Reduction of Leukocyte Microvascular Adherence and Preservation of Blood-Brain Barrier Function by Superoxide-Lowering Therapies in a Piglet Model of Neonatal Asphyxia

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 C 3 , 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 C 3 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 C 3 , 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.

Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury

“…Adhesion of peripheral immune cells to the cerebromicrovascular ECs following brain injuries profoundly contributes to the BBB disruption ( 33 ). Using two-photon in vivo imaging, we found that PIS mice had significantly increased adhesion of Rhodamine 6G-stained cells (mainly neutrophils and macrophages), indicating the increased presence of peripheral myeloid cells ( 34 , 35 ) on the ischemic cerebromicrovascular ECs compared to that of IS mice ( Fig. 3 A ) ( Movies S1 – S3 ).…”

Intramyocardial injection of human adipose-derived stem cells ameliorates cognitive deficit by regulating oxidative stress–mediated hippocampal damage after myocardial infarction

“…The present study demonstrates the hippocampal ROS levels were increased after MI, in a correlation with systemic ROS activation. A closer link between the brain and the heart after cardiac damage has been reported than with other nonhematopoietic organs [ 31 ]. Damaged cardiomyocytes at the site of MI can increase superoxide anions that rapidly enter the bloodstream.…”

Intramyocardial Injection of Human Adipose-Derived Stem Cells Ameliorates Cognitive Deficit By Regulating Oxidative Stress-Mediated Hippocampal Damage After Myocardial Infarction

“…Brain has very low levels of catalase and moderated levels of superoxide dismutase [8]. Thus, even low-grade ROS also substantially affects the blood-brain barrier [32]. Thus, on reaching brain, superoxide regulates acute cytokine response and mediates tra cking of hippocampus to injured hearts.…”