Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage

Abstract

Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

Keywords: TLR4; Toll-like receptor 4; blood-brain barrier; early brain injury; endothelial cell; inflammation; matricellular protein; subarachnoid hemorrhage; tight junction.

Figure 1

Schema of potential mechanisms (A) and signaling pathways (B) of blood-brain barrier disruption after subarachnoid hemorrhage (SAH). CSD: Cortical spreading depolarization; EC: endothelial cell; JAK: Janus kinase; MAPK: mitogen-activated protein kinase; MCP: matricellular protein; MMP-9: matrix metalloproteinase-9; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PKC-cAMP: protein kinase C-cyclic adenosine monophosphate; ROS: reactive oxygen species; STAT: signal transducer and activator of transcription; TJ: tight junction; TLR4: Toll-like receptor 4; VEGF-A: vascular endothelial growth factor-A.