title: rt-PA causes a dose-dependent increase in the extravasation of cellular and non-cellular blood elements after focal cerebral ischemia.
abstract: While recombinant tissue plasminogen activator (rt-PA) is successfully used for thrombolysis in human stroke, it may increase the risk of hemorrhagic complications. We describe the effects of different doses of rt-PA (saline, 0.9, 9, or 18 mg rt-PA/kg body weight) on the extravasation of blood components following experimental cerebral ischemia (3 h, 24 h reperfusion, suture model) in rats. The damage to the blood-brain barrier and the hemoglobin extravasation were quantified by Western blotting and immunohistochemistry. Both were significantly elevated in the ischemic cortex and basal ganglia. As rt-PA doses rose, the hemoglobin content as well as the damage to the blood-brain barrier in the ischemic side also rose significantly (p<0.001). This correlated significantly with the rising MMP-9 (matrix metalloproteinase) after increasing doses of rt-PA. Despite various benefits, rt-PA is responsible for a dose-dependent increase of edema and hemorrhage after cerebral ischemia. Clinicians should consider using the lowest effective dose of rt-PA in stroke patients.
authors.affiliation: Department of Neurology, Ludwig-Maximilians University, Klinikum Grosshadern, Marchioninistr. 15, 81377 Munich, Germany.
authors.forename: Dorothe
authors.initials: D
authors.lastname: Burggraf
authors.forename: Helge K
authors.initials: HK
authors.lastname: Martens
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Hamann
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001929:Brain Edema / Q000139:chemically induced* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D016548:Prosencephalon / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000139:chemically induced* / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D006454:Hemoglobins; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9