title: Effect of recombinant plasminogen activator timing on thrombolysis in a novel rat embolic stroke model.
abstract: The treatment of acute ischemic stroke (AIS) using thrombolysis with recombinant tissue-plasminogen activator (rtPA, alteplase) is limited by its narrow time window and the risk of hemorrhage. Recombinant plasminogen activator (rPA, reteplase) has been used clinically on coronary artery thrombosis and acute myocardial infarction. It is necessary to induce strokes experimentally as a means of validating the rPA timing on patients with AIS. However, current embolic models cannot mimic clinical situations well due to the embolus's composition of dried blood clots or artificial materials. In this paper, we used two novel rat thromboembolic models to determine the dosage-effect relationship and therapeutic time window of r-PA. Male rats were administered rPA or rtPA intravenously at 2-12h postischemia. Cerebral blood flow, behavioral outcomes and infarct volume within the same animal group were determined. Our results demonstrated that rPA (0.2 and 0.4mg/kg) or rtPA (0.2mg/kg) restored focal perfusion, reduced cerebral infarction, and improved behavioral outcomes at 2-4h postischemia. rPA but not rtPA significantly restored focal perfusion at 6h postischemia. However, delayed rPA-treatment neither decreased infarct volume nor improved the neurological disorder. Cerebral hemorrhage occurred at 6h postischemia detected by Evan's blue leakage and tissue hemoglobin content. Collectively, Thrombolysis with rPA may be beneficial in revascularization at an acceptable dosage of 0.2-0.4mg/kg within 6h after the cerebral infarct onset.
authors.affiliation: Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Yinzhong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Ziran
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Junke
authors.initials: J
authors.lastname: Song
authors.affiliation: Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Yihuang
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Beijing Key Laboratory of Drug Target and Screening Research, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China. Electronic address: dugh@imm.ac.cn.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Du
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D008297:Male; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013923:Thromboembolism / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; C087896:reteplase; D010959:Tissue Plasminogen Activator
keywords: Cerebral embolism; Stroke; Thrombolytic; Time window; rtPA