Roles of Toll-Like Receptor-4 and Hif-1 in Propofol-Involved Protection against Traumatic Brain Injury-Induced Dysfunction of the Blood-Brain Barrier

TBI is the leading cause of morbidity and mortality in individuals under the age of 45 yr in the world. Pathologic conditions associated with head injury are accompanied by endothelial cell dysfunction, leading to increased permeability across the blood-brain barrier (BBB), which might lead to the development of cerebral edema. The BBB is present at the level of the brain capillaries and is critical for ion homeostasis in the central nervous system. A lot of studies demonstrate that TBI results in BBB opening after injury contributing to posttraumatic inflammation. Today TBI is considered a neuroinflammatory condition of the CNS. Animal models of TBI have shown that an influx of peripheral neutrophils occurs following injury, with a time course that correlates with BBB disruption. Toll-like receptors (TLR), an integral part of the innate immune response, recognizes specific pathogen-associated molecular patterns displayed by microbes. Among them, TLR4 is widely expressed in brain. Furthermore, TLR4 has been demonstrated to play an important role in mediating the breakdown of the intestinal barrier. However, the true nature of the contribution of TLR4 to TBI-induced BBB disruption has not yet been clarified. Hypoxia is common finding following TBI. Hypoxia-inducible factor–1 alpha (HIF-1α) is thought to be one of the most crucial signaling molecules in tissue responses to hypoxia. Data from literature indicate that increased HIF-1α expression is associated with increasing BBB permeability. TLR4 is also reported to be associated with a risk of hypoxia-related diseases. However, it has not been entirely clear which transcriptional factors are involved in the regulation of TLR4 expression under TBI-induced hypoxia condition. Patients with head injuries are usually managed in the ICU, and sedation is part of the treatment algorithm to prevent secondary brain injury. Propofol is the hypnotic agent of choice in patients with an acute neurological insult as it is easily titratable and rapidly reversible once discontinued. Propofol has additional properties that may be beneficial in the head injured patient including a decrease in cerebral metabolic rate, decrease in intracranial pressure and prevention of lipid peroxidation. Previous studies also demonstrated that propofol may have immunomodulating effects. Based on these observations, we hypothesized that TBI may regulate TLR4 expression and HIF-1α activation therefore influence subsequent neural injury. The effect of propofol on modulating TLR4 expression could be a mechanism by which protecting BBB, reduced cerebral edema, and promoted behavioral recovery after TBI. We hope these results may display the roles of TLR4 for the TBI-induced BBB integrity disturbance and the protective effects of propofol administration, and then provide potential targets for the therapy of TBI-induced brain injury.