GELATINASE B MODULATES SELECTIVE OPENING OF THE BLOOD-BRAIN-BARRIER DURING INFLAMMATION

Matrix metalloproteinases (MMPs) are associated with neuroinflammatory diseases, and blood-brain barrier damage is a pathophysiological cons equence of central nervous system inflammation. We examined whether an increase in MMP production is coupled with the breakdown of blood-bra in barrier integrity in the lipopolysaccharide (LPS)-injured brain. Ra t brain stimulated with LPS showed a significant rise in gelatinase B (MMP-9) production at 24 h compared with either tumor necrosis factor- alpha (TNF-alpha) or saline-injected controls. Latent 92-kDa gelatinas e B was detected by 4 h, peaked at 8 h, and persisted for 24 h after L PS injection. Production of the active 84-kDa form of gelatinase B was less pronounced, but paralleled 92-kDa enzyme expression. Breakdown i n blood-brain barrier integrity, measured by the infiltration of radio labeled exogenous markers into the brain, was significant to [C-14]suc rose (molecular mass 342 Da) and [C-14]dextran (molecular mass 50-90 k Da) molecules in LPS-injected animals compared with saline-injected co ntrols. The extent of MMP involvement in barrier permeability was exam ined in animals treated with the MMP inhibitor BB-1101. A significant drop in gelatinase A and B production was detected in LPS-injured anim als receiving BE-1101 compared with untreated animals. This MMP inhibi tor also reduced [C-14]sucrose uptake in LPS-injected animals, but had no effect on [C-14]dextran uptake. MMP production is upregulated in L PS-injured brain tissue and is instrumental in regulating the size-dif ferentiated opening of the blood-brain barrier during acute neuroinfla mmation.