IMAGING THE CHANGES IN BLOOD-BRAIN BARRIER PERMEABILITY AFTER PRECLINICAL ISCHEMIC STROKE

Ischemic stroke induces matrix metalloproteinase (MMP) activation, leading to blood–brain barrier (BBB) disruption and neuronal damage. However, the mechanisms and temporal evolution of BBB disruption during subacute phase of ischemic stroke remain poorly understood. This study evaluates BBB integrity, neuroinflammatory response, and MMP activity following experimental stroke.
Male C57BL6/J mice (N=75) were subjected transient middle cerebral artery occlusion (tMCAO; 60 min). BBB permeability was assessed ex vivo using Evans Blue (EB) extravasation at baseline and at 1, 3 and 6 hours, and 1, 3 and 7 days post-tMCAO. In vivo BBB disruption was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using gadolinium. Neuroinflammation was analyzed ex vivo by immunohistochemical detection of vascular cell adhesion molecule-1 (VCAM-1). Finally, MMP activity was quantified by gelatin zymography.
Ischemic mice displayed a biphasic pattern of BBB disruption, characterized by an acute opening at 1-hour post-tMCAO, followed by partial recovery and a secondary disruption at day 7, as indicated by increased Ktrans values (DCE-MRI) and EB extravasation at these time points. VCAM-1 expression was markedly upregulated in ischemic cerebral vessels, indicating sustained vascular inflammation during subacute stroke. In parallel, neuroinflammation is currently being investigated using the TSPO radiotracer [¹⁸F]-DPA-714. In contrast zymography showed a peak increase in MMP-9 activity at 24 hours after stroke, followed by a progressive decline during the subsequent weeks.
These findings demonstrate a biphasic BBB opening after cerebral ischemia, with early disruption mediated by MMP activation and delayed breakdown likely driven by inflammatory processes during the subacute phase.