Doll DN, Hu H, Sun J, Lewis SE, Simpkins JW, and Ren X. Mitochondrial Crisis in Cerebrovascular Endothelial Cells Opens the Blood–Brain Barrier. Stroke. 2015
Blood-brain barrier (BBB) dysfunction is seen in many neurological conditions, including cerebrovascular and neurodegenerative disorders. Infection after stroke is known to worsen clinical outcomes and prior preclinical studies have demonstrated that bacterial infection has effects on the BBB. In this report, Doll et al aimed to evaluate the molecular and cellular mechanisms by which this occurs.
They tested the effects of bacterial infection by mimicking it in a mouse model of stroke with intraperitoneal lipopolysaccharide (LPS) injection prior to transient middle cerebral artery occlusion (tMCAO). BBB permeability was tested by assessing the penetration of Evans blue, a dye that has high affinity for albumin, which enters brain tissue when the BBB is compromised. They found that LPS exposure significantly increased infarct volume and cerebrovascular permeability after tMCAO compared to saline-injected controls. There was higher cerebral neutrophil accumulation, measured by flow cytometry 6 hours after tMCAO, in the LPS-treated mice compared to controls. Along with this, the neutrophil to lymphocyte (NLR) ratio was significantly decreased in the blood and spleen of LPS-treated mice. In a cultured cerebrovascular endothelial cell model, they found that LPS-induced signaling through toll-like receptor 4 (TLR4) compromised oxidative phosphorylation without causing cell death. This occurred through reduction in the expression of multiple mitochondrial respiratory chain proteins. Blocking the respiratory chain pharmacologically with rotenone or oligomycin (inhibitors of respiratory chain complex I and V) in this in vitro model led to increased cell permeability and disruption of cell-cell tight junctions. This was then confirmed in vivo – the authors applied rotenone to the epidural surface of mice and showed that led to increased BBB permeability compared to controls. Finally, they then were able to demonstrate that treating mice with rotenone prior to tMCAO led to increased BBB permeability, higher stroke volumes, and worsened neurologic deficits.
This is the first study suggesting that bacterial infection may worsen the injury resulting from stroke by affecting mitochondrial metabolism in the cerebrovascular endothelium. It gives further insight into pathophysiologic mechanisms that, if also occur in humans, may provide novel pharmacologic targets for prevention/reduction in cerebral edema and potentially improving overall outcomes after stroke. Continual improvements in neuroimaging capability and molecular imaging techniques may allow for improved evaluation of BBB permeability in human subjects. This report should have implications for future translational research.