title: Effects of tissue plasminogen activator and annexin A2 combination therapy on long-term neurological outcomes of rat focal embolic stroke.
abstract: OBJECTIVE
  Tissue-type plasminogen activator (tPA) in combination with recombinant annexin A2 (rA2) is known to reduce acute brain damage after focal ischemia. Here, we ask whether tPA-plus-rA2 combination therapy can lead to sustained long-term neurological improvements as well.
  
  
  METHODS
  We compared the effects of intravenous high-dose tPA alone (10 mg/kg) versus a combination of low-dose tPA (5 mg/kg) plus 10 mg/kg rA2 in a model of focal embolic cerebral ischemia in rats. All rats were treated at 3 hours after embolization. Brain tissue and neurological outcomes were assessed at 1 month. Surrogate biomarkers for endogenous neurovascular remodeling in peri-infarct area were analyzed by immunohistochemistry.
  
  
  RESULTS
  Compared with high-dose tPA alone, low-dose tPA-plus-rA2 significantly decreased infarction and improved neurological function at 1-month poststroke. In peri-infarct areas, tPA-plus-rA2 combination therapy also significantly augmented microvessel density, vascular endothelial growth factor, and synaptophysin expression.
  
  
  CONCLUSIONS
  Compared with conventional high-dose tPA alone, combination low-dose tPA plus rA2 therapy may provide a safe and effective way to improve long-term neurological outcomes after stroke.
authors.affiliation: From the Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China (Xiaoshu Wang, Z.L.); and Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA (Xiaoshu Wang, X.F., Z.Y., Z.L., J.Z., E.M., S.G., E.H.L., Xiaoying Wang).
authors.forename: Xiaoshu
authors.initials: X
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Fan
authors.forename: Zhanyang
authors.initials: Z
authors.lastname: Yu
authors.forename: Zhengbu
authors.initials: Z
authors.lastname: Liao
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhao
authors.forename: Emiri
authors.initials: E
authors.lastname: Mandeville
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Guo
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000627:therapeutic use*; D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D004621:Embolization, Therapeutic; D007150:Immunohistochemistry; D020766:Intracranial Embolism / Q000150:complications* / Q000401:mortality; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy / Q000209:etiology / Q000401:mortality / Q000628:therapy*; D016708:Synaptophysin / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D017306:Annexin A2; D000933:Antifibrinolytic Agents; D016708:Synaptophysin; D042461:Vascular Endothelial Growth Factor A; D010959:Tissue Plasminogen Activator
keywords: annexin A2; drug therapy, combination; rats; tissue plasminogen activator