MATRIX METALLOPROTEINASES AND TIMPS ARE ASSOCIATED WITH BLOOD-BRAIN-BARRIER OPENING AFTER REPERFUSION IN RAT-BRAIN

Background and Purpose-Reperfusion disrupts cerebral capillaries, caus ing cerebral edema and hemorrhage. Middle cerebral artery occlusion (M CAO) induces the matrix-degrading metalloproteinases, but their role i n capillary injury after reperfusion is unknown. Matrix metalloprotein ases (MMPs) and tissue inhibitors to metalloproteinases (TTMPs) modula te capillary permeability. Therefore, we measured blood-brain barrier (BBB) permeability, brain water and electrolytes, MMPs, and TIMPs at m ultiple times after reperfusion. Methods-Adult rats underwent MCAO for 2 hours by the suture method. Brain uptake of C-14-sucrose was measur ed from 3 hours to 14 days after reperfusion, Levels of MMPs and TIMPs were measured by zymography and reverse zymography, respectively, in contiguous tissues. Other rats had water and electrolytes measured at 3, 24, or 48 hours after reperfusion. Treatment with a synthetic MMP i nhibitor, BB-1101, on BBB permeability and cerebral edema was studied. Results-Brain sucrose uptake increased after 3 and 48 hours of reperf usion, with maximal opening at 48 hours and return to normal by 14 day s. There was a correlation between the levels of gelatinase A at 3 hou rs and the sucrose uptake (P<0.05). Gelatinase A (MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5 days. Gelatinase B a nd TIMP-1 were maximally elevated at 48 hours. The inhibitor of gelati nase B, TIMP-1, was also increased at 48 hours. Treatment with BB-1101 reduced BBB opening at 3 hours and brain edema at 24 hours, but neith er was affected at 48 hours. Conclusions-The initial opening at 3 hour s correlated with gelatinase A levels and was blocked by a synthetic M MP inhibitor. The delayed opening, which was associated with elevated levels of gelatinase B, failed to respond to the MMP inhibitor, sugges ting different mechanisms of injury for the biphasic BBB injury.