Abstract
Background: Asphyxia is the most common cause of brain damage in newborns. Substantial evidence indicates that leukocyte recruitment in the cerebral vasculature during asphyxia contributes to this damage. We tested the hypothesis that superoxide radical () promotes an acute post-asphyxial inflammatory response and blood-brain barrier (BBB) breakdown. We investigated the effects of removing by superoxide dismutase (SOD) or C3, the cell-permeable SOD mimetic, in protecting against asphyxia-related leukocyte recruitment. We also tested the hypothesis that xanthine oxidase activity is one source of this radical.Methods: Anesthetized piglets were tracheostomized, ventilated, and equipped with closed cranial windows for the assessment of post-asphyxial rhodamine 6G-labeled leukocyte-endothelial adherence and microvascular permeability to sodium fluorescein in cortical venules. Asphyxia was induced by discontinuing ventilation. SOD and C3 were administered by cortical superfusion. The xanthine oxidase inhibitor oxypurinol was administered intravenously.Results: Leukocyte-venular adherence significantly increased during the initial 2 h of post-asphyxial reperfusion. BBB permeability was also elevated relative to non-asphyxial controls. Inhibition of production by oxypurinol, or elimination of by SOD or C3, significantly reduced rhodamine 6G-labeled leukocyte-endothelial adherence and improved BBB integrity, as measured by sodium fluorescein leak from cerebral microvessels.Conclusion: Using three different strategies to either prevent formation or enhance elimination of during the post-asphyxial period, we saw both reduced leukocyte adherence and preserved BBB function with treatment. These findings suggest that agents which lower in brain may be attractive new therapeutic interventions for the protection of the neonatal brain following asphyxia.
Highlights
Asphyxia is a relatively common source of neonatal brain damage [1], affecting ∼2 in every 1,000 births [2]
Adherence was 62% greater at 1 h and 23% greater at 2 h in asphyxial animals in which the window was superfused with artificial cerebral spinal fluid (aCSF) (Figure 1B) relative to asphyxial animals in which the aCSF remained static during the experiment (Figure 1C)
Numerous studies in the brain have demonstrated that oxygen free radicals are produced upon reperfusion following ischemia, and that their generation through various biochemical pathways during reperfusion is associated with increases in blood-brain barrier (BBB) permeability [37]
Summary
Asphyxia is a relatively common source of neonatal brain damage [1], affecting ∼2 in every 1,000 births [2]. A dominant response to ischemia is inflammation [2, 3], resulting from the accumulation of circulating leukocytes in the cerebral microvasculature and their subsequent extravasation into brain parenchyma [4,5,6,7]. There is consensus that reactive oxygen species (ROS), formed during reperfusion following transient ischemia, including in the neonatal brain, modulate inflammation [11,12,13]. ROS are generated in multiple compartments within a cell and are produced by many sources, including mitochondria, peroxisomal lipid metabolism, NADPH oxidases, cyclooxygenase, and xanthine oxidase [14,15,16]. We tested the hypothesis that xanthine oxidase activity is one source of this radical
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
