Protecting blood -brain barrier integrity following traumatic brain injury
Blood-brain barrier (BBB), mainly composed by brain vascular endothelial cells and tight junction proteins, controls material exchange between the circulation and the brain. BBB integrity is critical for normal brain function and BBB disruption is a major contributor to the pathology of central nervous system disorders, including traumatic brain injury (TBI). Multiple pathological mechanisms are involved in BBB disruption following TBI, such as oxidative damage, glutamate toxicity, and activation of various proteases. Loss of BBB integrity following TBI can lead to cerebral edema, profound inflammation, and hemorrhage, which exacerbate brain damage and negatively affect outcome. The transcription factor NF-E2-related factor 2 (Nrf2) regulates the expression of multiple cytoprotective genes including antioxidants and detoxifying enzymes, and is a major component of the endogenous cellular protective system in the body. Using a rodent brain injury model, we tested the hypothesis that enhancing Nrf2-driven gene expression will protect BBB integrity following traumatic brain injury. Western blot and immunohistochemistry analysis indicated that vascular endothelial cell and tight junction protein loss occurred as a result of brain injury. The structural integrity disruption was associated with elevated BBB permeability revealed by increased Evans blue dye and fluorescein extravasation. Real-time PCR study demonstrated that systemic administration of an Nrf2 activator, sulforaphane, induced Nrf2-driven gene expression in the brain. Post-injury administration of sulforaphane significantly reduced endothelial cell and tight junction protein loss and attenuated the elevated BBB permeability. By measuring brain water content, we found that the protection of BBB integrity by sulforaphane was associated with decreased cerebral edema. The protective effects of sulforaphane were dependent on Nrf2 as its ability to reduce BBB disruption was blocked in injured animals pretreated with decoy oligonucleotides containing the Nrf2 binding site. Likewise, nrf2 (-/-) mice did not benefit from sulforaphane administration, and were found to have increased vulnerability to brain injury as indicated by exacerbated BBB disruption. In conclusion, these findings suggest that Nrf2-dependent gene expression protects the structural integrity and function of the BBB following traumatic brain injury.
Zhao, Jing, "Protecting blood -brain barrier integrity following traumatic brain injury" (2008). Texas Medical Center Dissertations (via ProQuest). AAI3312622.