Scientific Reports. 2017; 7: 43153.","DOI":"10.1038\/srep43153"},{"key":"ref99","doi-asserted-by":"publisher","unstructured":"Lu X, Zhang J, Ding Y, Wu J, Chen G. Novel Therapeutic Strategies for Ischemic Stroke: Recent Insights into Autophagy. Oxidative Medicine and Cellular Longevity. 2022; 2022: 3450207.","DOI":"10.1155\/2022\/3450207"},{"key":"ref100","doi-asserted-by":"publisher","unstructured":"Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014; 514: 187\u2013192.","DOI":"10.1038\/nature13683"},{"key":"ref101","doi-asserted-by":"publisher","unstructured":"Broz P, Pelegr\u00edn P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nature Reviews. Immunology. 2020; 20: 143\u2013157.","DOI":"10.1038\/s41577-019-0228-2"},{"key":"ref102","doi-asserted-by":"publisher","unstructured":"Matikainen S, Nyman TA, Cypryk W. Function and Regulation of Noncanonical Caspase-4\/5\/11 Inflammasome. Journal of Immunology (Baltimore, Md. : 1950). 2020; 204: 3063\u20133069.","DOI":"10.4049\/jimmunol.2000373"},{"key":"ref103","doi-asserted-by":"publisher","unstructured":"Wu X, Wan T, Gao X, Fu M, Duan Y, Shen X, et al. Microglia Pyroptosis: A Candidate Target for Neurological Diseases Treatment. Frontiers in Neuroscience. 2022; 16: 922331.","DOI":"10.3389\/fnins.2022.922331"},{"key":"ref104","doi-asserted-by":"publisher","unstructured":"Liang Y, Song P, Chen W, Xie X, Luo R, Su J, et al. Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation. Frontiers in Cellular Neuroscience. 2021; 14: 540669.","DOI":"10.3389\/fncel.2020.540669"},{"key":"ref105","doi-asserted-by":"publisher","unstructured":"Wang K, Sun Z, Ru J, Wang S, Huang L, Ruan L, et al. Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia. Frontiers in Neurology. 2020; 11: 577927.","DOI":"10.3389\/fneur.2020.577927"},{"key":"ref106","doi-asserted-by":"publisher","unstructured":"Kristi\u00e1n T, Siesj\u00f6 BK. Calcium in ischemic cell death. Stroke. 1998; 29: 705\u2013718.","DOI":"10.1161\/01.str.29.3.705"},{"key":"ref107","doi-asserted-by":"publisher","unstructured":"Jurcau A, Ardelean AI. Oxidative Stress in Ischemia\/Reperfusion Injuries following Acute Ischemic Stroke. Biomedicines. 2022; 10: 574.","DOI":"10.3390\/biomedicines10030574"},{"key":"ref108","doi-asserted-by":"publisher","unstructured":"Markgraf CG, Velayo NL, Johnson MP, McCarty DR, Medhi S, Koehl JR, et al. Six-hour window of opportunity for calpain inhibition in focal cerebral ischemia in rats. Stroke. 1998; 29: 152\u2013158.","DOI":"10.1161\/01.str.29.1.152"},{"key":"ref109","doi-asserted-by":"publisher","unstructured":"Wang WY, Shi JX, Chen MH, Zhuge XZ, Dai CG, Xie L. Calpain inhibitor MDL28170 alleviates cerebral ischemia\u2011reperfusion injury by suppressing inflammation and autophagy in a rat model of cardiac arrest. Experimental and Therapeutic Medicine. 2023; 25: 196.","DOI":"10.3892\/etm.2023.11895"},{"key":"ref110","doi-asserted-by":"publisher","unstructured":"Keller JN, Kindy MS, Holtsberg FW, St Clair DK, Yen HC, Germeyer A, et al. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 1998; 18: 687\u2013697.","DOI":"10.1523\/JNEUROSCI.18-02-00687.1998"},{"key":"ref111","doi-asserted-by":"publisher","unstructured":"Kim GW, Kondo T, Noshita N, Chan PH. Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia\/reperfusion in mice: implications for the production and role of superoxide radicals. Stroke. 2002; 33: 809\u2013815.","DOI":"10.1161\/hs0302.103745"},{"key":"ref112","doi-asserted-by":"publisher","unstructured":"Yang L, Tao Y, Luo L, Zhang Y, Wang X, Meng X. Dengzhan Xixin injection derived from a traditional Chinese herb Erigeron breviscapus ameliorates cerebral ischemia\/reperfusion injury in rats via modulation of mitophagy and mitochondrial apoptosis. Journal of Ethnopharmacology. 2022; 288: 114988.","DOI":"10.1016\/j.jep.2022.114988"},{"key":"ref113","doi-asserted-by":"publisher","unstructured":"Shi Y, Han L, Zhang X, Xie L, Pan P, Chen F. Selenium Alleviates Cerebral Ischemia\/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Fusion and Ferroptosis. Neurochemical Research. 2022; 47: 2992\u20133002.","DOI":"10.1007\/s11064-022-03643-8"},{"key":"ref114","doi-asserted-by":"publisher","unstructured":"Handy DE, Lubos E, Yang Y, Galbraith JD, Kelly N, Zhang YY, et al. Glutathione peroxidase-1 regulates mitochondrial function to modulate redox-dependent cellular responses. The Journal of Biological Chemistry. 2009; 284: 11913\u201311921.","DOI":"10.1074\/jbc.M900392200"},{"key":"ref115","doi-asserted-by":"publisher","unstructured":"Crack PJ, Taylor JM, de Haan JB, Kola I, Hertzog P, Iannello RC. Glutathione peroxidase-1 contributes to the neuroprotection seen in the superoxide dismutase-1 transgenic mouse in response to ischemia\/reperfusion injury. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2003; 23: 19\u201322.","DOI":"10.1097\/01.WCB.0000035181.38851.71"},{"key":"ref116","doi-asserted-by":"publisher","unstructured":"Hoehn B, Yenari MA, Sapolsky RM, Steinberg GK. Glutathione peroxidase overexpression inhibits cytochrome C release and proapoptotic mediators to protect neurons from experimental stroke. Stroke. 2003; 34: 2489\u20132494.","DOI":"10.1161\/01.STR.0000091268.25816.19"},{"key":"ref117","doi-asserted-by":"publisher","unstructured":"Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. Journal of Neuroscience Research. 2004; 76: 519\u2013527.","DOI":"10.1002\/jnr.20087"},{"key":"ref118","doi-asserted-by":"publisher","unstructured":"Imai H, Graham DI, Masayasu H, Macrae IM. Antioxidant ebselen reduces oxidative damage in focal cerebral ischemia. Free Radical Biology & Medicine. 2003; 34: 56\u201363.","DOI":"10.1016\/s0891-5849(02)01180-2"},{"key":"ref119","doi-asserted-by":"publisher","unstructured":"Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cellular and Molecular Life Sciences : CMLS. 2004; 61: 192\u2013208.","DOI":"10.1007\/s00018-003-3206-5"},{"key":"ref120","doi-asserted-by":"publisher","unstructured":"Young JM, Nelson JW, Cheng J, Zhang W, Mader S, Davis CM, et al. Peroxisomal biogenesis in ischemic brain. Antioxidants & Redox Signaling. 2015; 22: 109\u2013120.","DOI":"10.1089\/ars.2014.5833"},{"key":"ref121","doi-asserted-by":"publisher","unstructured":"Bernoud-Hubac N, Lo Van A, Lazar AN, Lagarde M. Ischemic Brain Injury: Involvement of Lipids in the Pathophysiology of Stroke and Therapeutic Strategies. Antioxidants (Basel, Switzerland). 2024; 13: 634.","DOI":"10.3390\/antiox13060634"},{"key":"ref122","doi-asserted-by":"publisher","unstructured":"Aoyama K, Watabe M, Nakaki T. Regulation of neuronal glutathione synthesis. Journal of Pharmacological Sciences. 2008; 108: 227\u2013238.","DOI":"10.1254\/jphs.08r01cr"},{"key":"ref123","doi-asserted-by":"publisher","unstructured":"Gu W, Zhao H, Yenari MA, Sapolsky RM, Steinberg GK. Catalase over-expression protects striatal neurons from transient focal cerebral ischemia. Neuroreport. 2004; 15: 413\u2013416.","DOI":"10.1097\/00001756-200403010-00006"},{"key":"ref124","doi-asserted-by":"publisher","unstructured":"Davis SM, Pennypacker KR. Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke. Neurochemistry International. 2017; 107: 23\u201332.","DOI":"10.1016\/j.neuint.2016.12.007"},{"key":"ref125","doi-asserted-by":"publisher","unstructured":"Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. Journal of Leukocyte Biology. 2010; 87: 779\u2013789.","DOI":"10.1189\/jlb.1109766"},{"key":"ref126","doi-asserted-by":"publisher","unstructured":"She X, Lan B, Tian H, Tang B. Cross Talk Between Ferroptosis and Cerebral Ischemia. Frontiers in Neuroscience. 2020; 14: 776.","DOI":"10.3389\/fnins.2020.00776"},{"key":"ref127","doi-asserted-by":"publisher","unstructured":"Ye Y, Xie X, Bi Y, Liu Q, Qiu L, Zhao H, et al. Nrf2 alleviates acute ischemic stroke induced ferroptosis via regulating xCT\/GPX4 pathway. Free Radical Biology & Medicine. 2025; 231: 153\u2013162.","DOI":"10.1016\/j.freeradbiomed.2025.02.040"},{"key":"ref128","doi-asserted-by":"publisher","unstructured":"Sheng H, Spasojevic I, Tse HM, Jung JY, Hong J, Zhang Z, et al. Neuroprotective efficacy from a lipophilic redox-modulating Mn(III) N-Hexylpyridylporphyrin, MnTnHex-2-PyP: rodent models of ischemic stroke and subarachnoid hemorrhage. The Journal of Pharmacology and Experimental Therapeutics. 2011; 338: 906\u2013916.","DOI":"10.1124\/jpet.110.176701"},{"key":"ref129","doi-asserted-by":"publisher","unstructured":"Tovmasyan A, Sheng H, Weitner T, Arulpragasam A, Lu M, Warner DS, et al. Design, mechanism of action, bioavailability and therapeutic effects of mn porphyrin-based redox modulators. Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre. 2013; 22: 103\u2013130.","DOI":"10.1159\/000341715"},{"key":"ref130","doi-asserted-by":"publisher","unstructured":"Wang P, Li Y, Yan B, Yang Z, Li L, Cao Z, et al. Manganese Porphyrin Promotes Post Cardiac Arrest Recovery in Mice and Rats. Biology. 2022; 11: 957.","DOI":"10.3390\/biology11070957"},{"key":"ref131","doi-asserted-by":"publisher","unstructured":"Batini\u0107-Haberle I, Cuzzocrea S, Rebou\u00e7as JS, Ferrer-Sueta G, Mazzon E, Di Paola R, et al. Pure MnTBAP selectively scavenges peroxynitrite over superoxide: comparison of pure and commercial MnTBAP samples to MnTE-2-PyP in two models of oxidative stress injury, an SOD-specific Escherichia coli model and carrageenan-induced pleurisy. Free Radical Biology & Medicine. 2009; 46: 192\u2013201.","DOI":"10.1016\/j.freeradbiomed.2008.09.042"},{"key":"ref132","doi-asserted-by":"publisher","unstructured":"Craig AJ, Housley GD. Evaluation of Gene Therapy as an Intervention Strategy to Treat Brain Injury from Stroke. Frontiers in Molecular Neuroscience. 2016; 9: 34.","DOI":"10.3389\/fnmol.2016.00034"},{"key":"ref133","doi-asserted-by":"publisher","unstructured":"Kim DW, Jeong HJ, Kang HW, Shin MJ, Sohn EJ, Kim MJ, et al. Transduced human PEP-1-catalase fusion protein attenuates ischemic neuronal damage. Free Radical Biology & Medicine. 2009; 47: 941\u2013952.","DOI":"10.1016\/j.freeradbiomed.2009.06.036"},{"key":"ref134","doi-asserted-by":"publisher","unstructured":"Reiter RJ, Tan DX, Sainz RM, Mayo JC, Lopez-Burillo S. Melatonin: reducing the toxicity and increasing the efficacy of drugs. The Journal of Pharmacy and Pharmacology. 2002; 54: 1299\u20131321.","DOI":"10.1211\/002235702760345374"},{"key":"ref135","doi-asserted-by":"publisher","unstructured":"Zhang C, Ma Y, Zhao Y, Guo N, Han C, Wu Q, et al. Systematic review of melatonin in cerebral ischemia-reperfusion injury: critical role and therapeutic opportunities. Frontiers in Pharmacology. 2024; 15: 1356112.","DOI":"10.3389\/fphar.2024.1356112"},{"key":"ref136","doi-asserted-by":"publisher","unstructured":"Sabbaghziarani F, Soleimani P, Eynshikh FR, Zafari F, Aali E. Reduced ischemia-reperfusion oxidative stress injury by melatonin and N-acetylcysteine in the male rat brain. IBRO Neuroscience Reports. 2024; 17: 131\u2013137.","DOI":"10.1016\/j.ibneur.2024.07.004"},{"key":"ref137","doi-asserted-by":"publisher","unstructured":"Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T. Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke. 2005; 36: 2220\u20132225.","DOI":"10.1161\/01.STR.0000182241.07096.06"},{"key":"ref138","doi-asserted-by":"publisher","unstructured":"Xu L, Gao Y, Hu M, Dong Y, Xu J, Zhang J, et al. Edaravone dexborneol protects cerebral ischemia reperfusion injury through activating Nrf2\/HO-1 signaling pathway in mice. Fundamental & Clinical Pharmacology. 2022; 36: 790\u2013800.","DOI":"10.1111\/fcp.12782"},{"key":"ref139","doi-asserted-by":"publisher","unstructured":"Gao H, Tan H, Wang J, Yang D, Liu Y, Wu T. Clinical efficacy of edaravone dexborneol in the treatment of acute ischemic stroke: meta-analysis. Frontiers in Neurology. 2025; 16: 1589307.","DOI":"10.3389\/fneur.2025.1589307"},{"key":"ref140","doi-asserted-by":"publisher","unstructured":"Xu L, Ding L, Su Y, Shao R, Liu J, Huang Y. Neuroprotective effects of curcumin against rats with focal cerebral ischemia-reperfusion injury. International Journal of Molecular Medicine. 2019; 43: 1879\u20131887.","DOI":"10.3892\/ijmm.2019.4094"},{"key":"ref141","doi-asserted-by":"publisher","unstructured":"Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in aging and chronic disease: a magnificent pathway. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2006; 61: 575\u2013584.","DOI":"10.1093\/gerona\/61.6.575"},{"key":"ref142","doi-asserted-by":"publisher","unstructured":"Vitturi BK, Gagliardi RJ. Effectiveness of statins on outcomes of patients with Embolic Stroke of Undetermined Source (ESUS). Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association. 2024; 33: 107469.","DOI":"10.1016\/j.jstrokecerebrovasdis.2023.107469"},{"key":"ref143","doi-asserted-by":"publisher","unstructured":"Zhao J, Kobori N, Aronowski J, Dash PK. Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neuroscience Letters. 2006; 393: 108\u2013112.","DOI":"10.1016\/j.neulet.2005.09.065"},{"key":"ref144","doi-asserted-by":"publisher","unstructured":"Zhao J, Moore AN, Redell JB, Dash PK. Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2007; 27: 10240\u201310248.","DOI":"10.1523\/JNEUROSCI.1683-07.2007"},{"key":"ref145","doi-asserted-by":"publisher","unstructured":"Belcher JD, Nguyen J, Chen C, Abdulla F, Nguyen P, Nguyen M, et al. Dimethyl fumarate induces cytoprotection and inhibits inflammation and vaso-occlusion in transgenic sickle mice. Blood. 2014; 124: 219.","DOI":"10.1182\/blood.V124.21.219.219"},{"key":"ref146","doi-asserted-by":"publisher","unstructured":"Yao Y, Miao W, Liu Z, Han W, Shi K, Shen Y, et al. Dimethyl Fumarate and Monomethyl Fumarate Promote Post-Ischemic Recovery in Mice. Translational Stroke Research. 2016; 7: 535\u2013547.","DOI":"10.1007\/s12975-016-0496-0"},{"key":"ref147","doi-asserted-by":"publisher","unstructured":"Shih AY, Li P, Murphy TH. A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. 2005; 25: 10321\u201310335.","DOI":"10.1523\/JNEUROSCI.4014-05.2005"},{"key":"ref148","doi-asserted-by":"publisher","unstructured":"Wang Z, Ji C, Wu L, Qiu J, Li Q, Shao Z, et al. Tert-butylhydroquinone alleviates early brain injury and cognitive dysfunction after experimental subarachnoid hemorrhage: role of Keap1\/Nrf2\/ARE pathway. PloS One. 2014; 9: e97685.","DOI":"10.1371\/journal.pone.0097685"},{"key":"ref149","doi-asserted-by":"publisher","unstructured":"Chien JY, Chou YY, Ciou JW, Liu FY, Huang SP. The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy. Antioxidants (Basel, Switzerland). 2021; 10: 1466.","DOI":"10.3390\/antiox10091466"},{"key":"ref150","doi-asserted-by":"publisher","unstructured":"Xu J, Wang A, Meng X, Yalkun G, Xu A, Gao Z, et al. Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke: A Phase III, Randomized, Double-Blind, Comparative Trial. Stroke. 2021; 52: 772\u2013780.","DOI":"10.1161\/STROKEAHA.120.031197"},{"key":"ref151","doi-asserted-by":"publisher","unstructured":"\u0218erban M, Toader C, Covache-Busuioc RA. The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration. International Journal of Molecular Sciences. 2025; 26: 7498.","DOI":"10.3390\/ijms26157498"},{"key":"ref152","doi-asserted-by":"publisher","unstructured":"Huang L, Chen Y, Zhou H, Chen H, Wu X, Wu Z, et al. Synthesis, target analysis, and cerebroprotective effects of novel imide antioxidants via the Nrf2\/HO-1 pathway in cerebral ischemia-reperfusion injury. Frontiers in Pharmacology. 2025; 16: 1552717.","DOI":"10.3389\/fphar.2025.1552717"},{"key":"ref153","doi-asserted-by":"publisher","unstructured":"Buga AM, Di Napoli M, Popa-Wagner A. Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation. Biogerontology. 2013; 14: 651\u2013662.","DOI":"10.1007\/s10522-013-9465-0"},{"key":"ref154","doi-asserted-by":"publisher","unstructured":"Popa-Wagner A, Glavan DG, Olaru A, Olaru DG, Margaritescu O, Tica O, et al. Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with\/without Comorbidities. International Journal of Molecular Sciences. 2018; 19: 356.","DOI":"10.3390\/ijms19020356"},{"key":"ref155","doi-asserted-by":"publisher","unstructured":"Sies H, Berndt C, Jones DP. Oxidative Stress. Annual Review of Biochemistry. 2017; 86: 715\u2013748.","DOI":"10.1146\/annurev-biochem-061516-045037"},{"key":"ref156","doi-asserted-by":"publisher","unstructured":"Hewlings SJ, Kalman DS. Curcumin: A Review of Its Effects on Human Health. Foods (Basel, Switzerland). 2017; 6: 92.","DOI":"10.3390\/foods6100092"},{"key":"ref157","doi-asserted-by":"publisher","unstructured":"Bu\u010devi\u0107 Popovi\u0107 V, Karahmet Farhat E, Banjari I, Jeli\u010di\u0107 Kadi\u0107 A, Puljak L. Bioavailability of Oral Curcumin in Systematic Reviews: A Methodological Study. Pharmaceuticals (Basel, Switzerland). 2024; 17: 164.","DOI":"10.3390\/ph17020164"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/7\/10.31083\/FBL48324","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:18:01Z","timestamp":1785413881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/31\/7\/10.31083\/FBL48324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":157,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026]]}},"alternative-id":["S2768-6701(26)02036-8"],"URL":"https:\/\/doi.org\/10.31083\/fbl48324","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"article-number":"48324"}}