A mouse model of hemorrhagic transformation by delayed tissue plasminogen activator administration after in situ thromboembolic stroke.
OBJECTIVE
thrombolytic treatment with tissue plasminogen activator (tPA) improves outcome of patients with stroke who can be treated within 3 hours of symptom onset. However, delayed treatment with tPA leads to increased risk of hemorrhagic transformation and can result in enhanced brain injury. The purpose of this study is to validate a reproducible mouse model of hemorrhagic transformation associated with delayed administration of tPA.


METHODS
mice were anesthetized and thrombin was injected into the middle cerebral artery to induce the formation of a clot as described by Orset et al. To induce reperfusion, tPA (10 mg/kg) was intravenously administered 20 minutes or 3 hours after thrombin injection.


RESULTS
thrombin produced a clot in 83.1% of the animals, which caused focal ischemia determined 24 hours after the injection. Different degrees of bleeding were found in the middle cerebral artery occlusion group, including hemorrhagic infarction type 1 (HI-1) in 46.2%, hemorrhagic infarction type 2 (HI-2) in 30.8% and parenchymal hemorrhage type 1 in 23.0%. Administration of tPA 20 minutes after the occlusion produced an effective reperfusion in 62.5% of the animals and reduced both infarct volume and appearance of severe hemorrhage (10% nonhemorrhage, 80% HI-1 and 10% HI-2). However, administration of tPA 3 hours after the occlusion led to effective reperfusion in 47.1% of the animals, did not reduce infarct volume, caused hemorrhagic transformation (25% HI-1, 37.5% HI-2, and 37.5% parenchymal hemorrhage type 1), and increased hemorrhage and brain swelling.


CONCLUSIONS
we have set up a reproducible mouse model of hemorrhagic transformation associated with delayed administration of tPA similar to that observed in humans.
Departamento de Farmacología. Facultad de Medicina, Universidad Complutense Madrid, 28040, Madrid, Spain.
Isaac
I
García-Yébenes
Mónica
M
Sobrado
Juan G
JG
Zarruk
Mar
M
Castellanos
Natalia
N
Pérez de la Ossa
Antoni
A
Dávalos
Joaquín
J
Serena
Ignacio
I
Lizasoain
María A
MA
Moro
D000818:Animals; D020520:Brain Infarction / Q000139:chemically induced* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D020766:Intracranial Embolism / Q000139:chemically induced* / Q000473:pathology; D020300:Intracranial Hemorrhages / Q000139:chemically induced* / Q000473:pathology; D020767:Intracranial Thrombosis / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D013917:Thrombin / Q000009:adverse effects* / Q000494:pharmacology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000494:pharmacology
D013917:Thrombin; D010959:Tissue Plasminogen Activator