Biphasic Opening of the Blood-Brain Barrier Following Transient Focal Ischemia: Effects of Hypothermia

Abstract

Objective: Tracer constants (K i ) for blood-to-brain diffusion of sucrose were measured in the rat to profile the time course of blood-brain barrier injury after temporary focal ischemia, and to determine the influence of post-ischemic hypothermia. Methods: Spontaneously hypertensive rats were subjected to transient (2 hours) clip occlusion of the right middle cerebral artery. Reperfusion times ranged from 1.5 min to 46 hours, and i.v.3 H-sucrose was circulated for 30 min prior to each time point (1h, 4h, 22h, and 46h; n=5-7 per time point). K i was calculated from the ratio of parenchymal tracer uptake and the time-integrated plasma concentration. Additional groups of rats (n=7-8) were maintained either normothermic (37.5 o C) or hypothermic (32.5 o C or 28.5 o C) for the first 6 hours of reperfusion, and K i was measured at 46 hours. Results: Rats injected after 1.5 -2 min exhibited a 10-fold increase in K i for cortical regions supplied by the right middle cerebral artery (p<0.01). This barrier opening had closed within 1 to 4 hours postreperfusion. By 22 hours, the blood-brain barrier had re-opened, with further opening 22 and 46 hours (p<0.01), resulting in edema. Whole body hypothermia (28 o C-29 o C) during the first six hours of reperfusion prevented opening, reducing K i by over 50% (p<0.05). Conclusions: Transient middle cerebral artery occlusion evokes a marked biphasic opening of the cortical blood-brain barrier, the second phase of which causes vasogenic edema. Hypothermic treatment reduced infarct volume and the late opening of the blood-brain barrier. This opening of the blood-brain barrier may enhance delivery of low permeability neuroprotective agents.RÉSUMÉ: Ouverture biphasique de la barrière hémato-encéphalique suite à une ischémie focale transitoire: effets de l'hypothermie. Objectif: Nous avons mesuré les constantes d'un traceur (K i ) de la diffusion de sucrose du sang vers le cerveau chez le rat afin d'observer l'évolution des dommages subis par la barrière hémato-encéphalique après une ischémie focale temporaire et pour déterminer les effets d'une hypothermie postischémique. Méthodes: Des rats spontanément hypertendus ont été soumis à une occlusion de deux heures de l'artère cérébrale moyenne par un clip. Le temps de reperfusion variait de 1.5 minute à 46 heures et une perfusion intraveineuse de 3 H-sucrose a été administrée pendant 30 minutes avant chaque évaluation ponctuelle (1h, 4h, 22h, et 46h; n=5-7 par évaluation ponctuelle). La constante K i a été calculée à partir de l'indice de captation du traceur par le parenchyme et de la concentration plasmatique en fonction du temps. Des groupes additionnels de rats (n=7-8) ont été maintenus soit à la température normale (37.5 o C) ou en hypothermie (32.5 o C ou 28.5 o C) pendant les 6 premières heures de la reperfusion et K i a été mesurée à 46 heures. Results: Les rats qui ont reçu l'injection après 1.5 -2 minutes présentaient une augmentation de K i de dix fois supérieure dans les régions corticales irriguées par l'artère cér...

Cerebral Cortical Aquaporin‐4 Expression in Brain Edema following Cardiac Arrest in Rats

“…34 In a focal cerebral ischemia study in rats, hypothermic treatment during the first six hours of reperfusion reduced infarct volume and the late opening of the blood-brain barrier. 35 The present study demonstrates that mild hypothermia induced before CA is associated with a reduction in AQP4 protein expression in the cerebral cortex.…”

The Blood–Brain Barrier

“…This leads to a subsequent increase in cerebral edema; however, the processes involved in the hypoxia-induced BBB permeability are not completely understood. Work in animal models of stroke has identified that there is a biphasic leakage of the BBB, with an early opening within hours following hypoxia/ischemia, followed by a refractory phase and then a second opening the next day (Kuroiwa et al 1985;Huang et al 1999). In addition, analysis in transgenic models has identified that there are stepwise alterations in the BBB, with an increase in transcytosis observed first followed by alterations in the TJs (Knowland et al 2014).…”

Use of Therapeutic Hypothermia in Cocaine-Induced Cardiac Arrest: Further Evidence

“…12 Cells injured by ischemia essentially have 3 options: become necrotic, undergo apoptosis, or recover. 12 The theoretical benefit of therapeutic hypothermia is that it combats injury by reducing cerebral edema, disruption of the blood brain barrier, 13 and free radical production as well as by stabilizing membranes. 10,14 Therapeutic hypothermia is also thought to reduce excitatory neurotoxic effects caused by impaired glutamate reuptake 10,15,16 and inflammatory cytokine release, specifically interleukins 1 and 6 and tumor necrosis factor-α.…”