MATRIX METALLOPROTEINASES IN BRAIN INJURY

Proteolytic remodeling of the extracellular matrix occurs normally dur ing development and pathologically in arthritis, tumor metastasis, wou nd healing, and angiogenesis. The major extracellular matrix-degrading proteinases belong to the matrix metalloproteinase (MMP) and plasmino gen activator gene families. Intracerebral injection of 72-kDa type TV collagenase (gelatinase A) opens the blood-brain barrier. During hemo rrhagic brain injury or intracerebral injection of proinflammatory cyt okines, endogenous production of 92-kDa type IV collagenase (gelatinas e B) occurs. The gelatinase B gene contains a phorbol ester responsive region (TRE) that binds AP-1 proteins, including c-Fos/c-Jun diner, t he early immediate response gene products, Maximum production of gelat inase B in injury occurs between 16 and 24 h, making this a late effec tor gene. The serine proteinase, urokinase-type plasminogen activator (uPA), is also produced at that time, Gelatinases and plasminogen acti vators work in concert to disrupt basement membranes proteolytically. A similar process opens the blood-brain barrier after ischemic and hem orrhagic brain injury, leading to secondary vasogenic brain edema. Del ayed damage by proteolytic cascade enzymes provides opportunities for treatment much later than had been thought possible. Potential treatme nts possible in this second therapeutic window include interfering wit h the genes that produce the MMPs or inhibiting the action of the gene products.