Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9 Expression During Reperfusion Injury

Abstract

Background and Purpose-Most experimental models of cerebral ischemia use mechanical methods of occlusion and reperfusion. However, differences between mechanical reperfusion versus clot thrombolysis may influence reperfusion injury profiles. In this study we compared blood flow recovery, blood-brain barrier (BBB) permeability, and matrix metalloproteinase-9 (MMP-9) expression in cortex after mechanical versus thrombolytic reperfusion in rat focal ischemia. Methods-Male spontaneously hypertensive rats were used. Mechanical ischemia/reperfusion was achieved with the use of an intraluminal filament to occlude the middle cerebral artery for 2 hours. Thrombolytic reperfusion was achieved by administering tissue plasminogen activator at 2 hours after embolic focal ischemia. Regional cortical blood flow was monitored by laser-Doppler flowmetry. BBB permeability in cortex was measured by Evans blue dye leakage. Cortical MMP-9 levels were assessed with zymography and immunohistochemistry. Results-Blood flow recovery during mechanical reperfusion was complete in both central and peripheral areas of ischemic cortex. However, after thrombolysis, reperfusion was incomplete, with moderate recovery in the periphery only. BBB permeability was mainly increased in the central regions of the ischemic cortex after mechanical reperfusion but was increased in both central and peripheral areas after thrombolysis. Overall, MMP-9 levels were higher after embolic versus mechanical ischemia/reperfusion, even though ischemic injury was similar in both models at 24 hours. Conclusions-There are significant differences in the profiles of blood flow recovery, BBB leakage, and MMP-9 upregulation in mechanical versus thrombolytic reperfusion after focal ischemia.

Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-β Peptide Catabolism

“…Consistent with these data, the expression and activity of MMP-2 was greater than that of MMP-9 in wildtype mice. MMP-2 is considered a constitutively expressed MMP, whereas MMP-9 is expressed at low levels under normal conditions (Gottschall et al, 1995;Yong et al, 1998;Planas et al, 2001) but is induced under pathological conditions, such as cerebral ischemia and neurodegeneration (Aoki et al, 2002;Lo et al, 2002;Lee et al, 2003). It is possible that under pathological conditions, MMP-9 may play a greater role in A␤ clearance; its expression is certainly increased in astrocytes surrounding amyloid plaques in aged APPsw mice.…”

Tissue-Type Plasminogen Activator Crosses the Intact Blood-Brain Barrier by Low-Density Lipoprotein Receptor–Related Protein-Mediated Transcytosis

“…30 tPA has no effect on the integrity of the BBB in physiological conditions either in vitro or in vivo. Some authors 34 but not all 18 suggest that tPA amplifies ischemia-induced BBB breakdown. Interestingly, the studies that showed an effect of tPA on BBB were performed on hypertensive rats.…”

“…Interestingly, the studies that showed an effect of tPA on BBB were performed on hypertensive rats. 34 In a recent report, Yepes and colleagues 15 showed that tPA can lead to an opening of the BBB by a mechanism that involves LRP. This discrepancy with the present results could be explained by the fact that here, tPA was injected intravenously, as it is usually performed in humans, whereas it was injected directly into the CSF in the study published by Yepes and colleagues.…”

tPA and Proteolysis in the Neurovascular Unit

“…15 In rat embolic stroke models, clot lysis with tPA increases ischemic brain MMP-9 levels, and co-treatment with MMP inhibitors reduced tPAinduced hemorrhagic transformation and brain injury. 16,17 The "tPA-induced MMP-9" hypothesis is further supported by a study showing that after focal cerebral ischemia, MMP-9 levels are lower in tPA knockout mice compared with wild-type mice. 18 But how does tPA amplify MMP-9?…”