Matrix Metalloproteinases and TIMPs Are Associated With Blood-Brain Barrier Opening After Reperfusion in Rat Brain

Abstract

Background and Purpose-Reperfusion disrupts cerebral capillaries, causing cerebral edema and hemorrhage. Middle cerebral artery occlusion (MCAO) induces the matrix-degrading metalloproteinases, but their role in capillary injury after reperfusion is unknown. Matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs) modulate capillary permeability. Therefore, we measured blood-brain barrier (BBB) permeability, brain water and electrolytes, MMPs, and TIMPs at multiple times after reperfusion. Methods-Adult rats underwent MCAO for 2 hours by the suture method. Brain uptake of 14 C-sucrose was measured from 3 hours to 14 days after reperfusion. Levels of MMPs and TIMPs were measured by zymography and reverse zymography, respectively, in contiguous tissues. Other rats had water and electrolytes measured at 3, 24, or 48 hours after reperfusion. Treatment with a synthetic MMP inhibitor, BB-1101, on BBB permeability and cerebral edema was studied. Results-Brain sucrose uptake increased after 3 and 48 hours of reperfusion, with maximal opening at 48 hours and return to normal by 14 days. There was a correlation between the levels of gelatinase A at 3 hours and the sucrose uptake (PϽ0.05). Gelatinase A (MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5 days. Gelatinase B and TIMP-1 were maximally elevated at 48 hours. The inhibitor of gelatinase B, TIMP-1, was also increased at 48 hours. Treatment with BB-1101 reduced BBB opening at 3 hours and brain edema at 24 hours, but neither was affected at 48 hours. Conclusions-The initial opening at 3 hours correlated with gelatinase A levels and was blocked by a synthetic MMP inhibitor. The delayed opening, which was associated with elevated levels of gelatinase B, failed to respond to the MMP inhibitor, suggesting different mechanisms of injury for the biphasic BBB injury. (Stroke. 1998;29:2189-2195.)

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

“…40,83 The rise in MMP-2 correlates with early opening of the BBB and degradation of the TJPs claudin-5 and occludin in rodent MCAO models. 78,80,84,85 In addition, direct injection of MMP-2 into rodent brain disrupts the BBB and results in hemorrhage, further supporting a role of MMP-2 in early BBB disruption and HT in stroke. 84 Though MMP-2 is associated with early BBB disruption after stroke, its role in HT and effect on stroke outcome remains less clear.…”

“…87 Though the MMP inhibitor (BB-1101) blocked MMP-2 increase in brain, a reduction in cerebral edema and BBB permeability was present only at 24 hours and not at 48 hours. 80 In contrast, a recent study of mice within 1 to 1.5 hours of MCAO found that MMP-2-deficient mice had a reduced rate of HT, smaller hemorrhage volume, and improved neurologic function compared with wild type. 79 The reasons for these differing results require further study to better understand the role of MMP-2 in acute stroke and early HT.…”

“…81 This supports the notion that leukocytes, including neutrophils, contribute to MMP-9 early in stroke, whereas brain cells are the predominant source of MMP-9 later in stroke. Indeed, brain levels of MMP-9 correlate with delayed opening at 24 to 48 hours, 80 whereas plasma levels of MMP-9 at 3 hours are predictive of HT. [60][61][62] Matrix metalloproteinase-9 degrades TJPs (claudin-5, occludin, and ZO-1), and basal lamina proteins (fibronectin, lamin, and collagen).…”

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

“…However, open factors such as biphasic opening of postischemic BBB and a relatively weak link between early permeability increase and eventual hemorrhagic transformation warrant investigations for elucidating technical advantage in WEI and involvement of other directly causative factors. 35,36 While further verification with pathologic indices is required for confirming such prognostic potential, the proposed WEI method provides simultaneous assessment of water permeability and CBV, which are closely related to the endogenous sources accountable for vasogenic edema and hemorrhagic transformation.…”

Matrix metalloproteinases in neuroinflammation

“…The increase in MMP-9 correlates with the time of maximal damage, while the later increase in MMP-2 is related to the increase in reactive astrocytes around the cyst. Middle cerebral artery occlusion for 90 min with reperfusion in SHR caused a biphasic opening of the BBB with a transient opening at 3 h and a second more severe injury at 48 h (Rosenberg et al, 1998). The early opening at 3 h correlated with an increase in MMP-2, while a later opening at 48 h correlated with increased expression of MMP-9.…”