Nitric oxide-induced blood-brain barrier dysfunction is not mediated by inhibition of mitochondrial respiratory chain activity and/or energy depletion.
Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the breakdown of blood-brain barrier (BBB) function which can occur during various inflammatory conditions. Recent evidence suggests a role for the free radical nitric oxide (NO) in the process of cytokine-induced barrier dysfunction. The mitochondrial enzyme cytochrome oxidase is inhibited by NO, and hence, using a coculture model of the BBB, we have investigated whether TNF-alpha alters barrier function by a NO-mediated mechanism and, if so, whether it is related to a reduction of endothelial cell respiration and ATP synthesis. TNF-alpha mediated a marked reduction in model BBB integrity that was partially prevented by inhibition of NO synthase activity. Additionally, exposure of BBB cultures to authentic gaseous NO also resulted in a progressive decline in barrier integrity. Authentic NO inhibited endothelial cell respiration in a reversible manner. Mitochondrial respiratory chain inhibitors induced significant reductions in endothelial cell respiratory rate and ATP levels, but did not mimic the action of NO on barrier function. We conclude that NO is partially responsible for the detrimental effect of TNF-alpha on BBB function. The mechanism of NO-induced barrier dysfunction does not involve an inhibition of endothelial mitochondrial electron transport chain and reduced energy resources.
Department of Neurochemistry, Institute of Neurology, University of London, United Kingdom.
R D
RD
Hurst
J B
JB
Clark
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004579:Electron Transport; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004734:Energy Metabolism; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014655:Vascular Resistance
D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide