Matrix metalloproteinases and free radicals in cerebral ischemia

Cerebral ischemia induces a complex series of molecular pathways involving signaling mechanisms, gene transcription, and protein formation. The proteases and free radicals involved are important, both individually and in concert, at each of the steps in the injury cascade. Matrix metalloproteinases (MMPs) and serine proteases are essential in the breakdown of the extracellular matrix around cerebral blood vessels and neurons, and their action leads to opening of the blood–brain barrier, brain edema, hemorrhage, and cell death. Reactive oxygen and nitrogen species affect the signaling pathways that induce the enzymes, the stability of the mRNA, and their activation processes. Mice that either lack MMP genes or overexpress free radical-removing genes exhibit diminished cerebral damage after stroke. Drugs that block MMP activity, or are free radical scavengers, significantly reduce ischemic damage. Understanding the relationship between proteases and free radicals in cerebral ischemia is critical for the design of therapeutic agents aimed at controlling cell death in ischemic tissues.