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

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Abstract

The first goal of the present study was to determine the effect of tumor necrosis factor-α (TNF-α) 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-α. 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-α; 10 ng/ml), TNF-α in the presence of an inhibitor of soluble guanylate cyclase (ODQ; 1.0 μM), and TNF-α in the presence of an inhibitor of protein tyrosine kinase (genistein; 10 μM). During superfusion with vehicle, clearance of FITC-dextran-10K from pial vessels remained relatively constant during the experimental period. In contrast, superfusion with TNF-α 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-α. Thus, TNF-α 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-α 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.

Original languageEnglish (US)
Pages (from-to)144-152
Number of pages9
JournalBrain Research
Volume927
Issue number2
DOIs
Publication statusPublished - Jan 15 2002

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Keywords

  • Cerebral venule
  • FITC-dextran
  • Genistein
  • ODQ
  • Soluble guanylate cyclase
  • Tyrosine kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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