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Cyclooxygenase Inhibition Limits Blood-Brain Barrier Disruption following Intracerebral Injection of Tumor Necrosis Factor-alpha in the Rat

Candelario-Jalil, Dr. Eduardo and Taheri, Dr. Saeid and Yang, Dr. Yi and Sood, Dr. Rohit and Grossetete, Dr. Mark and Estrada, Eduardo and Fiebich, Dr. Bernd L. and Rosenberg, Dr. Gary A. (2007) Cyclooxygenase Inhibition Limits Blood-Brain Barrier Disruption following Intracerebral Injection of Tumor Necrosis Factor-alpha in the Rat. [Journal (Paginated)]

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Abstract

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-alpha (TNF-a) is involved in BBB injury and edema formation through a mechanism involving matrix metalloproteinase (MMP) upregulation. 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-a to study the effect of COX inhibition on TNF-a-induced BBB breakdown, MMP expression/activity and oxidative stress. BBB disruption was evaluated by the uptake of 14C-sucrose into the brain and by magnetic resonance imaging (MRI) utilizing Gd-DTPA 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-a induced a significant upregulation of gelatinase B (MMP-9), stromelysin-1 (MMP-3) and COX-2. In addition, TNF-a significantly depleted glutathione as compared to 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-a. 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 E2 formation/signaling may be useful in clinical settings associated with BBB disruption.

Item Type:Journal (Paginated)
Keywords:cyclooxygenase-2; COX-2; COX-1; prostaglandin E2; neuroinflammation; blood-brain barrier; ischemia; stroke; matrix metalloproteinase; MMP-3; MMP-9; gelatinase B; stromelysin-1; oxidative stress; indomethacin; cyclooxygenase-1; glutathione; free radicals; MRI
Subjects:Neuroscience > Neurology
Neuroscience > Neuropharmacology
Neuroscience > Brain Imaging
Neuroscience > Neurochemistry
ID Code:5832
Deposited By:Candelario-Jalil, Dr Eduardo
Deposited On:22 Nov 2007 01:49
Last Modified:11 Mar 2011 08:57

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