Only Very Early Oxygen Therapy Attenuates Posthemorrhagic Edema Formation and Blood–Brain Barrier Disruption in Murine Intracerebral Hemorrhage

Abstract

Perihematomal edema exacerbates the mass effect of hematoma and contributes to early neurological deterioration after intracerebral hemorrhage (ICH). Oxygen therapy has protective effects on the blood-brain barrier (BBB). We aimed to examine the effects of oxygen therapy on edema formation and BBB permeability after ICH. ICH was induced in mice by injecting autologous blood (30µL) or collagenase (0.03U) intrastriatally. Development of posthemorrhagic edema formation and BBB disruption was characterized by wet-dry-weight assays and sodium- fluorescein fluorospectrometry 1d, 3d, and 7d after ICH induction. In subsequent experiments, mice received air, normobaric (NBO), or hyperbaric oxygen (HBO; 3ata) for 60min starting either 30, 60, or 120min after ICH induction. Expression of occludin, claudin-5, zonula occludens-1, matrix metalloproteinases (MMPs), and hypoxia-inducible factor-1α (HIF-1α) was measured by Western blot and zymography. Posthemorrhagic edema formation (water content: blood-injection model 80.6±0.3%; collagenase injection model 83.3±0.7%) and BBB disruption (interhemispheric ratio of extravasated sodium fluorescein: blood-injection model 1.75±0.07; collagenase injection model 3.02±0.15) peaked 3d after ICH. NBO and HBO initiated within 30min of ICH induction attenuated edema formation and BBB disruption (interhemispheric ratio of fluorescein; blood-injection air 1.75±0.12, NBO 1.52±0.08, HBO 1.49±0.09; collagenase: air 3.04±0.23, NBO 2.25±0.21, HBO 2.17±0.23) 3d after ICH, whereas delayed oxygen therapy had no effect. Early oxygen therapies prevented occludin degradation, MMP-9 activation, and reduced HIF-1α expression. Very early oxygen therapy can attenuate edema formation and BBB disruption after ICH, but the brief therapeutic time window suggests that the translational potential is limited.