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Gelatinase B modulates selective opening of the blood-brain barrier during inflammation
1Department of Neurology, University of New Mexico School of Medicine, Albuquerque 87131, USA.
Abstract:
Matrix metalloproteinases (MMPs) are associated with neuroinflammatory diseases, and blood-brain barrier damage is a pathophysiological consequence of central nervous system inflammation. We examined whether an increase in MMP production is coupled with the breakdown of blood-brain barrier integrity in the lipopolysaccharide (LPS)-injured brain. Rat 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 gelatinase B was detected by 4 h, peaked at 8 h, and persisted for 24 h after LPS injection. Production of the active 84-kDa form of gelatinase B was less pronounced, but paralleled 92-kDa enzyme expression. Breakdown in blood-brain barrier integrity, measured by the infiltration of radiolabeled exogenous markers into the brain, was significant to [14C]sucrose (molecular mass 342 Da) and injected animals compared with saline-injected controls. The extent of MMP involvement in barrier permeability was examined in animals treated with the MMP inhibitor BB-1101. A significant drop in gelatinase A and B production was detected in LPS-injured animals receiving BB-1101 compared with untreated animals. This MMP inhibitor also reduced [14C]sucrose uptake in LPS-injected animals, but had no effect on [14C]dextran uptake. MMP production is upregulated in LPS-injured brain tissue and is instrumental in regulating the size-differentiated opening of the blood-brain barrier during acute neuroinflammation.
Insights
Matrix metalloproteinases (MMPs) increase in LPS-injured brains, contributing to blood-brain barrier damage. MMP inhibition reduces this barrier permeability, highlighting their role in neuroinflammation.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Matrix metalloproteinases (MMPs) are implicated in neuroinflammatory diseases.
- Blood-brain barrier (BBB) damage is a key feature of central nervous system inflammation.
Purpose of the Study:
- To investigate the link between increased MMP production and BBB breakdown in lipopolysaccharide (LPS)-induced brain injury.
- To assess the role of MMPs in regulating BBB permeability during acute neuroinflammation.
Main Methods:
- LPS injection in rats to induce brain injury and inflammation.
- Quantification of gelatinase B (MMP-9) production and its active form.
- Measurement of BBB integrity using radiolabeled markers ([14C]sucrose, [14C]dextran).
- Administration of an MMP inhibitor (BB-1101) to evaluate its effects on MMP production and BBB permeability.
Main Results:
- LPS significantly increased MMP-9 production, with both latent and active forms detected.
- BBB integrity was compromised, allowing significant [14C]sucrose infiltration.
- MMP inhibitor BB-1101 reduced MMP production and [14C]sucrose uptake in LPS-treated rats.
- The inhibitor did not affect [14C]dextran uptake, suggesting size-selective BBB opening.
Conclusions:
- MMP production is upregulated in LPS-induced brain injury.
- MMPs play a crucial role in the size-differentiated opening of the BBB during acute neuroinflammation.
- Targeting MMPs may offer a therapeutic strategy for neuroinflammatory conditions involving BBB damage.