Stroke-Induced Brain Parenchymal Injury Drives Blood–Brain Barrier Early Leakage Kinetics: A Combined in Vivo/in Vitro Study

Abstract

The disappointing clinical outcomes of neuroprotectants challenge the relevance of preclinical stroke models and data in defining early cerebrovascular events as potential therapeutic targets. The kinetics of blood-brain barrier (BBB) leakage after reperfusion and the link with parenchymal lesion remain debated. By using in vivo and in vitro approaches, we conducted a kinetic analysis of BBB dysfunction during early reperfusion. After 60 minutes of middle cerebral artery occlusion followed by reperfusion times up to 24 hours in mice, a non-invasive magnetic resonance imaging method, through an original sequence of diffusion-weighted imaging, determined brain water mobility in microvascular compartments (D*) apart from parenchymal compartments (apparent diffusion coefficient). An increase in D* found at 4 hours post reperfusion concurred with the onset of both Evans blue/Dextran extravasations and in vitro BBB opening under oxygen-glucose deprivation and reoxygenation (R). The BBB leakage coincided with an emerging cell death in brain tissue as well as in activated glial cells in vitro. The co-culture of BBB endothelial and glial cells evidenced a recovery of endothelium tightness when glial cells were absent or non-injured during R. Preserving the ischemic brain parenchymal cells within 4 hours of reperfusion may improve therapeutic strategies for cerebrovascular protection against stroke.

Diabetic Microangiopathy: Impact of Impaired Cerebral Vasoreactivity and Delayed Angiogenesis After Permanent Middle Cerebral Artery Occlusion on Stroke Damage and Cerebral Repair in Mice

“…2) The magnitude of BBB opening after stroke determines the extent of the infarct (33). This is also observed in the diabetic mice in our study, whose cerebral vessels display an immature phenotype with a relative decrease in proangiogenic factors and BBB proteins, suggesting BBB "fragility."…”

Exendin-4-Loaded PLGA Microspheres Relieve Cerebral Ischemia/Reperfusion Injury and Neurologic Deficits through Long-Lasting Bioactivity-Mediated Phosphorylated Akt/eNOS Signaling in Rats

“…The release of Ex-4 from degradable PEx-4 then activated GLP-1R in the brain, leading to the effects on the brain cerebral blood flow intensity and microcirculation. Under DM and stroke insults, BBB endothelial leakage was enhanced, 32,33 possibly resulting in more PEx-4 microspheres and fragments entry into the brain parenchyma.…”

Blood-Brain Barrier Dysfunction and Cerebral Small Vessel Disease (Arteriolosclerosis) in Brains of Older People

“…Studies in experimental animals show that in healthy brain tissue with a fully functional BBB, trans-endothelial permeability is exceedingly low and that there is minimal passive extravasation of plasma proteins, inorganic solutes or even water molecules (1, 3, 4). The BBB is disrupted in various animal models of CNS disorders, including acute ischemia (5), multiple sclerosis (6, 7), chronic white matter ischemia (8), and acute cold injury (9). …”