Toll-Like Receptor-4 Pathway As A Possible Molecular Mechanism For Brain Injuries After Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is known as an acute catastrophic neurological disease that continues to be a serious and significant health problem worldwide. The mechanisms contributing to brain injury after SAH remain unclear despite decades of study focusing on early brain injury (EBI) and delayed brain injury (DBI). Neuroinflammation is a well-recognized consequence of SAH and may be responsible for EBI, cerebral vasospasm, and DBI. Toll-like receptors (TLRs) play a crucial role in the inflammatory response by recognizing damage-associated molecular patterns derived from the SAH. TLR4 is the most studied Toll-like receptor and is widely expressed in the central nervous system (CNS). It can be activated by the extravasated blood components in myeloid differentiation primary response-88/Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-beta (MyD88/TRIF)-dependent pathway after SAH. Transcription factors, such as nuclear factor-kappa B (NF-kappa B), mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF), that regulate the expression of proinflammatory cytokine genes are initiated by the activation of TLR4, which cause the brain damage after SAH. TLR4 may therefore be a useful therapeutic target for overcoming EBI and DBI in post-SAH neuroinflammation, thereby improving SAH outcome. In the present review, we summarized recent findings from basic and clinical studies of SAH, with a primary focus on the biological characteristics and functions of TLR4 and discussed the mechanisms associated with TLR4 signaling pathway in EBI and DBI following SAH.