Cardiotonic Steroids as Modulators of Neuroinflammation

Orellana, Ana Maria; Kinoshita, Paula Fernanda; Leite, Jacqueline Alves; Kawamoto, Elisa Mitiko; Scavone, Cristóforo

doi:10.3389/fendo.2016.00010

Cited by 35 publications

(41 citation statements)

References 121 publications

(164 reference statements)

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“…Besides that, ouabain effects on CNS could be associated with its role in bipolar and depressive disorders (Goldstein et al, 2006 ; Tonin et al, 2014 ). The interaction between neuroinflammation and cardiac steroids is more substantially detailed by Orellana et al ( 2016 ).…”

Section: Ouabain As a Modulator Of Inflammationmentioning

confidence: 99%

Much More than a Cardiotonic Steroid: Modulation of Inflammation by Ouabain

et al. 2017

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Since the discovery of ouabain as a cardiotonic steroid hormone present in higher mammals, research about it has progressed rapidly and several of its physiological and pharmacological effects have been described. Ouabain can behave as a stress hormone and adrenal cortex is its main source. Direct effects of ouabain are originated due to the binding to its receptor, the Na+/K+-ATPase, on target cells. This interaction can promote Na+ transport blockade or even activation of signaling transduction pathways (e.g., EGFR/Src-Ras-ERK pathway activation), independent of ion transport. Besides the well-known effect of ouabain on the cardiovascular system and blood pressure control, compelling evidence indicates that ouabain regulates a number of immune functions. Inflammation is a tightly coordinated immunological function that is also affected by ouabain. Indeed, this hormone can modulate many inflammatory events such as cell migration, vascular permeability, and cytokine production. Moreover, ouabain also interferes on neuroinflammation. However, it is not clear how ouabain controls these events. In this brief review, we summarize the updates of ouabain effect on several aspects of peripheral and central inflammation, bringing new insights into ouabain functions on the immune system.

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Section: Ouabain As a Modulator Of Inflammationmentioning

confidence: 99%

Much More than a Cardiotonic Steroid: Modulation of Inflammation by Ouabain

et al. 2017

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“…These signals result in the activation of the inflammatory-associated transcription factor NF-κB and the subsequent production of inflammatory cytokines. In contrast, however, several reports showed that ouabain has the ability to suppress the production of inflammatory cytokines, suggesting an anti-inflammatory effect of cardiac glycosides [7]. Thus, the precise role of the Na + /K + -ATPase in inflammation remains controversial.…”

Section: Discussionmentioning

confidence: 99%

The cardiac glycoside ouabain activates NLRP3 inflammasomes and promotes cardiac inflammation and dysfunction

et al. 2017

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Cardiac glycosides such as digoxin are Na+/K+-ATPase inhibitors that are widely used for the treatment of chronic heart failure and cardiac arrhythmias; however, recent epidemiological studies have suggested a relationship between digoxin treatment and increased mortality. We previously showed that nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, which regulate caspase-1-dependent interleukin (IL)-1β release, mediate the sterile cardiovascular inflammation. Because the Na+/K+–ATPase is involved in inflammatory responses, we investigated the role of NLRP3 inflammasomes in the pathophysiology of cardiac glycoside-induced cardiac inflammation and dysfunction. The cardiac glycoside ouabain induced cardiac dysfunction and injury in wild-type mice primed with a low dose of lipopolysaccharide (LPS), although no cardiac dysfunction was observed in mice treated with either ouabain or LPS alone. Ouabain also induced cardiac inflammatory responses, such as macrophage infiltration and IL-1β release, when mice were primed with LPS. These cardiac manifestations were all significantly attenuated in mice deficient in IL-1β. Furthermore, deficiency of NLRP3 inflammasome components, NLRP3 and caspase-1, also attenuated ouabain-induced cardiac dysfunction and inflammation. In vitro experiments revealed that ouabain induced NLRP3 inflammasome activation as well as subsequent IL-1β release from macrophages, and this activation was mediated by K+ efflux. Our findings demonstrate that cardiac glycosides promote cardiac inflammation and dysfunction through NLRP3 inflammasomes and provide new insights into the mechanisms underlying the adverse effects of cardiac glycosides.

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“…In this study, ouabain exhibited therapeutic effects on JEV infection in an adult mouse model by decreasing viral loads and alleviating pathological injuries in the brain, which significantly improved the survival rate of JEV-infected mice. Some evidence suggested that cardiac glycosides mediate inflammatory processes via the activation of the phosphoinositide 3-kinase/Akt pathway and the Src/mitogen-activated protein kinase pathway (28,29). First, ouabain may block JEV infection by inducing the cellular stress response.…”

Section: Ouabain Blocks Jev Infectionmentioning

confidence: 99%

Screening of Natural Extracts for Inhibitors against Japanese Encephalitis Virus Infection

Guo

Jia

Liu

et al. 2020

Antimicrob Agents Chemother

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The mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide that is associated with high morbidity and mortality. Currently, there are no effective drugs approved for the treatment of JEV infection. Drug-repurposing screening is an alternative approach to discover potential antiviral agents. In this study, high-content screening (HCS) of a natural extracts library was performed, and two hit FDA-approved Na ϩ /K ϩ -ATPase inhibitors, ouabain and digoxin, were identified as having robust efficiency against JEV infection with the selectivity indexes over 1,000. The results indicated that ouabain and digoxin blocked the JEV infection at the replication stage by targeting the Na ϩ /K ϩ -ATPase. Furthermore, it was proven that ouabain significantly reduced the morbidity and mortality caused by JEV in a BALB/c mouse model. This work demonstrated that Na ϩ /K ϩ -ATPase could serve as the target of treatment of JEV infection, and ouabain has the potential to be developed as an effective anti-JEV drug.Ethics statements and mice. All animal experimental procedures were carried out according to ethical guidelines and were approved by the Animal Care Committee of the Wuhan Institute of Virology (permit number, WIVA25201705).Cells and viruses. BHK-21, Vero, and Huh-7 cells were maintained in Dulbecco modified Eagle medium (DMEM) (HyClone, Logan, UT, USA) supplement with 10% fetal bovine serum (FBS) (Gibco, Grand Island, NY, USA). U251 cells were maintained in minimum essential medium (MEM) (HyClone) supplement with 10% FBS. JEV AT31 and SA14 strains were generated by using the infectious clones of pMWJEAT-AT31 (kindly provided by T. Wakita, Tokyo Metropolitan Institute for Neuroscience) and pACYC-JEV-SA14 (GenBank accession no. U14163) as previously described (32), respectively. The infectious clone plasmids were linearized, subjected to in vitro transcription, and electroporated into BHK-21 cells. Three days later, the supernatant was collected and stored at Ϫ80°C in aliquots (33, 34). The virus stocks were propagated and titrated by a plaque assay in BHK-21 cells.Optimization of HCS assay conditions. The cell density, infective dose, and assay endpoint were optimized for the HCS assay. Different densities (2,000 to 10,000 cells per well) of Vero cells were infected at MOI values ranging from 0.2 to 1. Cell viability was detected at different times (24 to 72 h) after JEV inoculation. The appropriate cell density, infective dose, and assay endpoint for the HCS assay were selected by comparing the signal-to-basal ratio (S/B), the coefficient of variation (CV), and z values under different conditions as previously described (11); 10 M manidipine and 0.5% DMSO were used as positive and negative controls, respectively.HCS assay of drug library screening. A library of 1,034 compounds from natural extracts was purchased from Weikeqi Biotech (Sichuan, China). Compounds were stored as 10 mM stock solutions in DMSO at -80°C until use. As shown in Fig. 1A, Vero cells were dissociated and seeded at a density of ...

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Cardiotonic Steroids as Modulators of Neuroinflammation

Cited by 35 publications

References 121 publications

Much More than a Cardiotonic Steroid: Modulation of Inflammation by Ouabain

Much More than a Cardiotonic Steroid: Modulation of Inflammation by Ouabain

The cardiac glycoside ouabain activates NLRP3 inflammasomes and promotes cardiac inflammation and dysfunction

Screening of Natural Extracts for Inhibitors against Japanese Encephalitis Virus Infection

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