Urokinase versus Alteplase for intraventricular hemorrhage fibrinolysis.
Intraventricular hemorrhage (IVH) is the most severe form of stroke with intraventricular fibrinolysis (IVF) as a hopeful treatment. Urokinase (uPA) and tissue-type plasminogen activator (tPA) are used for IVF in Human. No clinical trial has evaluated the differential impact of these two fibrinolytics for IVF. Thus, we decided here to compare the use of these two fibrinolytics in a pre-clinical study. IVH was induced in rats by injection of collagenase type VII within the brain parenchyma followed by an IVF. Rats were randomized to receive uPA, tPA or saline within the ventricle, and cerebrospinal fluid was aspirated. Hematoma and ventricular volumes, brain water contents, inflammation and neurological deficits were measured at day three post-treatments. We also performed in vitro studies, in which neuronal cultures were subjected to an excitotoxic paradigm in the presence of either uPA or tPA. In the IVH model, we showed that although both uPA and tPA led to reduced ventricular volumes, only uPA significantly improved functional recovery. These results could be explained by the fact that uPA, in contrast of tPA, fails to promote inflammatory processes and neurotoxicity. Our study provides evidence supporting the use of uPA for fibrinolysis of IVH. A clinical trial could be warranted if tPA failed to improve outcomes in human IVH.
Department of Neurosurgery, Caen University Hospital, Avenue de la côte de Nacre, 14000 Caen, France; Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France. Electronic address: thomas.gaberel@hotmail.fr.
Thomas
T
Gaberel
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Axel
A
Montagne
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Flavie
F
Lesept
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Maxime
M
Gauberti
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Eloïse
E
Lemarchand
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Cyrille
C
Orset
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Romain
R
Goulay
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Thomas
T
Bertrand
Department of Neurosurgery, Caen University Hospital, Avenue de la côte de Nacre, 14000 Caen, France; Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Evelyne
E
Emery
Inserm, Inserm UMR-S U919, Serine Protease and Pathophysiology of the Neurovascular Unit, Université Caen Basse-Normandie, GIP Cyceron, bd Becquerel, 14074 Caen, France.
Denis
D
Vivien
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017364:Collagenases; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006406:Hematoma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006849:Hydrocephalus / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases
Animal model; Cerebral hemorrhage; Fibrinolytic agents; Intraventricular; Tissue-type plasminogen activator; Urokinase-type plasminogen activator; Ventriculostomy