Mechanisms of neuroinflammation and inflammatory mediators involved in brain injury following subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disorder. Neuroinflammation is a critical cause of brain injury following SAH in both acute and chronic phases. While accumulating evidence has shown that therapies targeting neuroinflammation exerted beneficial effects in experimental SAH, there is little clinical evidence. One of the factors making neuroinflammation complicated is that inflammatory signaling pathways and mediators act as protective or detrimental responses at different phases. In addition, biomarkers to detect neuroinflammation are little known in clinical settings. In this review, first, we discuss how the inflammatory signaling pathways contribute to brain injury and other secondary pathophysiological changes in SAH. Damage-associated molecular patterns arising from mechanical stress, transient global cerebral ischemia, red blood cell breakdown and delayed cerebral ischemia following SAH trigger to activate pattern recognition receptors (PRRs) such as Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and receptors for advanced glycation end products. Most of PRRs activate common downstream signaling transcriptional factor nuclear factor-kappa B and mitogen-activated protein kinases, releasing pro-inflammatory mediators and cytokines. Next, we focus on how pro-inflammatory substances play a role during the course of SAH. Finally, we highlight an important inducer of neuroinflammation, matricellular protein (MCP). MCPs are a component of extracellular matrix and exert beneficial and harmful effects through binding to receptors, other matrix proteins, growth factors, and cytokines. Treatment targeting MCPs is being proved efficacious in preclinical models for preventing brain injury including neuroinflammation in SAH. In addition, MCPs may be a candidate of biomarkers predicting brain injury following SAH in clinical settings.