{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T03:47:55Z","timestamp":1768621675720,"version":"3.49.0"},"reference-count":72,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2017,12,19]],"date-time":"2017-12-19T00:00:00Z","timestamp":1513641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["16POST27520023"],"award-info":[{"award-number":["16POST27520023"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications\u2014especially HT\u2014associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte-colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy.<\/jats:p>","DOI":"10.3390\/ijms18122756","type":"journal-article","created":{"date-parts":[[2017,12,19]],"date-time":"2017-12-19T10:48:40Z","timestamp":1513680520000},"page":"2756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Adjunctive Therapy Approaches for Ischemic Stroke: Innovations to Expand Time Window of Treatment"],"prefix":"10.3390","volume":"18","author":[{"given":"Talia","family":"Knecht","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA"},{"name":"Department of Psychology, University of California, San Diego, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob","family":"Story","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA"},{"name":"Department of Neuroscience, University of California, Riverside, CA 92521, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willie","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cesar","family":"Borlongan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, FL 33612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ike","family":"Dela Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1001\/jama.2014.7692","article-title":"Stroke incidence and mortality trends in US communities, 1987 to 2011","volume":"312","author":"Koton","year":"2014","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"NINDS rt-PA Stroke Study Group (1997). Intracerebral hemorrhage after intravenous tPA therapy for ischemic stroke. Stroke, 28, 2109\u20132118.","DOI":"10.1161\/01.STR.28.11.2109"},{"key":"ref_3","first-page":"e28","article-title":"American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics\u20142014 update: A report from the American Heart Association","volume":"129","author":"Go","year":"2014","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1161\/01.STR.0000101752.23813.C3","article-title":"Tissue plasminogen activator for acute ischemic stroke in clinical practice: A meta-analysis of safety data","volume":"34","author":"Graham","year":"2003","journal-title":"Stroke"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1161\/STROKEAHA.106.479477","article-title":"Estimated cost savings of increased use of intravenous tissue plasminogen activator for acute ischemic stroke in Canada","volume":"38","author":"Yip","year":"2007","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2174\/187152707783220901","article-title":"Neurogenesis and stroke","volume":"6","author":"Greenberg","year":"2007","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1161\/01.STR.0000163257.66207.2d","article-title":"Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association\/American Stroke Association","volume":"36","author":"Adams","year":"2005","journal-title":"Stroke"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1161\/01.STR.0000143219.16695.af","article-title":"Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke","volume":"35","author":"Wang","year":"2004","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.5853\/jos.2016.01515","article-title":"Strategies to Extend Thrombolytic Time Window for Ischemic Stroke Treatment: An Unmet Clinical Need","volume":"19","author":"Borlongan","year":"2017","journal-title":"J. Stroke"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/978-3-211-09469-3_34","article-title":"Mechanisms and markers for hemorrhagic transformation after stroke","volume":"105","author":"Rosell","year":"2008","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1007\/s12035-014-8952-x","article-title":"Hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke: Mechanisms, models, and biomarkers","volume":"52","author":"Wang","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/jcbfm.2013.203","article-title":"Hemorrhagic transformation after ischemic stroke in animals and humans","volume":"34","author":"Jickling","year":"2014","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s11910-002-0051-0","article-title":"Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment","volume":"2","author":"Lapchak","year":"2002","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"240","DOI":"10.5551\/jat.RV16006","article-title":"Therapeutic strategies to attenuate hemorrhagic transformation after tissue plasminogen activator treatment for acute ischemic stroke","volume":"24","author":"Kanazawa","year":"2017","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/bcpt.12413","article-title":"Ascorbic acid reduces the adverse effects of delayed daministration of tissue plasminogen activator in a rat stroke model","volume":"117","author":"Allahtavakoli","year":"2015","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1038\/jcbfm.2009.105","article-title":"Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats","volume":"29","author":"Zhang","year":"2009","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1161\/hs0302.104542","article-title":"Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats","volume":"33","author":"Sumii","year":"2002","journal-title":"Stroke"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.ejphar.2015.07.035","article-title":"Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats","volume":"764","author":"Tan","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2668","DOI":"10.1007\/s11064-013-1185-y","article-title":"Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke","volume":"38","author":"Ishrat","year":"2013","journal-title":"Neurochem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s12035-015-9243-x","article-title":"Dodecafluoropentane emulsion extends window for tPA therapy in a rabbit stroke model","volume":"52","author":"Culp","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.neuroscience.2012.06.015","article-title":"A Rho kinase (ROCK) inhibitor, fasudil, prevents matrix metalloproteinase-9-related hemorrhagic transformation in mice treated with tissue plasminogen activator","volume":"220","author":"Ishiguro","year":"2012","journal-title":"Neuroscience"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/jcbfm.2014.208","article-title":"Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis","volume":"35","author":"Yoo","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuroscience.2011.12.042","article-title":"A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice","volume":"205","author":"Mishiro","year":"2012","journal-title":"Neuroscience"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nm1787","article-title":"Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke","volume":"14","author":"Su","year":"2008","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1111\/ejn.12551","article-title":"IMM-H004 prevents toxicity induced by delayed treatment of tPA in a rat model of focal cerebral ischemia involving PKA-and PI3K-dependent Akt activation","volume":"39","author":"Zuo","year":"2014","journal-title":"Eur. J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3372","DOI":"10.1161\/STROKEAHA.108.514026","article-title":"Extension of the thrombolytic time window with minocycline in experimental stroke","volume":"39","author":"Murata","year":"2008","journal-title":"Stroke"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1096\/fasebj.31.1_supplement.693.6","article-title":"Neural Stem Cells Reduce Symptomatic Inflammation and Mortality in Aged Stroke Mice following Delayed tPA Treatment","volume":"31","author":"Eckert","year":"2017","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1161\/STROKEAHA.114.008599","article-title":"Normobaric hyperoxia slows blood-brain barrier damage and expands the therapeutic time window for tissue-type plasminogen activator treatment in cerebral ischemia","volume":"46","author":"Liang","year":"2015","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2003.12.016","article-title":"The blood-brain barrier: An overview: Structure, regulation, and clinical implications","volume":"16","author":"Ballabh","year":"2004","journal-title":"Neurobiol. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ishiguro, M., Mishiro, K., Fujiwara, Y., Chen, H., Izuta, H., Tsuruma, K., Shimazawa, M., Yoshimura, S., Satoh, M., and Iwama, T. (2010). Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015178"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/2045-8118-11-18","article-title":"Vascular disruption and blood-brain barrier dysfunction in intracerebral hemorrhage","volume":"11","author":"Keep","year":"2014","journal-title":"Fluids Barriers CNS"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12788","DOI":"10.1523\/JNEUROSCI.3485-08.2008","article-title":"Activated protein C promotes neovascularization and neurogenesis in post-ischemic brain via protease activated receptor 1","volume":"28","author":"Thiyagarajan","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1177\/0148607106030002108","article-title":"Antioxidant supplementa-tion with or without B-group vitamins after acute ischemic stroke: A randomized controlled trial","volume":"30","author":"Ullegaddi","year":"2006","journal-title":"JPEN J. Parenter Enter. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1161\/STROKEAHA.113.002411","article-title":"Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke","volume":"44","author":"Tan","year":"2013","journal-title":"Stroke"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1111\/j.1538-7836.2007.02628.x","article-title":"Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice","volume":"5","author":"Suzuki","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1097\/00004647-199609000-00023","article-title":"Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine","volume":"16","author":"Huang","year":"1996","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.atherosclerosissup.2005.09.003","article-title":"Cilostazol in secondary prevention of stroke: Impact of the cilostazol stroke prevention study","volume":"6","author":"Matsumoto","year":"2005","journal-title":"Atheroscler. Suppl."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.2353\/ajpath.2007.060693","article-title":"Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells","volume":"170","author":"Koto","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3171\/jns.1992.76.4.0571","article-title":"Effect of AT877 on cerebral vasospasm after aneurismal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial","volume":"76","author":"Shibuya","year":"1992","journal-title":"J. Neurosurg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/00062752-199805000-00013","article-title":"Anti-inflammatory effects of granulocyte colony-stimulating factor","volume":"5","author":"Hartung","year":"1998","journal-title":"Curr. Opin. Hematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1111\/j.1538-7836.2010.03897.x","article-title":"Association of growth factors with arterial recanalization and clinical outcome in patients with ischemic stroke treated with tPA","volume":"8","author":"Sobrino","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1006\/exer.1998.0637","article-title":"Galardin inhibits collagen degradation by rabbit keratocytes by inhibiting the activation of pro-matrix metalloproteinases","volume":"68","author":"Hao","year":"1999","journal-title":"Exp. Eye Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1161\/01.STR.32.1.240","article-title":"Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage","volume":"32","author":"Mayne","year":"2001","journal-title":"Stroke"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3813","DOI":"10.2174\/1381612043382710","article-title":"Natural and synthetic coumarin derivatives with anti-inflammatory\/antioxidant activities","volume":"30","author":"Fylaktakidou","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Machado, L.S., Kozak, A., Ergul, A., Hess, D., Borlongan, C.V., and Fagan, S.C. (2006). Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci., 7.","DOI":"10.1186\/1471-2202-7-56"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1161\/STROKEAHA.110.582601","article-title":"Minocycline to improve neurologic outcome in stroke (MINOS): A dose-finding study","volume":"41","author":"Fagan","year":"2010","journal-title":"Stroke"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1161\/STROKEAHA.111.618215","article-title":"Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke","volume":"42","author":"Switzer","year":"2011","journal-title":"Stroke"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Blacker, D.J., Prentice, D., Alvaro, A., Bates, T.R., Bynevelt, M., Kelly, A., Kho, L.K., Kohler, E., Hankey, G.J., and Thompson, A. (2013). Reducing haemorrhagic transformation after thrombolysis for stroke: A strategy utilising minocycline. Stroke Res. Treat., 2013.","DOI":"10.1155\/2013\/362961"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1038\/leu.2011.167","article-title":"Bone marrow stem cell mobilization in stroke: A \u2018bonehead\u2019 may be good after all!","volume":"25","author":"Borlongan","year":"2011","journal-title":"Leukemia"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shetty, A. (2015). Stem cell-based neuroprotective strategies in stroke. Neural Stem Cells in Health and Disease, World Scientific.","DOI":"10.1142\/9309"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.nicl.2014.02.003","article-title":"Prediction of stroke thrombolysis outcome using CT brain machine learning","volume":"4","author":"Bentley","year":"2014","journal-title":"Neuroimage Clin."},{"key":"ref_52","first-page":"1009","article-title":"A randomized trial of intraarterial treatment for acute ischemic stroke","volume":"372","author":"Berkhemer","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1161\/STROKEAHA.116.012619","article-title":"Outcome after thrombectomy and intravenous thrombolysis in patients with acute ischemic stroke: A prospective observational study","volume":"47","author":"Minnerup","year":"2016","journal-title":"Stroke"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Huang, L., Wong, S., Snyder, E.Y., Hamblin, M.H., and Lee, J.P. (2014). Human neural stem cells rapidly ameliorate symptomatic inflammation in early-stage ischemic-reperfusion cerebral injury. Stem Cell Res. Ther., 5.","DOI":"10.1186\/scrt519"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Anderson, J.D., Pham, M.T., Contreras, Z., Hoon, M., Fink, K., Johansson, H.J., Rossignol, J., Dunbar, G.L., Showalter, M., and Fiehn, O. (2016). Mesenchymal stem cell-based therapy for ischemic stroke. Chin. Neurosurg. J., 2.","DOI":"10.1186\/s41016-016-0053-4"},{"key":"ref_56","first-page":"1","article-title":"Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats","volume":"6","author":"Nakazaki","year":"2017","journal-title":"J. Neurosurg."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/ana.20501","article-title":"Autologous mesenchymal stem cell transplantation in stroke patients","volume":"57","author":"Bang","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1002\/jnr.23104","article-title":"Intracerebral transplantation of bone marrow stromal cells ameliorates tissue plasminogen activator-induced brain damage after cerebral ischemia in mice detected by in vivo and ex vivo optical imaging","volume":"90","author":"Liu","year":"2012","journal-title":"J. Neurosci. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1179\/016164107X181815","article-title":"A review of oxygen therapy in ischemic stroke","volume":"29","author":"Singhal","year":"2007","journal-title":"Neurol. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1111\/j.1471-4159.2008.05664.x","article-title":"Normobaric hyperoxia inhibits NADPH oxidase-mediated matrix metalloproteinase-9 induction in cerebral microvessels in experimental stroke","volume":"107","author":"Liu","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1006\/exnr.2000.7506","article-title":"Hyperbaric oxygen therapy for treatment of postischemic stroke in adult rats","volume":"166","author":"Chang","year":"2000","journal-title":"Exp. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1161\/STROKEAHA.116.015753","article-title":"Hyperbaric Oxygen reduces infarction volume and hemorrhagic transformation through ATP\/NAD+\/Sirt1 pathway in hyperglycemic middle cerebral artery occlusion rats","volume":"48","author":"Hu","year":"2017","journal-title":"Stroke"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4103\/2045-9912.184721","article-title":"Hyperbaric oxygen therapy in experimental and clinical stroke","volume":"6","author":"Zhai","year":"2016","journal-title":"Med. Gas Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1037\/neu0000149","article-title":"Improvement of memory impairments in poststroke patients by hyperbaric oxygen therapy","volume":"29","author":"Golan","year":"2015","journal-title":"Neuropsychology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e647","DOI":"10.1161\/STROKEAHA.109.564872","article-title":"Recombinant human erythropoietin in the treatment of acute ischemic stroke","volume":"40","author":"Ehrenreich","year":"2009","journal-title":"Stroke"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/S1474-4422(16)30076-X","article-title":"Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: A secondary analysis of an individual patient data meta-analysis","volume":"15","author":"Whiteley","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1161\/STROKEAHA.111.618850","article-title":"Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies","volume":"42","author":"Albers","year":"2011","journal-title":"Stroke"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s12975-012-0209-2","article-title":"RIGOR guidelines: Escalating STAIR and STEPS for effective translational research","volume":"4","author":"Lapchak","year":"2013","journal-title":"Transl. Stroke Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1161\/STROKEAHA.114.007105","article-title":"One, two, three steps toward cell therapy for stroke","volume":"46","author":"Diamandis","year":"2015","journal-title":"Stroke"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1177\/1941874415576204","article-title":"What to do with wake-up stroke","volume":"5","author":"Rubin","year":"2015","journal-title":"Neurohospitalist"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1056\/NEJMoa1109842","article-title":"A randomized trial of tenecteplase versus alteplase for acute ischemic stroke","volume":"366","author":"Parsons","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/s12975-015-0444-4","article-title":"Extending the Time Window for Endovascular and Pharmacological Reperfusion","volume":"7","author":"Henninger","year":"2016","journal-title":"Transl. Stroke Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2756\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:54:36Z","timestamp":1760208876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,19]]},"references-count":72,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["ijms18122756"],"URL":"https:\/\/doi.org\/10.3390\/ijms18122756","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,19]]}}}