Blood-brain barrier breakdown and repair by Src after thrombin-induced injury.
OBJECTIVE
Thrombin mediates the life-threatening cerebral edema that occurs after intracerebral hemorrhage. Therefore, we examined the mechanisms of thrombin-induced injury to the blood-brain barrier (BBB) and subsequent mechanisms of BBB repair.


METHODS
Intracerebroventricular injection of thrombin (20U) was used to model intraventricular hemorrhage in adult rats.


RESULTS
Thrombin reduced brain microvascular endothelial cell (BMVEC) and perivascular astrocyte immunoreactivity-indicating either cell injury or death-and functionally disrupted the BBB as measured by increased water content and extravasation of sodium fluorescein and Evans blue dyes 24 hours later. Administration of nonspecific Src family kinase inhibitor (PP2) immediately after thrombin injections blocked brain edema and BBB disruption. At 7 to 14 days after thrombin injections, newborn endothelial cells and astrocytes were observed around cerebral vessels at the time when BBB permeability and cerebral water content resolved. Delayed administration of PP2 on days 2 through 6 after thrombin injections prevented resolution of the edema and abnormal BBB permeability.


CONCLUSIONS
Thrombin, via its protease-activated receptors, is postulated to activate Src kinase phosphorylation of molecules that acutely injure the BBB and produce edema. Thus, acute administration of Src antagonists blocks edema. In contrast, Src blockade for 2 to 6 days after thrombin injections is postulated to prevent resolution of edema and abnormal BBB permeability in part because Src kinase proto-oncogene members stimulate proliferation of newborn BMVECs and perivascular astrocytes in the neurovascular niche that repair the damaged BBB. Thus, Src kinases not only mediate acute BBB injury but also mediate chronic BBB repair after thrombin-induced injury.
Liu
Da-Zhi
DZ
Department of Neurology, University of California at Davis, Sacramento, CA 95817, USA. dzliu@ucdavis.edu
Ander
Bradley P
BP
Xu
Huichun
H
Shen
Yan
Y
Kaur
Pali
P
Deng
Wenbin
W
Sharp
Frank R
FR
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D001929:Brain Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005070:Evans Blue; D019793:Fluorescein; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006490:Hemostatics / Q000009:adverse effects*; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000009:adverse effects*; D013997:Time Factors; D014867:Water / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C412373:AG 1879; D000954:Antigens, Surface; D005904:Glial Fibrillary Acidic Protein; D006490:Hemostatics; D011743:Pyrimidines; C114781:endothelial barrier antigen, rat; D014867:Water; D005070:Evans Blue; D019061:src-Family Kinases; D013917:Thrombin; D001973:Bromodeoxyuridine; D019793:Fluorescein