Blood-Brain Barrier Permeability Is Increased After Acute Adult Stroke But Not Neonatal Stroke in the Rat

Abstract

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 if 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, Gd-DTPA) tracers remained largely undisturbed 24h 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 24h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1,266 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 MMP-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin and ZO-1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of CINC-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.

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

“…This possibly explains, at least partly, our findings that HI induces accumulation and activation of resident microglia as well as infiltration of blood‐derived macrophages earlier in the immature hippocampus than that in the mature hippocampus. However, there is a conflicting report demonstrating that the immature BBB is more resistant to HI brain damage than its adult counterpart (Fernández‐López et al, 2012), so further studies are needed to resolve this issue.…”

Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway

“…Furthermore, pericytes are a vital component to maintaining the integrity of the BBB by forming tight junctions with endothelial cells along the capillary wall (13,39). In several neurodegenerative diseases, such as stroke and vascular dementia, there is evidence of impaired cerebrovascular integrity, primarily through BBB breakdown (40,41). Therefore, when pericytes are depleted at capillaries because of external stress or toxic conditions, the BBB likely becomes vulnerable to invasion by peripheral immune cells and substances which can exacerbate any pathological conditions within the CNS (39).…”

Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

“…Agents such as Evans blue dye or fluoresceintagged molecules can be effective to determine sites of vascular leakage where there are large volumes of tissue that are sparsely vascularized (Nishioku et al 2009;Fernandez-Lopez et al 2012;He et al 2014). However, the inner ear of the mouse is tiny, the vessels are in close proximity to the tissues and fluids of interest, and sectioning the inner ear and imaging those sections to determine the extent of dye extravasation from vessels into adjacent tissues can pose challenges of interpretation.…”