IMAGING THE TEMPORAL DYNAMICS OF BLOOD-BRAIN BARRIER DYSFUNCTION AND EXTRACELLULAR MATRIX METALLOPROTEINASE INVOLVEMENT AFTER ISCHEMIC STROKE IN RATS

Ischemic stroke is a cerebrovascular disease caused by interruption of blood flow to the brain triggering an ischemic cascade that disrupts the blood-brain barrier (BBB). During ischemia, increased BBB permeability allows the entry of proinflammatory mediators, contributing to brain damage. However, the mechanisms underlying BBB dysfunction and the role of matrix metalloproteinases (MMPs) during subacute and chronic phases after stroke remain poorly understood. The aim of this study is to evaluate BBB integrity, neuroinflammation and MMP activity during the first month after ischemia. Adult male Sprague Dawley rats (N=102) where subjected to a transient middle cerebral artery occlusion (tMCAO) for 75 min followed by reperfusion, and were studied at days 0, 1, 3, 7, 14, 21 and 28 post-stroke. In vivo BBB integrity was assessed using dynamic contrast-enhanced MRI (DCE-MRI), while ex vivo BBB permeability and vascular inflammation were measured by Evans Blue extravasation and VCAM immunohistochemistry. MMPs activity was quantified using [18F]BR351 PET imaging, as well as in situ and gel zymography. Our results showed BBB permeability increase during the first week, with a peak at day 7, followed by a recovery during the chronic phase. VCAM expression correlated with BBB leakage, indicating an association between vascular inflammation and BBB disruption. In contrast, [18F]BR351 signal and MMP-9 activity peaked within the first 24 hours, while MMP-2 activity peaked at day 7, likely contributing to vascular repair and remodeling. These findings suggest that subacute BBB disruption after subacute ischemic stroke is primarily mediated by inflammation rather than by MMPs activity.