Mechanisms Of Blood-brain Barrier Disruption Research Articles

Transcellular transport as a mechanism of blood-brain barrier disruption during stroke.

It is well-known that ischemia causes disruption of the blood-brain barrier (BBB), which leads to the formation of vasogenic brain edema. One major mechanism of BBB opening is enhanced pinocytotic vesicle formation that may be induced after transient focal ischemia by several mechanisms, including nitric oxide production, release of neurotransmitters, inflammatory mediators and hemodynamic alterations. In the present study we sought to characterize the extent of pinocytosis in cerebral endothelium during both ischemia/reperfusion (I/R) and elevated intravascular pressure. Transient focal ischemia was induced for 1 hour with 24 hours of reperfusion using the filament occlusion model in male Wistar rats, after which occluded middle cerebral arteries (MCAs) were dissected and mounted on glass cannulas in an arteriograph chamber. This system allowed control over intravascular pressure, measurement of lumen diameter and perfusion with various tracers (Lucifer Yellow and horseradish peroxidase) for measurement of transcellular transport and quantification of pinocytosis using transmission electron microscopy. I/R was found to increase vesicle formation by 166% basolaterally without a change in vesicle formation apically compared to non-ischemic control MCAs at 75 mmHg (p less than 0.01). Similarly, an acute increase in pressure to 200 mmHg caused a 78% increase in apical pinocytosis (p less than 0.05) and a non-significant 42% increase basolaterally. These results were confirmed by permeability measurements using Lucifer Yellow and demonstrate that both I/R and acute elevations in intravascular pressure enhance cerebral endothelial cell pinocytosis. The increase in basolateral pinocytosis during ischemia suggests enhanced efflux mechanisms that may be transporting substances from brain to blood. In addition, since the enhanced pinocytosis after an increase in pressure occurred in isolated arteries in vitro without the influence of metabolic or neuronal factors, these findings demonstrate that elevated intravascular pressure is a primary stimulus for pinocytosis in cerebral endothelial cells.

Physiopathologie de la barrière hématoencéphalique et œdème cérébral d’origine ischémique

Cerebral oedema is a potentially lethal complication of brain infarction. Ischemia, by altering membrane ionic pump function, induces cell swelling and cytotoxic oedema. It also initiates early oxidative and inflammatory cascades leading to blood-brain barrier disruption, vasogenic oedema and haemorrhagic transformation. The mechanisms of blood-brain barrier disruption involve endothelial cell activation and endothelial basal membrane degradation by matrix metalloproteinases. Reperfusion by tissue plasminogen activators is the only treatment improving stroke prognosis. This treatment also increases vasogenic oedema and the risk of symptomatic haemorrhagic transformation, reducing the benefit of reperfusion. Experimental studies suggest that the inhibition of blood-brain barrier proteolysis reduces vasogenic oedema and the risk of haemorrhage. This recent progress in the understanding of blood-brain barrier disruption during ischaemia brings forward new therapeutic strategies using agents capable of interfering with the ischaemic cascade in order to increase the therapeutic window between the onset of ischaemia and thrombolytic reperfusion.