Early Appearance of Activated Matrix Metalloproteinase-9 after Focal Cerebral Ischemia in Mice: A Possible Role in Blood—Brain Barrier Dysfunction

During cerebral ischemia blood–brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly ( P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745,7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability, Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly ( P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.

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Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.59 ◽

2008 ◽

Vol 28 (10) ◽

pp. 1674-1685 ◽

Cited By ~ 86

Author(s):

Motoaki Fujimoto ◽

Yasushi Takagi ◽

Tomohiro Aoki ◽

Makoto Hayase ◽

Takeshi Marumo ◽

...

Keyword(s):

Cerebral Ischemia ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Vasogenic Edema ◽

Ischemic Injury ◽

Artery Occlusion ◽

Brain Barrier ◽

Tissue Inhibitor ◽

Blood Brain ◽

Significant Difference

Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood—brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1−/−and TIMP-2−/− mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1−/− mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.

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Matrix Metalloproteinase Inhibition Prevents Oxidative Stress-Associated Blood–Brain Barrier Disruption after Transient Focal Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200112000-00003 ◽

2001 ◽

Vol 21 (12) ◽

pp. 1393-1400 ◽

Cited By ~ 270

Author(s):

Yvan Gasche ◽

Jean-Christophe Copin ◽

Taku Sugawara ◽

Miki Fujimura ◽

Pak H. Chan

Keyword(s):

Oxidative Stress ◽

Blood Brain Barrier ◽

Focal Cerebral Ischemia ◽

Vasogenic Edema ◽

Ischemia Reperfusion ◽

Hemorrhagic Transformation ◽

Brain Barrier ◽

Critical Event ◽

Blood Brain Barrier Disruption ◽

Blood Brain

Oxidative stress generated during stroke is a critical event leading to blood–brain barrier (BBB) disruption with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of thrombolytic reperfusion. In this study, the authors demonstrate that ischemia-reperfusion–induced BBB disruption in mice deficient in copper/zinc-superoxide dismutase (SOD1) was reduced by 88% ( P < 0.0001) and 73% ( P < 0.01), respectively, after 3 and 7 hours of reperfusion occurring after 1 hour of ischemia by the inhibition of matrix metalloproteinases. Accordingly, the authors show that local metalloproteinase-generated proteolytic imbalance is more intense in ischemic regions of SOD1 mice than in wild-type litter mates. Moreover, active in situ proteolysis is, for the first time, demonstrated in ischemic leaking capillaries that produce reactive oxygen species. By showing that oxidative stress mediates BBB disruption through metalloproteinase activation in experimental ischemic stroke, this study provides a new target for future therapeutic strategies to prevent BBB disruption and potentially reperfusion-triggered intracerebral hemorrhage.

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