How are structural components of the BBB affected in diseases of the brain and spinal cord, where barrier function is impaired?
With more than 795,000 new cases every year, stroke is the fifth leading cause of mortality and the first leading cause of long-term disability in the U.S. More than 85% of all strokes are ischemic, caused by the occlusion of one of the arteries supplying blood to the brain.
We have shown that in a murine model of ischemic stroke (transient middle cerebral artery occlusion – tMCAo), stroke-induced BBB breakdown appears as two distinct waves of increased vascular permeability: the first one, occurring between 6 and 12 hours after reperfusion, caused by increased rates of transcytosis, and the second one, starting from 24 hours after reperfusion. We have also shown in mice that elimination of Caveolin-1 (Cav1-/-), a protein essential for the transcellular transport through caveolae, can effectively rescue the first wave of increased BBB permeability without affecting degradation of AJ and TJs, indicating that the two processes are mechanistically independent.
Despite the huge medical need, thrombolytic treatment with tPA remains the only FDA-approved therapy for ischemic stroke. However not every patient is eligible for tPA treatment, since it increases the risk for intracerebral hemorrhage (ICH), an event recognized as secondary due to BBB breakdown. tPA has also been shown to exacerbate BBB damage during stroke intervention.
Research in our laboratory aims at exploring the mechanisms of BBB dysfunction during stroke pathogenesis in order to identify potential novel candidates for targeted therapies able to restore BBB functionality after ischemic stroke and reperfusion, with the ultimate objective of addressing the safety concerns arising from reperfusion injury
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