Tacrolimus (FK506) suppresses rt-PA-induced hemorrhagic transformation in a rat thrombotic ischemia stroke model.
The aim of this study was to evaluate the effect of tacrolimus on recombinant tissue-plasminogen activator (rt-PA)-induced hemorrhagic transformation, and to characterize its suppressive action for hemorrhage. Thrombotic occlusion of the middle cerebral artery (MCA) was induced by photochemical reaction in spontaneously hypertensive rats, and hemorrhagic scores and brain damage were measured 24 h after MCA occlusion. Administration of rt-PA 3 h after MCA occlusion significantly worsened spontaneous hemorrhagic changes and tended to aggravate brain damage. Hematoma was observed in 7 of 15 rats treated with rt-PA, and 0 of 15 rats in the control group. Tacrolimus alone administered intravenously 3 h after MCA occlusion did not produce any hemorrhagic changes. The combined treatment of tacrolimus followed by rt-PA significantly decreased the incidence of hematoma and brain damage in comparison with that of the rt-PA treated group. Permeability of the blood-brain-barrier (BBB) detected by extravasations of Evans blue was investigated 6 h after MCA occlusion, as was the integrity of microvascular endothelial cells as determined by immunohistochemical assessment of the prevalence of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31). Combined treatment of rt-PA with tacrolimus reduced the rt-PA-induced extravasation of Evans blue and preserved CD31-positive cells in the ischemic hemisphere. Thus, tacrolimus was able to reduce the rt-PA-induced hemorrhagic transformation, which might be due to the protective effects on cerebral microvascular endothelial cells after thrombotic cerebral ischemia during the acute phase of cerebral ischemia. In conclusion, the combination of rt-PA with tacrolimus may be useful for decreasing the risk of thrombolytic therapy.
Maeda
Masashi
M
Pharmacology Research Labs, Astellas Pharma Inc., Kashima, Osaka, Japan. masashi.maeda@jp.astellas.com
Furuichi
Yasuhisa
Y
Noto
Takahisa
T
Matsuoka
Nobuya
N
Mutoh
Seitaro
S
Yoneda
Yukio
Y
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D042783:Endothelial Cells / Q000378:metabolism; D005070:Evans Blue; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D055806:Microvessels / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011994:Recombinant Proteins / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011994:Recombinant Proteins; D005070:Evans Blue; D010959:Tissue Plasminogen Activator; D016559:Tacrolimus