Increased permeability of the blood-brain barrier (BBB) is important in
neurological disorders.
Neuroinflammation is associated with increased BBB breakdown and
brain injury.
Tumor necrosis factor (
TNF)-alpha is involved in BBB injury and
edema formation through a mechanism involving
matrix metalloproteinase (
MMP) up-regulation. There is emerging evidence indicating that
cyclooxygenase (COX) inhibition limits BBB disruption following
ischemic stroke and
bacterial meningitis, but the mechanisms involved are not known. We used intracerebral injection of
TNF-alpha to study the effect of COX inhibition on
TNF-alpha-induced BBB breakdown,
MMP expression/activity, and oxidative stress. BBB disruption was evaluated by the uptake of (14)C-sucrose into the brain and by magnetic resonance imaging utilizing
gadolinium-diethylenetriaminepentaacetic
acid as a paramagnetic
contrast agent. Using selective inhibitors of each COX
isoform, we found that COX-1 activity is more important than COX-2 in BBB opening.
TNF-alpha induced a significant up-regulation of
gelatinase B (MMP-9), stromelysin-1 (MMP-3), and COX-2. In addition,
TNF-alpha significantly depleted
glutathione as compared with saline.
Indomethacin (10 mg/kg i.p.), an inhibitor of COX-1 and COX-2, reduced BBB damage at 24 h.
Indomethacin significantly attenuated MMP-9 and MMP-3 expression and activation and prevented the loss of endogenous radical scavenging capacity following intracerebral injection of
TNF-alpha. Our results show for the first time that BBB disruption during
neuroinflammation can be significantly reduced by administration of COX inhibitors. Modulation of COX in
brain injury by COX inhibitors or agents modulating
prostaglandin E(2) formation/signaling may be useful in clinical settings associated with BBB disruption.