RGD Reference Report - Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. - Rat Genome Database

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Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat.

Authors: Candelario-Jalil, E  Taheri, S  Yang, Y  Sood, R  Grossetete, M  Estrada, EY  Fiebich, BL  Rosenberg, GA 
Citation: Candelario-Jalil E, etal., J Pharmacol Exp Ther. 2007 Nov;323(2):488-98. Epub 2007 Aug 17.
RGD ID: 2325928
Pubmed: PMID:17704356   (View Abstract at PubMed)
DOI: DOI:10.1124/jpet.107.127035   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
maintenance of blood-brain barrier  IMP 2325928; 2325928 RGD 
response to tumor necrosis factor  IEP 2325928; 2325928; 2325928 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mmp3  (matrix metallopeptidase 3)
Mmp9  (matrix metallopeptidase 9)
Ptgs1  (prostaglandin-endoperoxide synthase 1)
Ptgs2  (prostaglandin-endoperoxide synthase 2)


Additional Information