Toll-Like Receptor 4 Mediates Hemorrhagic Transformation After Delayed Tissue Plasminogen Activator Administration in In Situ Thromboembolic Stroke.

Hemorrhagic transformation is the main complication of revascularization therapies after stroke. Toll-like receptor 4 (TLR4) is implicated in cerebral damage and inflammation in stroke. This study was designed to determine the role of TLR4 in hemorrhagic transformation development after tissue plasminogen activator (tPA) administration. Mice expressing (TLR4+/+) or lacking functional TLR4 (TLR4-/-) were subjected to middle cerebral artery occlusion using an in situ thromboembolic model by thrombin injection into the middle cerebral artery, and tPA (10 mg/kg) was administered 20 minutes or 3 hours after ischemia. Infarct size, hemorrhages, IgG extravasation, matrix metalloproteinase 9 expression, and neutrophil infiltration were assessed 24 hours after ischemia. In TLR4+/+, early reperfusion (tPA at 20 minutes) resulted infarct volume, whereas late recanalization (tPA at 3 hours) did not modify lesion size and increased the rate of the most severe hemorrhages. In TLR4-/- mice, both early and late reperfusion did not modify lesion size. Importantly, late tPA administration did not result in worse hemorrhages and in an increased bleeding area as occurred in TLR4+/+ group. In TLR4-/- animals, late reperfusion produced a lesser increase in matrix metalloproteinase 9 expression when compared with TLR4+/+ animals. Our results demonstrate TLR4 involvement in hemorrhagic transformation induced by delayed tPA administration, very likely by increasing matrix metalloproteinase 9 expression.

García-Culebras A ，Palma-Tortosa S ，Moraga A ，García-Yébenes I ，Durán-Laforet V ，Cuartero MI ，de la Parra J ，Barrios-Muñoz AL ，Díaz-Guzmán J ，Pradillo JM ，Moro MA ，Lizasoain I ... -  《-》

Effects of tissue plasminogen activator timing on blood-brain barrier permeability and hemorrhagic transformation in rats with transient ischemic stroke.

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.

Zhang Y ，Wang Y ，Zuo Z ，Wang Z ，Roy J ，Hou Q ，Tong E ，Hoffmann A ，Sperberg E ，Bredno J ，Berr SS ，Xie M ，Lee K ，Wintermark M ... -  《-》

A mouse model of hemorrhagic transformation by delayed tissue plasminogen activator administration after in situ thromboembolic stroke.

García-Yébenes I ，Sobrado M ，Zarruk JG ，Castellanos M ，Pérez de la Ossa N ，Dávalos A ，Serena J ，Lizasoain I ，Moro MA ... -  《-》

Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice.

García-Yébenes I ，García-Culebras A ，Peña-Martínez C ，Fernández-López D ，Díaz-Guzmán J ，Negredo P ，Avendaño C ，Castellanos M ，Gasull T ，Dávalos A ，Moro MA ，Lizasoain I ... -  《-》

Phthalide derivative CD21 attenuates tissue plasminogen activator-induced hemorrhagic transformation in ischemic stroke by enhancing macrophage scavenger receptor 1-mediated DAMP (peroxiredoxin 1) clearance.

Liu DL ，Hong Z ，Li JY ，Yang YX ，Chen C ，Du JR ... -  《Journal of Neuroinflammation》