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

Published online by Cambridge University Press:  02 December 2014

Z. Gao Huang
Alberta Stroke Program, Department of Clinical Neurosciences, University of Calgary, Alberta Institute for Biological Sciences, National Research Council, Ottawa, Ontario, Canada
Dong Xue
Alberta Stroke Program, Department of Clinical Neurosciences, University of Calgary, Alberta Institute for Biological Sciences, National Research Council, Ottawa, Ontario, Canada
Hasneen Karbalai
Alberta Stroke Program, Department of Clinical Neurosciences, University of Calgary, Alberta
Alastair M. Buchan
Alberta Stroke Program, Department of Clinical Neurosciences, University of Calgary, Alberta
Z. Gao Huang
Institute for Biological Sciences, National Research Council, Ottawa, Ontario, Canada
Dong Xue
Institute for Biological Sciences, National Research Council, Ottawa, Ontario, Canada
Edward Preston
Institute for Biological Sciences, National Research Council, Ottawa, Ontario, Canada
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Tracer constants (Ki) 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.


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. 3H-sucrose was circulated for 30 min prior to each time point (1h, 4h, 22h, and 46h; n=5-7 per time point). Ki 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 (37.5oC) or hypothermic (32.5oC or 28.5oC) for the first 6 hours of reperfusion, and Ki was measured at 46 hours.


Rats injected after 1.5 - 2 min exhibited a 10-fold increase in Ki for cortical regions supplied by the right middle cerebral artery (p<0.01). This barrier opening had closed within 1 to 4 hours post-reperfusion. 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 (28oC-29oC) during the first six hours of reperfusion prevented opening, reducing Ki by over 50% (p<0.05).


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.



Nous avons mesuré les constantes d’un traceur (Ki) 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.


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 3H-sucrose a été administrée pendant 30 minutes avant chaque évaluation ponctuelle (1h, 4h, 22h, et 46h; n=5-7 par évaluation ponctuelle). La constante Ki 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±C) ou en hypothermie (32.5±C ou 28.5±C) pendant les 6 premières heures de la reperfusion et Ki a été mesurée à 46 heures.


Les rats qui ont reçu l’injection après 1.5 – 2 minutes présentaient une augmentation de Ki de dix fois supérieure dans les régions corticales irriguées par l’artère cérébrale moyenne (p<0.01). Cette ouverture de la barrière s’était refermée 1 à 4 heures post-reperfusion. À 22 heures, la barrier hémato-encéphalique s’était réouverte, davantage à 22 et à 46 heures (p<0.01), ce qui a donné lieu à de l’oedème. L’hypothermie généralisée (28±C - 29±C) pendant les 6 premières heures de la reperfusion a empêché son ouverture, diminuant ainsi la constante Ki de plus de 50% (p<0.05).


L’occlusion transitoire de l’artère cérébrale moyenne provoque une ouverture biphasique importante de la barrière hémato-encéphalique corticale don’t la deuxième phase cause de l’oedème. L’hypothermie a diminué la taille de l’infarctus cérébral et l’ouverture tardive de la barrière hémato-encéphalique. Cette ouverture de la barrière hémato-encéphalique peut accroître la distribution d’agents neuroprotecteurs à basse perméabilité.

Experimental Neurosciences
Copyright © The Canadian Journal of Neurological 1999


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