HMGB1 promotes neurovascular remodeling via Rage in the late phase of subarachnoid hemorrhage

High-mobility group box1 (HMGB1) is a nuclear protein widely expressed in the central nervous system. Extracellular HMGB1 serves as a proinflammatory cytokine and contributes to brain injury during the acute stage post-stroke. Recently, increasing evidence has demonstrated beneficial effects of HMGB1 in some types of brain injury, but little is known about its effects during the late phase of subarachnoid hemorrhage (SAH). This study was designed to explore the potential roles and mechanisms of HMGB1 and its receptor, receptor for advanced glycation end-products (Rage), on brain recovery in the late stage of experimental SAH. Two inhibitors of HMGB1, ethyl pyruvate and glycyrrhizin (EP and GA), and Rage antagonist FPS-ZM1 were used to determine whether HMGB1 promotes brain recovery after SAH. The administration of EP, GA, and FPS-ZM1 effectively reduced HMGB1 and Rage expression. Correspondingly, protein levels of beneficial growth factors (NGF, BDNF, and VEGF) and numbers of BrdU and DCX positive neurons in the cortex were also decreased. The biphasic roles of HMGB1 may be based on the different redox modifications of cysteine residues. In this research, rats injected with two different redox status HMGB1 showed different prognosises at 7-14 day after SAH. Recombinant HMGB1 can promote cytokine stimulating activity and aggravate brain injury. However, oxidized HMGB1 was unable to stimulate TNF production but can promote brain recovery by promoting neurotrophin expression. In conclusion, our investigation identified that HMGB1 promotes neurovascular recovery via Rage and may act in the oxidized state in the late stage of SAH.