fps-zm1 and Brain-Edema

Intracerebral hemorrhage (ICH) is a devastating disease with no specific treatment. Increasing evidence indicates that inflammatory response plays a critical role in ICH-induced damage. High mobility group box-1 protein (HMGB1) may trigger inflammatory response via three putative receptors: receptor for advanced glycation end-products (RAGE), toll-like receptor-2 (TLR2) and toll-like receptor-4 (TLR4). Which receptor participates in HMGB1-induced inflammation during acute ICH is unknown. Using a rat model to examine the early phase of injury in collagenase-induced ICH, we found that treating animals with HMGB1 antagonist significantly reduced the expression of all three receptors. Treating animals with the HMGB1 antagonist EP or RAGE antagonist FPS-ZM1 significantly reduced inflammatory cell infiltration and expression of IL-1β, matrix metalloproteinase-9 in the perihematoma after ICH. Treatment with EP or FPS-ZM1 also led to greater neurobehavioral function and less brain edema, hemorrhage volume and brain damage after ICH. In contrast, treatment with TLR2/4 antagonists did not significantly affect these post-ICH outcomes. Our results suggest that RAGE may play a specific role in the acute phase of ICH, so targeting the HMGB1-RAGE signaling pathway may be a promising therapeutic strategy.

Topics: Acute Disease; Animals; Apoptosis; Benzamides; Brain; Brain Edema; Cerebral Hemorrhage; HMGB1 Protein; Inflammation; Interleukin-1beta; Male; Matrix Metalloproteinase 9; Pyruvates; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 4