The Effects of Carbenoxolone against Experimental Autoimmune Encephalomyelitis in a Mouse Model

Chen, Ying; Hu, Zhaoqi; Li, Rui; Qiu, Wei; Zhou, Zhiming

doi:10.1159/000505333

Cited by 4 publications

(6 citation statements)

References 21 publications

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“… 34 Carbenoxolone, as a derivative of GA, significantly reversed the severity and pathology in experimental autoimmune encephalomyelitis. 35 IL-17-secreting and IFN-γ-secreting CD4 + T lymphocytes were remarkably lower in the spleen after carbenoxolone treatment in mice with experimental autoimmune encephalomyelitis. These data show that 18β-GA can regulate the homeostasis of CD4 + T helper cells, which is consistent with our research.…”

Section: Discussionmentioning

confidence: 85%

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Enhancing regulatory T-cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia

Wang

et al. 2022

haematol

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Primary immune thrombocytopenia (ITP) is the most common acquired autoimmune bleeding disorder. Abnormally increased levels of High Mobility Group Box 1 Protein (HMGB1) associate with thrombocytopenia and therapeutic outcome in ITP. Previous studies proposed that a natural inhibitor of HMGB1, 18β-glycyrrhetinic acid (18β-GA), has been used for its anti-inflammatory and immune-modulatory effects, although its capability of correcting immune balance in ITP is unclear. In this study, we discovered that plasma HMGB1 correlated negatively with platelet counts in ITP patients, and confirmed that 18β-GA stimulated the production of regulatory T cells (Tregs), restored the balance of CD4+ T cell subsets and enhanced the suppressive function of Tregs through blocking the effect on HMGB1 in patients with ITP. HMGB1 short hairpin RNA interference masked the effect of 18β-GA in Tregs of ITP patients. Furthermore, we found that 18β-GA alleviated thrombocytopenia in ITP mice. Briefly, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to induce a murine model of severe ITP. The proportion of circulating Tregs significantly increased, while the level of plasma HMGB1 and serum antiplatelet antibodies significantly decreased in ITP mice along 18β-GA treatment. In addition, 18β-GA reduced phagocytic activity of macrophages towards platelets both in ITP patients and ITP mice. These results indicated that 18β-GA has the potential to restore immune balance in ITP via inhibition of HMGB1 signaling. In short, this study reveals the role of HMGB1 in ITP, which may serve as a potential target for thrombocytopenia therapy.

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Section: Discussionmentioning

confidence: 85%

“…Carbenoxolone (CBX), as a derivative of GA, significantly reversed the severity and pathology in experimental autoimmune encephalomyelitis (EAE) (35). IL-17-secreting and IFN-γ-secreting CD4 + T lymphocytes were remarkably lower in the spleen after CBX treatment in mice with EAE.…”

Section: Discussionmentioning

confidence: 99%

Enhancing regulatory T-cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia

Wang

et al. 2022

haematol

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“…A study showed that CBX treatment decreases the reactive gliosis and scar formation after a needle-track injury model to the brain ( Andersson et al, 2011 ). Previous studies have shown that in the MOG EAE model, CBX treatment delays the onset of neurological symptoms and decreases the severity ( Shijie et al, 2009 ; Endong et al, 2011 ; Chen et al, 2020 ). The authors explain the beneficial effects of CBX by lowering the production of interleukin (IL)-23 and, therefore, the differentiation of T helper (TH)-1 and TH-17, protecting from excitotoxicity by inhibiting glutamate release from microglia and increasing brain-derived neurotrophic factor.…”

Section: Discussionmentioning

confidence: 99%

“…It also exerts its anti-fibrotic actions in the pancreatic and hepatic stellate cell cultures, which are very similar to brain pericytes hence they are named as hepatic and pancreatic pericytes ( Uyama et al, 2003 ; Masamune et al, 2013 ). Previous studies have shown that in the MOG EAE model, CBX treatment delays the onset and decreases the severity of neurological symptoms ( Shijie et al, 2009 ; Endong et al, 2011 ; Chen et al, 2020 ). Due to its anti-fibrotic effects as well as effects on satellite cells (pericytes of liver and pancreas) and possible role of fibrosis in EAE models pathophysiology, we want to detect antifibrotic effect of CBX on PLP induced EAE model and define possible therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Carbenoxolone mitigates extensive fibrosis formation in PLP-induced EAE model and multiple sclerosis serum-exposed pericyte culture

Ucar,

Ozkan,

Shomalizadeh

et al. 2024

Front. Cell. Neurosci.

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IntroductionMultiple sclerosis (MS) is one of the most common causes of disability in young adults. Nearly, 85% of MS cases start with attacks and remissions, classified as relapsing-remitting multiple sclerosis (RRMS). With repeating attacks, MS causes brain-spinal cord atrophy and enhanced disability as disease progresses. PLP-induced EAE is one of the most established models for pathophysiology and treatment of RRMS. Recent studies demonstrated the possible role of pericytes in perivascular and intra-lesional fibrosis in PLP-induced EAE, whose importance remains elusive. Hence, we have investigated the possible role of pericytes in fibrosis formation and amelioration with a hemichannel blocker, Carbenoxolone (CBX).MethodsPLP-induced experimental autoimmune encephalitis (EAE) model is used and the effect of CBX is investigated. Clinical scores were recorded and followed. Perivascular Collagen 1 and 3 accumulations were demonstrated as markers of fibrosis in the spinal cord. To delineate the role of pericytes, human brain vascular pericytes (HBVP) were incubated with the sera of MS patients to induce in-vitro MS model and the fibrosis formation was investigated.ResultsIn the PLP induced in-vivo model, both intracerebroventricular and intraperitoneal CBX have significantly mitigated the disease progression followed by clinical scores, demyelination, and fibrosis. Moreover, CBX significantly mitigated MS-serum-induced fibrosis in the HBVP cell culture.DiscussionThe study demonstrated two important findings. First, CBX decreases fibrosis formation in both in-vivo and in-vitro MS models. Secondly, it improves neurological scores and decreases demyelination in the EAE model. Therefore, CBX can be potential novel therapeutic option in treating Multiple Sclerosis.

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“…Carbenoxolone, a gap junction blocker targeting Cx43, has been evaluated in animal models of MS. The authors found that carbenoxolone significantly reduced the severity of autoimmune encephalomyelitis (the most commonly applied model for MS) and reduced the quantity of inflammatory mediators ( Table 3 ) [ 150 ]. More studies are needed to see if modulation of Cx43 hemichannel activation in MS could aid in the progression of the disease.…”

Section: Clinical Correlationmentioning

confidence: 99%

Connexins and Pannexins: Important Players in Neurodevelopment, Neurological Diseases, and Potential Therapeutics

et al. 2022

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Cell-to-cell communication is essential for proper embryonic development and its dysfunction may lead to disease. Recent research has drawn attention to a new group of molecules called connexins (Cxs) and pannexins (Panxs). Cxs have been described for more than forty years as pivotal regulators of embryogenesis; however, the exact mechanism by which they provide this regulation has not been clearly elucidated. Consequently, Cxs and Panxs have been linked to congenital neurodegenerative diseases such as Charcot-Marie-Tooth disease and, more recently, chronic hemichannel opening has been associated with adult neurodegenerative diseases (e.g., Alzheimer’s disease). Cell-to-cell communication via gap junctions formed by hexameric assemblies of Cxs, known as connexons, is believed to be a crucial component in developmental regulation. As for Panxs, despite being topologically similar to Cxs, they predominantly seem to form channels connecting the cytoplasm to the extracellular space and, despite recent research into Panx1 (Pannexin 1) expression in different regions of the brain during the embryonic phase, it has been studied to a lesser degree. When it comes to the nervous system, Cxs and Panxs play an important role in early stages of neuronal development with a wide span of action ranging from cellular migration during early stages to neuronal differentiation and system circuitry formation. In this review, we describe the most recent available evidence regarding the molecular and structural aspects of Cx and Panx channels, their role in neurodevelopment, congenital and adult neurological diseases, and finally propose how pharmacological modulation of these channels could modify the pathogenesis of some diseases.

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The Effects of Carbenoxolone against Experimental Autoimmune Encephalomyelitis in a Mouse Model

Cited by 4 publications

References 21 publications

Enhancing regulatory T-cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia

Enhancing regulatory T-cell function via inhibition of high mobility group box 1 protein signaling in immune thrombocytopenia

Carbenoxolone mitigates extensive fibrosis formation in PLP-induced EAE model and multiple sclerosis serum-exposed pericyte culture

Connexins and Pannexins: Important Players in Neurodevelopment, Neurological Diseases, and Potential Therapeutics

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