Blood-brain barrier permeability following intracerebral hemorrhage is related to local ion dyshomeostasis

• Author / Creator

  Nadeau, Colby A

• Background: Increased blood-brain barrier (BBB) permeability is seen after intracerebral hemorrhage (ICH). Following ICH, BBB dysfunction occurs due to direct (e.g. mechanical damage) and indirect (e.g. inflammation) injury. Damage to the BBB prevents maintenance of brain homeostasis. This thesis seeks to elucidate the time course of BBB permeability after ICH and investigate its relationship to local ion dyshomeostasis using novel imaging techniques. Methods: Bacterial collagenase was used to cause a striatal hemorrhage in rats. In experiment 1, animals were euthanized at days 3, 7, and 14 post-ICH following injection of Evans Blue dye to measure BBB permeability. In experiment 2, animals were euthanized at day 3 post-ICH after injection with a gadolinium-based contrast agent. A novel in situ biospectroscopic imaging technique was used to spatially assess changes in iron, chlorine, potassium, manganese, zinc, calcium, and copper in relation to BBB permeability. Results: After stroke, BBB permeability was significantly elevated at day 3 and decreased over time (time main effect; P < 0.001). At day 3 and day 7, BBB permeability was significantly elevated in the IPSI hemisphere as compared to SHAM samples (P < 0.001; P < 0.05, respectively). Contralateral BBB permeability did not differ between experimental groups at any survival time (P > 0.05). A subset of animals displayed BBB hyperpermeability (i.e. greater than maximum SHAM levels) at all times sampled. Chloride, iron, potassium, and manganese dyshomeostasis occurred in the hematoma (P < 0.001). Chloride, iron, and potassium levels normalized with distance into the perihematoma zone (distance main effect; P < 0.001, P < 0.001, P < 0.001, respectively). Elevated gadolinium levels were found in the hematoma (P < 0.05) and the perihematoma zone (distance main effect; P < 0.001). There was a relationship between gadolinium levels and ion dyshomeostasis in the perihematoma, but not hematoma, zone. Conclusions: After experimental ICH, BBB permeability is elevated acutely, and BBB dysfunction may persist for two weeks. A subset of animals display hyperpermeability at days 3, 7, and 14 after ICH. This elevated permeability may indicate the presence of cerebral microbleeds or angiogenesis. Furthermore, ion dyshomeostasis and BBB dysfunction occur in the perihematoma zone three days after ICH. Future work should directly assess the contribution of BBB disruption to ion dyshomeostasis and its impact on functional outcome.

• Subjects / Keywords

  • Blood-brain barrier
  • Ion dyshomeostasis
  • Intracerebral hemorrhage

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R33X8406P

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.