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. 3H- 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°C) or hypothermic (32.5°C or 28.5°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°C-29°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.