Decreased Level of sRAGE in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

Glasnović, Anton; Cvija, Hrvoje; Stojić, Maristela; Tudorić-Đeno, Ivana; Ivčević, Sanja; Romić, Dominik; Tičinović, Nino; Vuletić, Vladimira; Lazibat, Ines; Grčević, Danka

doi:10.1159/000357002

Cited by 26 publications

(22 citation statements)

References 34 publications

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“…6,7 RAGE activation is also involved in BBB damage in a variety of human brain disorders, including multiple sclerosis, diabetes mellitus, and Alzheimer disease. [8][9][10] Indeed, inflammatory responses, increased BBB permeability, and brain edema are significantly reduced after brain trauma in RAGE knockout rats. 11 Furthermore, intravenous injection of anti-HMGB1 monoclonal antibodies attenuates ischemic BBB damage.…”

mentioning

confidence: 99%

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Yang

Wang

Zhang³

et al. 2015

Stroke

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Background and Purpose-To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1). Methods-Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood-brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection. Results-Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood-brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-κB p65 upregulation were also observed when FeCl 2 was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood-brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor-κB p65, proinflammatory mediators interleukin 1β, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl 2 -induced RAGE and nuclear factor-κB p65 upregulation. Conclusions-RAGE signaling is involved in blood-brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH. .).The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl

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confidence: 99%

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Yang

Wang

Zhang³

et al. 2015

Stroke

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“…Glasnović et al compared sRAGE level and RAGE transcript levels in the peripheral blood and cerebrospinal fluid (CSF) of 27 newly diagnosed MS patients with those of healthy subjects and found lower levels of sRAGE in the CSF of MS patients [19]. Dorota et al evaluated serum levels of sRAGE in 44 MS patients (including both rapidly and slowly progressive patients) and found significantly increased levels of sRAGE in the serum of MS patients when compared to controls [20].…”

Section: Discussionmentioning

confidence: 99%

Soluble Receptor for Advanced Glycation End Products (sRAGE) is Up-Regulated in Multiple Sclerosis Patients Treated with Interferon β-1a

Rahimi

Afjeh

Omrani

et al. 2018

Cell Physiol Biochem

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Background/Aims: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Considering the role of immune system in its pathogenesis, researchers have focused on evaluation of the expression of immune-related genes or proteins in MS patients. Among proteins whose participation in inflammatory process has been documented is the receptor for advanced glycation end products (RAGE). Methods: In the present study, we compared RAGE transcript levels by means of quantitative real-time PCR as well as the serum level of soluble RAGE (sRAGE) by means of enzyme- linked immunosorbent assay (ELISA) in 50 IFNβ-1a responsive relapsing-remitting MS patients when compared with age and sex-matched healthy subjects. Results: Elevated expression of RAGE as well as higher levels of sRAGE were detected in IFN-β responsive MS patients compared with the controls. A significant inverse correlation between sRAGE plasma concentrations and the expanded disability status scale (EDSS) was also detected in which each unit of increase in sRAGE level resulted in a 0.308 unit decrease in EDSS. Conclusion: Considering the stable clinical state of the MS patients in this study and their response to IFNβ-1a, the elevated levels of sRAGE in patients compared with healthy subjects could be related to the effects of this kind of treatment.

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“…Paired PBL and CSF samples were collected from the MS patients at clinical onset and the healthy controls. In order to maximize the sample size and the reproducibility of data, we also tested part of the sample (healthy controls and MS patients at clinical onset) from our previous study [24]. Only PBL samples were obtained from RR-MS patients with advanced disease during the remission phase, since lumbar puncture is not part of routine clinical assessment at this stage.…”

Section: Study Participants and Clinical Datamentioning

confidence: 99%

“…PBL and CSF samples were collected for enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (qPCR) analysis as previously described [24]. Briefly, CSF samples were collected by lumbar puncture in siliconized glass tubes and centrifuged immediately to obtain acellular supernatant.…”

Section: Pbl and Csf Samplesmentioning

confidence: 99%

“…Total RNA was extracted from PBMC using TRIzol Reagent (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA), converted into complementary DNA, and amplified by qPCR in an ABI Prism 7500 Sequence Detection System (Applied Biosystems) instrument as previously described [24]. Gene expressions of RANKL/RANK/OPG and proinflammatory/immunoregulatory mediators (IL-4, IL-10, IL-17, CCL2, and CXCL12) were analyzed using the commercially available TaqMan gene expression assays (Applied Biosystems).…”

Section: Gene Expression Analysis By Qpcrmentioning

confidence: 99%

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RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

Glasnović

Stojić

Dežmalj

et al. 2018

Neuroimmunomodulation

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Objectives: Our study focused on the RANKL (receptor activator of nuclear factor-κB ligand)/RANK/OPG (osteoprotegerin) axis and selected proinflammatory/immunoregulatory upstream mediators in the peripheral blood (PBL) and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. Methods: PBL and CSF were collected from healthy controls (n = 35) and MS patients at the clinical onset of the disease (n = 33). In addition, PBL samples were obtained from relapse-remitting (RR)-MS patients (n = 30). Patients were assessed by means of the expanded disability status scale (EDSS) and routine laboratory parameters. Soluble (s)RANKL and OPG were measured in the CSF and plasma; gene expression was detected for RANKL, RANK, OPG, and selected cytokines/chemokines (interleukin [IL]-4, IL-10, IL-17, CCL2, and CXCL12) in PBL mononuclear cells. Results: The OPG level in the CSF was lower in MS patients at clinical onset than in controls. Moreover, the sRANKL/OPG ratio was higher in the CSF of MS patients at clinical onset and in the plasma of RR-MS patients than in controls. Gene expression of RANKL/RANK/OPG in PBL mononuclear cells was higher only in RR-MS patients. IL-4, CCL2, and CXCL12 were positively correlated and IL-10 was negatively correlated with RANKL/RANK expression. OPG was negatively correlated with EDSS and alkaline phosphatase level. Conclusion: Our study revealed that changes of RANKL/RANK/OPG axis are associated with MS, particularly the decreased OPG level in the CSF at disease onset. Therefore, these factors may serve as disease biomarkers and molecular targets of novel therapeutic approaches.

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Decreased Level of sRAGE in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

Cited by 26 publications

References 34 publications

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Soluble Receptor for Advanced Glycation End Products (sRAGE) is Up-Regulated in Multiple Sclerosis Patients Treated with Interferon β-1a

RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

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