Abstract
The blood-brain barrier (BBB) strictly limits the flux from the blood to the brain. The BBB thereby protects the brain against harmful blood-derived substances and simultaneously allows the supply with essential nutrients. The disruption of the BBB accompanies many neurological disease conditions, such as those induced by trauma, hypoxia, metabolic abnormalities or inflammation. The grade of brain edema formation, which is one clinical representation of BBB impairment, has been shown to be an independent predictor of unfavorable patient outcome.
Treatment options for BBB protection are still rare, partially due to the fact that only few substances can sufficiently cross this barrier. Promising drugs are lipophilic molecules such as volatile anesthetics which have been shown to be beneficial in cases of hypoxia reoxygenation injury (H/R) in the heart, liver, lung and kidney. Whether and how such compounds change intracranial pressure is still a matter of debate. Although of high clinical relevance, only few data are available concerning the action of volatile anesthetics on the BBB.
In order to tackle this problem, this dissertation aimed to elucidate whether and how volatile anesthetics impact the BBB through two specific projects addressing the following questions:
1. Does sevoflurane impact brain endothelial cells after H/R injury? And which signaling pathways are involved?
2. Does brain inflammation change in response to sevoflurane treatment in an animal model of sepsis? And which signaling pathways are involved and modified?
Immortalized rat brain endothelial cells (RBE4) were used to assess the effect of sevoflurane treatment after H/R injury, in a so called postconditioning setup, where cells are exposed to sevoflurane after initiation of injury. For this reason, permeability as well as tight and adherens junctions’ architecture were further analyzed. In order to detect potential mediators of the response, reactive oxygen species (ROS), inflammatory mediators (IL-6, TNF alpha, MMP9), protein kinase C (PKC) and vascular endothelial growth factor (VEGF) were quantified in the cells’ supernatant. Using this approach, we demonstrated that sevoflurane changes the permeability pattern in rat brain endothelial cells and modifies the architecture of the junctional components ZO-1 and β-catenin. ROS, PKC and VEGF were shown to be downregulated in response to sevoflurane treatment. Interestingly, RBE4 cells did not show any inflammatory response after H/R alone. In experiments in a rat animal model of sepsis, neuroinflammation with and without sevoflurane post-conditioning was assessed in more detail by our team. Inflammatory body response was significantly decreased due to sevoflurane treatment, but neuroinflammation was not affected.
Taking those studies together, we conclude that sevoflurane reduces barrier leakage of rat brain endothelial cells, modifies the cytoskeleton and junctional components and reduces important mediators of H/R injury such as ROS, PKC and VEGF. In contrast to its systemic action, sevoflurane does not alleviate early inflammatory response in the brain. Nevertheless, it is tempting to further elucidate the effects of sevoflurane postconditioning in patients.
Restin, Tanja