{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T22:34:17Z","timestamp":1788042857294,"version":"build-2784847793"},"reference-count":69,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Circ"],"published-print":{"date-parts":[[2018]]},"DOI":"10.4103\/bc.bc_21_18","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T02:51:25Z","timestamp":1539053485000},"page":"99","source":"Crossref","is-referenced-by-count":50,"title":["Combination therapy for ischemic stroke: Novel approaches to lengthen therapeutic window of tissue plasminogen activator"],"prefix":"10.4103","volume":"4","author":[{"given":"Ike","family":"dela Pe\u00f1a","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Knecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar","family":"Borlongan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"key-10.4103\/2394-8108.242910-1","first-page":"259","volume-title":"Stroke incidence and mortality trends in US communities, 1987 to 2011","author":"Koton","year":"2014","journal-title":"JAMA"},{"key":"key-10.4103\/2394-8108.242910-2","first-page":"2109","volume-title":"The NINDS t-PA stroke study group","author":"Intracerebral","year":"1997","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-3","first-page":"e28","volume-title":"Heart disease and stroke statistics-2014 update: A report from the American Heart Association","author":"Go","year":"2014","journal-title":"Circulation"},{"key":"key-10.4103\/2394-8108.242910-4","first-page":"2847","volume-title":"Tissue plasminogen activator for acute ischemic stroke in clinical practice: A meta-analysis of safety data","author":"Graham","year":"2003","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-5","first-page":"1952","volume-title":"Estimated cost savings of increased use of intravenous tissue plasminogen activator for acute ischemic stroke in Canada","author":"Yip","year":"2007","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-6","first-page":"321","volume-title":"Neurogenesis and stroke","author":"Greenberg","year":"2007","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"key-10.4103\/2394-8108.242910-7","first-page":"916","volume-title":"et al. 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","author":"Adams","year":"2005","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-8","first-page":"2726","volume-title":"Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke","author":"Wang","year":"2004","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-9","first-page":"50","volume-title":"Strategies to extend thrombolytic time window for ischemic stroke treatment: An unmet clinical need","author":"Pe\u00f1a","year":"2017","journal-title":"J Stroke"},{"key":"key-10.4103\/2394-8108.242910-10","first-page":"173","volume-title":"Mechanisms and markers for hemorrhagic transformation after stroke","author":"Rosell","year":"2008","journal-title":"Acta Neurochir Suppl"},{"key":"key-10.4103\/2394-8108.242910-11","first-page":"1572","volume-title":"Hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke: Mechanisms, models, and biomarkers","author":"Wang","year":"2015","journal-title":"Mol Neurobiol"},{"key":"key-10.4103\/2394-8108.242910-12","first-page":"185","volume-title":"Hemorrhagic transformation after ischemic stroke in animals and humans","author":"Jickling","year":"2014","journal-title":"J Cereb Blood Flow Metab"},{"key":"key-10.4103\/2394-8108.242910-13","first-page":"38","volume-title":"Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment","author":"Lapchak","year":"2002","journal-title":"Curr Neurol Neurosci Rep"},{"key":"key-10.4103\/2394-8108.242910-14","first-page":"240","volume-title":"Therapeutic strategies to attenuate hemorrhagic transformation after tissue plasminogen activator treatment for acute ischemic stroke","author":"Kanazawa","year":"2017","journal-title":"J Atheroscler Thromb"},{"key":"key-10.4103\/2394-8108.242910-15","first-page":"335","volume-title":"Ascorbic acid reduces the adverse effects of delayed administration of tissue plasminogen activator in a rat stroke model","author":"Allahtavakoli","year":"2015","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"key-10.4103\/2394-8108.242910-16","first-page":"831","volume-title":"Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats","author":"Sumii","year":"2002","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-17","first-page":"404","volume-title":"Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats","author":"Tan","year":"2015","journal-title":"Eur J Pharmacol"},{"key":"key-10.4103\/2394-8108.242910-18","first-page":"3490","volume-title":"Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke","author":"Tan","year":"2013","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-19","first-page":"1732","volume-title":"Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice","author":"Suzuki","year":"2007","journal-title":"J Thromb Haemost"},{"key":"key-10.4103\/2394-8108.242910-20","first-page":"1389","volume-title":"Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells","author":"Koto","year":"2007","journal-title":"Am J Pathol"},{"key":"key-10.4103\/2394-8108.242910-21","first-page":"979","volume-title":"Dodecafluoropentane emulsion extends window for tPA therapy in a rabbit stroke model","author":"Culp","year":"2015","journal-title":"Mol Neurobiol"},{"key":"key-10.4103\/2394-8108.242910-22","first-page":"221","volume-title":"Anti-inflammatory effects of granulocyte colony-stimulating factor","author":"Hartung","year":"1998","journal-title":"Curr Opin Hematol"},{"key":"key-10.4103\/2394-8108.242910-23","first-page":"1567","volume-title":"Association of growth factors with arterial recanalization and clinical outcome in patients with ischemic stroke treated with tPA","author":"Sobrino","year":"2010","journal-title":"J Thromb Haemost"},{"key":"key-10.4103\/2394-8108.242910-24","first-page":"240","volume-title":"Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage","author":"Mayne","year":"2001","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-25","first-page":"3813","volume-title":"Natural and synthetic coumarin derivatives with anti-inflammatory\/antioxidant activities","author":"Fylaktakidou","year":"2004","journal-title":"Curr Pharm Des"},{"key":"key-10.4103\/2394-8108.242910-26","first-page":"3372","volume-title":"Extension of the thrombolytic time window with minocycline in experimental stroke","author":"Murata","year":"2008","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-27","first-page":"56","volume-title":"Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke","author":"Machado","year":"2006","journal-title":"BMC Neurosci"},{"key":"key-10.4103\/2394-8108.242910-28","first-page":"917","volume-title":"Intravenous infusion of mesenchymal stem cells inhibits intracranial hemorrhage after recombinant tissue plasminogen activator therapy for transient middle cerebral artery occlusion in rats","author":"Nakazaki","year":"2017","journal-title":"J Neurosurg"},{"key":"key-10.4103\/2394-8108.242910-29","first-page":"610","volume-title":"Improvement of memory impairments in poststroke patients by hyperbaric oxygen therapy","author":"Boussi-Gross","year":"2015","journal-title":"Neuropsychology"},{"key":"key-10.4103\/2394-8108.242910-30","first-page":"302","volume-title":"Arho kinase (ROCK) inhibitor, fasudil, prevents matrix metalloproteinase-9-related hemorrhagic transformation in mice treated with tissue plasminogen activator","author":"Ishiguro","year":"2012","journal-title":"Neuroscience"},{"key":"key-10.4103\/2394-8108.242910-31","first-page":"1","volume-title":"The blood-brain barrier: An overview: Structure, regulation, and clinical implications","author":"Ballabh","year":"2004","journal-title":"Neurobiol Dis"},{"key":"key-10.4103\/2394-8108.242910-32","first-page":"e15178","volume-title":"Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA","author":"Ishiguro","year":"2010","journal-title":"PLoS One"},{"key":"key-10.4103\/2394-8108.242910-33","first-page":"18","volume-title":"Vascular disruption and blood-brain barrier dysfunction in intracerebral hemorrhage","author":"Keep","year":"2014","journal-title":"Fluids Barriers CNS"},{"key":"key-10.4103\/2394-8108.242910-34","first-page":"12788","volume-title":"Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1","author":"Thiyagarajan","year":"2008","journal-title":"J Neurosci"},{"key":"key-10.4103\/2394-8108.242910-35","first-page":"1816","volume-title":"Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats","author":"Zhang","year":"2009","journal-title":"J Cereb Blood Flow Metab"},{"key":"key-10.4103\/2394-8108.242910-36","first-page":"2668","volume-title":"Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke","author":"Ishrat","year":"2013","journal-title":"Neurochem Res"},{"key":"key-10.4103\/2394-8108.242910-37","first-page":"981","volume-title":"Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine","author":"Huang","year":"1996","journal-title":"J Cereb Blood Flow Metab"},{"key":"key-10.4103\/2394-8108.242910-38","first-page":"33","volume-title":"Cilostazol in secondary prevention of stroke: Impact of the cilostazol stroke prevention study","author":"Matsumoto","year":"2005","journal-title":"Atheroscler Suppl"},{"key":"key-10.4103\/2394-8108.242910-39","first-page":"571","volume-title":"Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage.Results of a prospective placebo-controlled double-blind trial","author":"Shibuya","year":"1992","journal-title":"J Neurosurg"},{"key":"key-10.4103\/2394-8108.242910-40","first-page":"338","volume-title":"Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis","author":"dela","year":"2015","journal-title":"J Cereb Blood Flow Metab"},{"key":"key-10.4103\/2394-8108.242910-41","first-page":"565","volume-title":"Galardin inhibits collagen degradation by rabbit keratocytes by inhibiting the activation of pro-matrix metalloproteinases","author":"Hao","year":"1999","journal-title":"Exp Eye Res"},{"key":"key-10.4103\/2394-8108.242910-42","first-page":"39","volume-title":"Abroad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice","author":"Mishiro","year":"2012","journal-title":"Neuroscience"},{"key":"key-10.4103\/2394-8108.242910-43","first-page":"731","volume-title":"Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke","author":"Su","year":"2008","journal-title":"Nat Med"},{"key":"key-10.4103\/2394-8108.242910-44","first-page":"2107","volume-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","author":"Zuo","year":"2014","journal-title":"Eur J Neurosci"},{"key":"key-10.4103\/2394-8108.242910-45","first-page":"2283","volume-title":"Minocycline to improve neurologic outcome in stroke (MINOS): A dose-finding study","author":"Fagan","year":"2010","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-46","first-page":"2633","volume-title":"Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke","author":"Switzer","year":"2011","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-47","first-page":"362961","volume-title":"Reducing haemorrhagic transformation after thrombolysis for stroke: A strategy utilising minocycline","author":"Blacker","year":"2013","journal-title":"Stroke Res Treat"},{"key":"key-10.4103\/2394-8108.242910-48","doi-asserted-by":"crossref","unstructured":"Borlongan CV. Bone marrow stem cell mobilization in stroke: A 'bonehead' may be good after all! Leukemia 2011;25:1674-86.","DOI":"10.1038\/leu.2011.167"},{"key":"key-10.4103\/2394-8108.242910-49","first-page":"1344","volume-title":"Normobaric hyperoxia slows blood-brain barrier damage and expands the therapeutic time window for tissue-type plasminogen activator treatment in cerebral ischemia","author":"Liang","year":"2015","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-50","first-page":"635","volume-title":"Prediction of stroke thrombolysis outcome using CT brain machine learning","author":"Bentley","year":"2014","journal-title":"Neuroimage Clin"},{"key":"key-10.4103\/2394-8108.242910-51","first-page":"11","volume-title":"Arandomized trial of intraarterial treatment for acute ischemic stroke","author":"Berkhemer","year":"2015","journal-title":"N Engl J Med"},{"key":"key-10.4103\/2394-8108.242910-52","first-page":"1584","volume-title":"Outcome after thrombectomy and intravenous thrombolysis in patients with acute ischemic stroke: A Prospective observational study","author":"Minnerup","year":"2016","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-53","first-page":"129","volume-title":"Human neural stem cells rapidly ameliorate symptomatic inflammation in early-stage ischemic-reperfusion cerebral injury","author":"Huang","year":"2014","journal-title":"Stem Cell Res Ther"},{"key":"key-10.4103\/2394-8108.242910-54","doi-asserted-by":"crossref","unstructured":"Eckert AD, Hamblin M, Lee JP. Neural stem cells reduce symptomatic inflammation and mortality in aged stroke mice following delayed tpa treatment. FASEB J 2017;31 Suppl 1:693.6-693.6.","DOI":"10.1096\/fasebj.31.1_supplement.693.6"},{"key":"key-10.4103\/2394-8108.242910-55","first-page":"36","volume-title":"Mesenchymal stem cell-based therapy for ischemic stroke","author":"Anderson","year":"2016","journal-title":"Chin Neurosurg J"},{"key":"key-10.4103\/2394-8108.242910-56","first-page":"874","volume-title":"Autologous mesenchymal stem cell transplantation in stroke patients","author":"Bang","year":"2005","journal-title":"Ann Neurol"},{"key":"key-10.4103\/2394-8108.242910-57","first-page":"2086","volume-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","author":"Liu","year":"2012","journal-title":"J Neurosci Res"},{"key":"key-10.4103\/2394-8108.242910-58","first-page":"173","volume-title":"A review of oxygen therapy in ischemic stroke","author":"Singhal","year":"2007","journal-title":"Neurol Res"},{"key":"key-10.4103\/2394-8108.242910-59","first-page":"298","volume-title":"Hyperbaric oxygen therapy for treatment of postischemic stroke in adult rats","author":"Chang","year":"2000","journal-title":"Exp Neurol"},{"key":"key-10.4103\/2394-8108.242910-60","first-page":"1655","volume-title":"Hyperbaric oxygen reduces infarction volume and hemorrhagic transformation through ATP\/NAD+\/Sirt1 pathway in hyperglycemic middle cerebral artery occlusion rats","author":"Hu","year":"2017","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-61","first-page":"111","volume-title":"Hyperbaric oxygen therapy in experimental and clinical stroke","author":"Zhai","year":"2016","journal-title":"Med Gas Res","ISSN":"https:\/\/id.crossref.org\/issn\/2045-9912","issn-type":"print"},{"key":"key-10.4103\/2394-8108.242910-62","first-page":"e647","volume-title":"Recombinant human erythropoietin in the treatment of acute ischemic stroke","author":"Ehrenreich","year":"2009","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-63","first-page":"925","volume-title":"Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: A secondary analysis of an individual patient data meta-analysis","author":"Whiteley","year":"2016","journal-title":"Lancet Neurol"},{"key":"key-10.4103\/2394-8108.242910-64","first-page":"2645","volume-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","author":"Albers","year":"2011","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-65","first-page":"279","volume-title":"RIGOR guidelines: Escalating STAIR and STEPS for effective translational research","author":"Lapchak","year":"2013","journal-title":"Transl Stroke Res"},{"key":"key-10.4103\/2394-8108.242910-66","first-page":"588","volume-title":"One, two, three steps toward cell therapy for stroke","author":"Diamandis","year":"2015","journal-title":"Stroke"},{"key":"key-10.4103\/2394-8108.242910-67","first-page":"161","volume-title":"What to do with wake-up stroke","author":"Rubin","year":"2015","journal-title":"Neurohospitalist"},{"key":"key-10.4103\/2394-8108.242910-68","first-page":"1099","volume-title":"Arandomized trial of tenecteplase versus alteplase for acute ischemic stroke","author":"Parsons","year":"2012","journal-title":"N Engl J Med"},{"key":"key-10.4103\/2394-8108.242910-69","first-page":"284","volume-title":"Extending the time window for endovascular and pharmacological reperfusion","author":"Henninger","year":"2016","journal-title":"Transl Stroke Res"}],"container-title":["Brain Circulation"],"original-title":[],"language":"en","deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T18:40:22Z","timestamp":1786732822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/bc.bc_21_18"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018]]},"references-count":69,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018]]}},"alternative-id":["242910"],"URL":"https:\/\/doi.org\/10.4103\/bc.bc_21_18","relation":{},"ISSN":["2394-8108"],"issn-type":[{"value":"2394-8108","type":"print"}],"subject":[],"published":{"date-parts":[[2018]]}}}