Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat.
The immaturity of the CNS at birth greatly affects injury after stroke but the contribution of the blood-brain barrier (BBB) to the differential response to stroke in adults and neonates is poorly understood. We asked whether the structure and function of the BBB is disrupted differently in neonatal and adult rats by transient middle cerebral artery occlusion. In adult rats, albumin leakage into injured regions was markedly increased during 2-24 h reperfusion but leakage remained low in the neonates. Functional assays employing intravascular tracers in the neonates showed that BBB permeability to both large (70 kDa dextran) and small (3 kDa dextran), gadolinium (III)-diethyltriaminepentaacetic acid tracers remained largely undisturbed 24 h after reperfusion. The profoundly different functional integrity of the BBB was associated with the largely nonoverlapping patterns of regulated genes in endothelial cells purified from injured and uninjured adult and neonatal brain at 24 h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1266 probe sets in injured adults and 361 probe sets in neonates, changes in the gene expression of the basal lamina components, adhesion molecules, the tight junction protein occludin, and matrix metalloproteinase-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin, and zonula occludens protein 1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of cytokine-induced neutrophil chemoattractant-1 in the systemic circulation enhanced neutrophil infiltration, BBB permeability, and injury. The markedly more integrant BBB in neonatal brain than in adult brain after acute stroke may have major implications for the treatment of neonatal stroke.
Department of Neurology, University of California San Francisco, San Francisco, California 94143-0633, USA.
David
D
Fernández-López
Joel
J
Faustino
Richard
R
Daneman
Lu
L
Zhou
Sarah Y
SY
Lee
Nikita
N
Derugin
Michael F
MF
Wendland
Zinaida S
ZS
Vexler
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000254:growth & development / Q000503:physiopathology*; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D003911:Dextrans / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005070:Evans Blue; D005260:Female; D005456:Fluorescent Dyes; D007839:Functional Laterality; D019786:Gadolinium DTPA; D005786:Gene Expression Regulation / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D037102:Lectins / Q000378:metabolism; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015424:Reperfusion; D012710:Serum Albumin, Bovine; D018709:Statistics, Nonparametric; D013997:Time Factors
D003911:Dextrans; D005456:Fluorescent Dyes; D037102:Lectins; D008565:Membrane Proteins; D012710:Serum Albumin, Bovine; D005070:Evans Blue; D003094:Collagen; D020794:Receptor Protein-Tyrosine Kinases; D019786:Gadolinium DTPA