title: Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke.
abstract: Recombinant tissue plasminogen activator (rt-PA) is currently the only approved drug for ischemic stroke treatment, with a dose of 0.9 mg/kg. Since the fibrinolytic activity of rt-PA has been reported in vitro to be 10-fold less potent in rodent than in human, in most in vivo experimental models of cerebral ischemia rt-PA is used at 10 mg/kg. The purpose of this study was to compare the effects of the "human" (0.9 mg/kg) and "rodent" (10 mg/kg) doses of rt-PA given at an early or a delayed time point in a mouse model of cerebral ischemia. Cerebral ischemia was induced by thrombin injection into the left middle cerebral artery of mice. Rt-PA (0.9 or 10 mg/kg) was intravenously administered 30 min or 4 h after the onset of ischemia. The degree of reperfusion after rt-PA was followed for 90 min after its injection. The neurological deficit, infarct volumes, edema and hemorrhagic transformations (HT) were assessed at 24 h. Reperfusion was complete after early administration of rt-PA at 10 mg/kg but partial with rt-PA at 0.9 mg/kg. Both doses given at 4 h induced partial reperfusion. Early administration of both doses of rt-PA reduced the neurological deficit, lesion volume and brain edema, without modifying post-ischemic HT. Injected at 4 h, rt-PA at 0.9 and 10 mg/kg lost its beneficial effects and worsened HT. In conclusion, in the mouse thrombin stroke model, the "human" dose of rt-PA exhibits effects close to those observed in clinic.
authors.affiliation: EA4475, Pharmacologie de la Circulation Cérébrale, UFR des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. mohamad.el-amki@parisdescartes.fr
authors.forename: Mohamad
authors.initials: M
authors.lastname: El Amki
authors.forename: Dominique
authors.initials: D
authors.lastname: Lerouet
authors.forename: Bérard
authors.initials: B
authors.lastname: Coqueran
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Curis
authors.forename: Cyrille
authors.initials: C
authors.lastname: Orset
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Michel
authors.initials: M
authors.lastname: Plotkine
authors.forename: Catherine
authors.initials: C
authors.lastname: Marchand-Leroux
authors.forename: Isabelle
authors.initials: I
authors.lastname: Margaill
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006470:Hemorrhage / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008297:Male; D051379:Mice; D009422:Nervous System Diseases / Q000209:etiology; D011897:Random Allocation; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000209:etiology*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator