Functional Role of Soluble Receptor for Advanced Glycation End Products in Stroke

Abstract

Objective-Little is known about the involvement of the soluble form of receptor for advanced glycation end products (sRAGE) in acute ischemic stroke (IS). Here, we aim to identify the role of plasma sRAGE and high mobility group box 1 (HMGB1) in imaging-confirmed IS patients, as well as mice subjected to focal ischemic stroke. Methods and Results-IS patients were recruited and plasma samples were collected for the measurement of sRAGE and HMGB1 after stroke. The relation of sRAGE and HMGB1 with acute IS was also investigated in a C57BL/6J mouse model of focal ischemic stroke and primary cortical neurons subjected to oxygen and glucose deprivation. Plasma levels of sRAGE and HMGB1 were both significantly increased within 48 hours after IS, and the sRAGE level was an independent predictor of functional outcome at 3 months poststroke. Immunoprecipitation assays revealed that the binding of plasma HMGB1 to sRAGE increased progressively after IS both in patients and mice. Administration of recombinant sRAGE significantly reduced infiltrating immune cells and improved the outcome of injury in mice, protected cultured neurons against oxygen and glucose deprivation-induced cell death, and ameliorated the detrimental effect of recombinant HMGB1. Conclusion-Early

Cerebrospinal fluid high mobility group box 1 is associated with neuronal death in subarachnoid hemorrhage

“…12,20,[30][31][32][33] We have recently established that plasma levels of HMGB1 as well as interactions between HMGB1 and RAGE were increased significantly after ischemic stroke onset both in human and mice. 14 We also found that administration of recombinant sRAGE effectively protects mice from ischemic reperfusion injury and protects primary neurons from energy deprivation-induced cell death via a mechanism involving reduced RAGE-associated inflammatory pathways. 14 The present study showed that CSF levels of HMGB1 increased significantly in SAH patients, and the values were positively correlated with outcome even after adjustment for clinical variables.…”

“…14 We also found that administration of recombinant sRAGE effectively protects mice from ischemic reperfusion injury and protects primary neurons from energy deprivation-induced cell death via a mechanism involving reduced RAGE-associated inflammatory pathways. 14 The present study showed that CSF levels of HMGB1 increased significantly in SAH patients, and the values were positively correlated with outcome even after adjustment for clinical variables. In addition, RAGE expression increased in cultured neurons exposed to post-SAH CSF.…”

“…[13][14][15] Soluble form of RAGE (sRAGE) may counteract the detrimental effects of RAGE. We and others have recently established that blockage of HMGB1-RAGE signaling by exogenous administration of either HMGB1 blocking antibody or sRAGE significantly improves cell survival and reduces infarct volume in experimental stroke models.…”

Soluble RAGE levels in plasma of patients with cerebrovascular events

“…The differences of sRAGE levels among different stroke subtypes could be related to acute stroke severity rather than different etiologies of the stroke subtypes [23].…”

“…Intravenous administration of sRAGE may capture and eliminate circulating RAGE ligand, thus acting as a decoy receptor and protecting against tissue damage. Systemic administration of sRAGE may be an effective therapeutic approach for all RAGE-mediated vascular disorders [23].…”