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NEUROPHARMACOLOGY

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

Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico (E.C.-J., Y.Y., M.G., E.Y.E., G.A.R.); Magnetic Resonance Imaging Core, Biomedical Research and Integrative NeuroImaging (BRaIN) Center, University of New Mexico, Albuquerque, New Mexico (S.T., R.S.); and Neurochemistry Research Group, Department of Psychiatry, University of Freiburg Medical School, Freiburg, Germany (B.L.F.)

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)- 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- to study the effect of COX inhibition on TNF--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 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- induced a significant up-regulation of gelatinase B (MMP-9), stromelysin-1 (MMP-3), and COX-2. In addition, TNF- 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-. 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.

Address correspondence to: Dr. Eduardo Candelario-Jalil, Department of Neurology, University of New Mexico Health Sciences Center, MSC10 5620, Albuquerque, NM 87131-0001. E-mail: ecandelario-jalil{at}salud.unm.edu