Matrix Metalloproteinases

Recent work has focused intense study on the MMPs and their contribution to BBB disruption, brain edema, and hemorrhage (141,142). MMPs are a family of extracellular-soluble or membrane-bound proteases that are involved in remodeling the extracellular matrix. MMPs are divided into 4 major classes: (i) interstitial collagenases (MMP-1), (ii) stromelysins (MMP-3), () ii) gelatinases (MMP-2, MMP-7, and MMP-9), and ()v) membrane-type MMP (MMP-14). Several endogenous inhibitors, known as tissue inhibitors of metalloproteinases (TIMPs), also exist. MMP-2, -3, -7, and -9 and TIMP-1, -2 and -3 (143) in relation to cerebral ischemia. MMPs are normally found in the cytosol in a proactivated or inactivated state and are cleaved by proteases, such as plasmin (which is cleaved to its active form from plasminogen by tissue plas-minogen activator), to their active state (142). Thus, MMPs might be an important therapeutic target. In fact, prior work has shown that MMP inhibition reduces infarct size, brain edema, and hemorrhage following experimental stroke (144,145). MMP-9 appears to play a more significant role in stroke, compared to MMP-2. Mice deficient in MMP-9 were found to have smaller infarcts compared to wild-type controls (146). MMP-2-deficient mice, on the other hand, fared no better than wild type (147 ).

MMPs have also been implicated in the disruption of the BBB. Brain edema due to swelling and compromise of adjacent health tissue can worsen outcome from stroke and other neurologic disorders. Accumulated data indicate that increased BBB permeability or disruption results from focal ischemia and induces the formation of vasogenic edema through seepage of serum elements into the brain parenchyma. In the setting of reperfusion, vasogenic edema is thought to play a critical role in brain edema formation due to MMP activation. MMPs, by virtue of their ability to disrupt the extracellular matrix, are thought to contribute to this process. MMP-9 has largely been observed in peripheral leukocytes (148) and microglia (143 ), thus linking the role of MMPs to the inflammatory system. In fact, peripheral inflammatory cell MMP-9 might contribute significantly to ischemic brain injury, as mice transplanted with bone marrow from MMP-9-deficient mice suffered less injury and less BBB disruption than mice transplanted with marrow containing intact MMP-9 (149). At the clinical level, MMPs might also be important in mediating significant cerebral hemorrhage in the setting of throm-bolytic use. In fact, mice treated with a thrombolytic plus an MMP inhibitor suffered less hemorrhagic transformation following embolic stroke, compared to those that only received a thrombolytic (150).

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