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Abstract
A sensitive quantitative fluorescence method was used to explore the time course and
regional pattern of blood-brain barrier (BBB) opening after transient middle cerebral
artery occlusion (MCAo). Male Sprague-Dawley rats were anesthetized with halothane
and subjected to 2 h of temporary MCAo by retrograde insertion of an intraluminal
nylon suture, coated with poly-L-lysine, through the external carotid artery into
the internal carotid artery and MCA. Damage to the BBB was judged by extravasation
of Evans Blue (EB) dye, which was administered either 2, 3, 24 or 48 h after onset
of MCAo. Fluorometric quantitation of EB was performed 1 or 2 h later in six brain
regions. Cerebral infarction volumes were quantitated from histopathological material
at 72 h. EB extravasation first became grossly visible in the ipsilateral caudoputamen
and neocortex following 3 h of MCAo, was grossly unapparent at 24-26 h, and was maximal
at 48-50 h. Fluorescence quantitation confirmed that BBB opening was absent at 2-3
h but present at all later times. In the hemisphere ipsilateral to MCAo, a 179% mean
increase in extravasation of EB (compared to sham rats) was measured at 4 h, 407%
at 5 h, 311% at 26 h and 264% at 50 h. (in each case, P < 0.05 vs. sham). The volume
of infarcted tissue at 72 h in this model was 163.6 +/- 7.7 mm3. Our results indicate
that an initial, acute disruption of the BBB occurs between 3 and 5 h following MCAo,
and that a later, more widespread increase in regional BBB permeability is present
at 48 h. Regional measurement of Evans Blue extravasation offers a precise means of
quantitating BBB disruption in focal cerebral ischemia; this method will be of considerable
utility in assessing the BBB-protective properties of pharmacological agents.