title: Low dose tPA plus annexin A2 combination attenuates tPA delayed treatment-associated hemorrhage and improves recovery in rat embolic focal stroke.
abstract: We previously have shown that tissue type plasminogen activator (tPA) in combination with its receptor annexin A2 (rA2) protein significantly improved tPA thrombolytic efficacy. In this study we aimed to examine the therapeutic effects of the combination when treated at delayed 4-hour window after stroke compared to standard conventional tPA alone in an embolic focal stroke rat model. We compared effects of intravenous tPA alone (10 mg/kg) versus a combination of low-dose tPA (5 mg/kg) plus 10 mg/kg rA2. Totally 152 rats were used. Our results showed that: (1) at 24 h after stroke, the combination slightly reduced brain infarction compared to saline (9.2% reduction), and tPA (7.4% reduction), although the reductions did not reach statistical significance; while the combination significantly reduced (22.2% reduction) the conventional tPA-elevated intracerebral hemorrhagic (ICH) transformation; (2) at 7 days after stroke, the combination significantly attenuated conventional tPA alone-elevated iron deposition at peri-lesion area (68.2% reduction); (3) at 28 days after stroke, the combination significantly improved performance of adhesive tape-removal test, which was accompanied by a significantly higher micro vessel density at peri- infarct areas compared to conventional tPA alone group.In conclusion, compared to conventional tPA alone, when treated at delayed 4-hour after stroke, the combination of low-dose tPA plus rA2 therapy provides a safer profile by lowering risk of ICH transformation and improves neurological function recovery after stroke.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School. Boston, MA, USA.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Research Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School. Boston, MA, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fan
authors.affiliation: Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School. Boston, MA, USA.
authors.forename: Zhanyang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School. Boston, MA, USA.
authors.forename: Chongjie
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School. Boston, MA, USA.
authors.forename: Xiao-Shu
authors.initials: XS
authors.lastname: Wang
authors.affiliation: Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School. Boston, MA, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Neuroscience Program, Harvard Medical School. Boston, MA, USA. Electronic address: wangxi@helix.mgh.harvard.edu.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004359:Drug Therapy, Combination; D020766:Intracranial Embolism / Q000150:complications*; D008297:Male; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D017306:Annexin A2; D010959:Tissue Plasminogen Activator
keywords: Annexin A2; Combination thrombolytic therapy; Embolic focal stroke; Intracerebral hemorrhagic transformation; Long term neurological outcomes; Tissue plasminogen activator