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Mechanisms That Regulate Blood-Brain Barrier Dysfunction and Hyperpermeability
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Blood-brain barrier (BBB) disruption is the hallmark feature of the secondary injuries that occur following traumatic and ischemic brain injuries. Microvascular hyperpermeability that occurs consequently leads to vasogenic edema and elevated intracranial pressure. Structurally, the BBB is comprised of the brain endothelial cells and the tight junction between them formed by the tight junction proteins (TJPs). Zonula occludens-1 (ZO-1) is an important membrane-bound scaffolding TJP that links transmembrane TJPs to intracellular actin cytoskeletal assembly. Studies indicate that adenosine triphosphate (ATP) that is released into the extracellular space following trauma binds to and activates the purinergic receptor (P2X7R), leading to the production of interleukin-1β (IL-1β); which in turn is shown to activate various downstream proteases. Matrix metalloproteinase-9 (MMP-9) and calpains are proteases known to induce BBB breakdown. However, the mechanisms by which ATP and IL-1β induce BBB dysfunction and hyperpermeability and the involvement of proteases in this process are vastly unknown. We hypothesize that ATP and IL-1β-induced BBB dysfunction and hyperpermeability occurs via P2X7R and /MMP-9/calpain-mediated pathways, respectively. And thus, P2X7R/MMP-9/calpain inhibitions play an important role in mediating BBB dysfunction and hyperpermeability following traumatic injuries in brain. The results from these studies demonstrate that MMP-9/calpain inhibition attenuated IL-1β-induced monolayer hyperpermeability, f-actin stress fiber formation, and loss of ZO-1/TJ integrity and enhanced MMP-9/calpain activity in RBMECs. However, IL-1β treatment did not alter intracellular calcium levels, total number of viable cells, total ZO-1 protein, and mRNA expression. Purinergic receptor (P2X7R) inhibition attenuated Bz-ATP (potent agonist of P2X7R)-induced endothelial cell hyperpermeability, loss of ZO-1/TJ integrity and f-actin stress fiber formation. Although Bz-ATP treatment reduced ZO-1 protein expression, it did not alter total number of viable cells or ZO-1 mRNA expression in vitro. Melatonin (a pineal hormone with MMP-9 inhibitory properties), calpain inhibitor III (calpain inhibitor), and KN-62 (PX7R inhibitor) pretreatment attenuated TBI-induced BBB hyperpermeability in C57BL/6 mice. P2X7R knockout mice demonstrated reduced TBI-induced BBB hyperpermeability compared to the wild-type animals. In conclusion, ATP-sensitive P2X7R are involved in promoting BBB dysfunction and hyperpermeability via IL-1β-mediated activation of MMP-9/calpain pathways and subsequent disorganization of the TJs. Inhibition of this pathway can provide potential therapeutic targets against TBI-induced BBB hyperpermeability in vivo.
endothelial cell dysfunction
calpain inhibitor III
Alluri, Himakarnika (2015). Mechanisms That Regulate Blood-Brain Barrier Dysfunction and Hyperpermeability. Doctoral dissertation, Texas A & M University. Available electronically from