title: Effects of tissue plasminogen activator timing on blood-brain barrier permeability and hemorrhagic transformation in rats with transient ischemic stroke.
abstract: The goal of our study was to determine if the timing of the tissue plasminogen activator (tPA) administration influenced its effect on blood-brain barrier (BBB) permeability and the subsequent risk of hemorrhagic transformation. Thirty spontaneously hypertensive male rats were subjected to a 90-minute unilateral middle cerebral artery occlusion. Six rats did not receive tPA treatment (vehicle control: Group 0), intravenous tPA was administered immediately after reperfusion (Group 1) or 4h after reperfusion (Group 2). Dynamic contrast enhancement (DCE) and gradient-echo (GRE) MR sequences were used to assess the dynamic evolution of BBB permeability and hemorrhagic transformation changes at the following time points: during occlusion, and 3h, 6h, and 24h post reperfusion. In all groups, BBB permeability values in the ischemic tissue were low during occlusion. In Group 0, BBB permeability values increased at 3h after reperfusion (p=0.007, compared with the values during occlusion), and further at 6h after reperfusion (p=0.004, compared with those at 3h post reperfusion). At 24h post reperfusion, the values decreased to a level relative to but still higher than those during occlusion (p=0.025, compared with the values during occlusion). At 3h after reperfusion, BBB permeability values in the ischemic tissue increased, but to a greater extent in Group 1 than in Group 0 (p=0.034) and Group 2 (p=0.010). At 6h after reperfusion, BBB permeability values in the ischemic tissue increased further in Group 2 than in Group 0 (p=0.006) and Group 1 (p=0.001), while Group 1 exhibited BBB permeability that were still abnormal but less than those observed at 3h (p=0.001). Group 2 tended to have a higher hemorrhage incidence (36.4%, 4/11) than Group 1 (10.0%, 1/10, p=0.311) and Group 0 (0%), and hemorrhages occurred around 6h after reperfusion when BBB permeability values were the highest. Mortality was higher in Group 2 (63.6%, 7/11) than in Group 0 (0%) and Group 1 (10.0%, 1/10, p=0.024). The findings suggest that the timing of tPA administration is of importance for its impact on BBB permeability and subsequent risk of hemorrhagic transformation.
authors.affiliation: Department of Ultrasound, Union hospital, Tongji Medical College, HuazhongUniversity of Science and Technology, Wuhan, Hubei, China; University of Virginia, Department of Radiology, Neuroradiology Division, Charlottesville, VA, United States.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, University of Virginia, Charlottesville, VA, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States; Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Radiology, University of Virginia, Charlottesville, VA, United States.
authors.forename: Jack
authors.initials: J
authors.lastname: Roy
authors.affiliation: University of Virginia, Department of Radiology, Neuroradiology Division, Charlottesville, VA, United States; Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Hou
authors.affiliation: Department of Radiology, University of Virginia, Charlottesville, VA, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tong
authors.affiliation: University of Virginia, Department of Radiology, Neuroradiology Division, Charlottesville, VA, United States; Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Department of Pharmacy, University of Virginia, Charlottesville, VA, United States.
authors.forename: Emily
authors.initials: E
authors.lastname: Sperberg
authors.affiliation: Philips Healthcare, CT and Nuclear Medicine, Imaging Physics and System Analysis, San Jose, CA, United States.
authors.forename: Joerg
authors.initials: J
authors.lastname: Bredno
authors.affiliation: Department of Radiology, University of Virginia, Charlottesville, VA, United States.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Berr
authors.affiliation: Department of Ultrasound, Union hospital, Tongji Medical College, HuazhongUniversity of Science and Technology, Wuhan, Hubei, China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Neuroscience, University of Virginia, Charlottesville, VA, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.affiliation: University of Virginia, Department of Radiology, Neuroradiology Division, Charlottesville, VA, United States. Electronic address: Max.Wintermark@gmail.com.
authors.forename: Max
authors.initials: M
authors.lastname: Wintermark
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D015427:Reperfusion Injury / Q000188:drug therapy; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
keywords: Blood–brain barrier permeability; Hemorrhagic transformation; Ischemic stroke; MR imaging; Tissue plasminogen activator