Cellular mechanisms by which tumor necrosis factor-alpha produces disruption of the blood-brain barrier.
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.
Mayhan
William G
WG
Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, NE 68198-4575, USA. wgmayhan@unmc.edu
D000818:Animals; D001160:Arterioles / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003911:Dextrans / Q000493:pharmacokinetics; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D008833:Microcirculation / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D011920:Rats, Inbred WF; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
D003911:Dextrans; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D006162:Guanylate Cyclase