Vasogenic Edema Secondary to Tight Junction Disruption by Matrix Metalloproteinases in Cerebral Ischemia

Cerebral ischemia causes cell swelling and breakdown of the blood-brain barrier (BBB). Cytotoxic edema results from energy failure, and vasogenic edema occurs when the blood vessels are damaged. Proteases and free radicals are the end result of a molecular injury cascade. Matrix metalloproteinases (MMPs) are a gene family of extracellular matrix-degrading enzymes that disrupt the BBB. Tight junction proteins (TJPs), occludin and claudin-5, which form the endothelial barrier, are vulnerable to attack by MMPs. Basal lamina proteins, such as fibronectin, laminin, and heparan sulfate, are also degraded by MMPs. Reperfusion injury leads to a biphasic opening of the BBB, with the early opening occurring several hours after the onset of reperfusion due to activation of the constitutive enzyme gelatinase A (MMP-2). This initial opening is transient and followed 24 to 48 hours later by more intense damage to the blood vessel, which is associated with the expression and activation of gelatinase B (MMP-9) and stromelysin-1 (MMP-3). Synthetic MMP inhibitors restore the early integrity of the BBB but are ineffective in the later opening. Because these inhibitors block MMPs involved in angiogenesis and neurogenesis, they also slow recovery. The challenge is to identify agents that will protect the BBB, blocking vasogenic edema without interfering with recovery.

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