Cellular mechanisms by which tumor necrosis factor-alpha produces disruption of the blood-brain barrier.

Abstract

The first goal of the present study was to determine the effect of tumor necrosis factor-alpha (TNF-alpha) on the permeability of the blood-brain barrier in vivo. The second goal of this study was to investigate cellular pathways responsible for changes in permeability of the blood-brain barrier in response to TNF-alpha. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier was quantitated by calculating the clearance of fluorescent-labeled dextran (mol. wt=10,000; FITC-dextran-10K) during superfusion with vehicle, tumor necrosis factor (TNF-alpha; 10 ng/ml), TNF-alpha in the presence of an inhibitor of soluble guanylate cyclase (ODQ; 1.0 microM), and TNF-alpha in the presence of an inhibitor of protein tyrosine kinase (genistein; 10 microM). During superfusion with vehicle, clearance of FITC-dextran-10K from pial vessels remained relatively constant during the experimental period. In contrast, superfusion with TNF-alpha markedly increased clearance of FITC-dextran-10K from the cerebral microcirculation. Topical application of ODQ and genistein, significantly inhibited increases in permeability of the blood-brain barrier to FITC-dextran-10K during application of TNF-alpha. Thus, TNF-alpha increases the permeability of the blood-brain barrier to a moderately sized molecule via a mechanism which appears to involve activation of soluble guanylate cyclase and protein tyrosine kinase. In light of evidence suggesting that TNF-alpha production is increased during cerebrovascular trauma, we suggest that the findings of this study may contribute to our understanding of the pathogenesis of disruption of the blood-brain barrier during brain trauma and inflammation.

• Authors: William G Mayhan
• Journal: Brain research (Brain Res) Vol. 927 Issue 2 Pg. 144-52 (Feb 15 2002) ISSN: 0006-8993 [Print] Netherlands
• PMID: 11821008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Dextrans
• Tumor Necrosis Factor-alpha
• Protein-Tyrosine Kinases
• Guanylate Cyclase

Topics

• Animals
• Arterioles (anatomy & histology, drug effects, metabolism)
• Blood-Brain Barrier (drug effects, physiology)
• Capillary Permeability (drug effects, physiology)
• Dextrans (pharmacokinetics)
• Guanylate Cyclase (antagonists & inhibitors, physiology)
• Male
• Microcirculation (cytology, drug effects, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, physiology)
• Rats
• Rats, Inbred WF
• Tumor Necrosis Factor-alpha (pharmacology, physiology)