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
These results suggest that Pin1 contributes to the pathogenesis of ischemic stroke by promoting Notch signaling, and that inhibition of Pin1 is a novel approach for treating ischemic stroke.
We aim to determine the cerebrospinal fluid levels of high mobility group box 1 in subarachnoid hemorrhage patients and to investigate the involvement of the receptor for advanced glycation end products and high mobility group box 1 in the pathogenesis of post-subarachnoid hemorrhage neuronal death. The study included 40 patients (mean age, 59 AE 19 years) with Fisher's grade ! III aneurysmal subarachnoid hemorrhage. Cerebrospinal fluid was collected on the seventh day post-hemorrhage. Receptor for advanced glycation end products expression was examined in rat brain tissue following subarachnoid hemorrhage and in cultured neurons exposed to post-subarachnoid hemorrhage cerebrospinal fluid. Therapeutic effects of the recombinant soluble form of RAGE on subarachnoid hemorrhage models were also investigated. The results indicated that a higher level of cerebrospinal fluid high mobility group box 1 was independently associated with unfavorable outcome at three months post-subarachnoid hemorrhage (OR ¼ 1.061, 95% CI: 1.005-1.121). Expression of RAGE increased in post-subarachnoid hemorrhage rat brain cells and in cultured neuron with stimulation of post-subarachnoid hemorrhage cerebrospinal fluid. Administration of recombinant soluble form of RAGE significantly reduced the number of positive TUNEL staining cells in subarachnoid hemorrhage rat and improved cell viability in post-subarachnoid hemorrhage cerebrospinal fluid-treated cultured neurons. Thus, the level of cerebrospinal fluid high mobility group box 1 can be a prognostic indicator for patients with Fisher's grade ! III aneurysmal subarachnoid hemorrhage and that treatment with soluble form of RAGE is a novel approach for subarachnoid hemorrhage.
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