Ouabain activates NFκB through an NMDA signaling pathway in cultured cerebellar cells

Lima, Larissa de Sá; Kawamoto, Elisa Mitiko; Munhoz, Carolina Demarchi; Kinoshita, Paula Fernanda; Orellana, Ana Maria; Curi, Rui; Rossoni, Luciana Venturini; Avellar, Maria Christina W.; Scavone, Cristóforo

doi:10.1016/j.neuropharm.2013.06.006

Cited by 39 publications

(45 citation statements)

References 54 publications

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“…Other pro-inflammatory cytokine changes were also evident: LPS did not activate IL-1β, while OUA increased IL-1β release, which was lost when the α2 isoform was silenced. These findings corroborate previous studies that showed that OUA can upregulate IL-1β mRNA levels in the rat hippocampus 47 .…”

Section: Discussionsupporting

confidence: 93%

“…Our group showed that OUA in cerebellar neurons can activate NF-κB via the NMDAr-Ras-Raf-ERK signaling cascade. This signaling cascade leads to increased Bdnf mRNA levels, indicating an important adaptive response 47 . However, OUA did not activate NF-κB in glial cells at the times measured in the present study, but rather decreased LPS-induced NF-κB activation.…”

Section: Discussionmentioning

confidence: 99%

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Alpha 2 Na+,K+-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells

Kinoshita

Yshii

Orellana

et al. 2017

Sci Rep

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Ouabain (OUA) is a cardiac glycoside that binds to Na+,K+-ATPase (NKA), a conserved membrane protein that controls cell transmembrane ionic concentrations and requires ATP hydrolysis. At nM concentrations, OUA activates signaling pathways that are not related to its typical inhibitory effect on the NKA pump. Activation of these signaling pathways protects against some types of injury of the kidneys and central nervous system. There are 4 isoforms of the alpha subunit of NKA, which are differentially distributed across tissues and may have different physiological roles. Glial cells are important regulators of injury and inflammation in the brain and express the α1 and α2 NKA isoforms. This study investigated the role of α2 NKA in OUA modulation of the neuroinflammatory response induced by lipopolysaccharide (LPS) in mouse primary glial cell cultures. LPS treatment increased lactate dehydrogenase release, while OUA did not decrease cell viability and blocked LPS-induced NF-κB activation. Silencing α2 NKA prevented ERK and NF-κB activation by LPS. α2 NKA also regulates TNF-α and IL-1β levels. The data reported here indicate a significant role of α2 NKA in regulating central LPS effects, with implications in the associated neuroinflammatory processes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Alpha 2 Na+,K+-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells

Kinoshita

Yshii

Orellana

et al. 2017

Sci Rep

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“…Postsynaptic NKA also regulates NF‐κB/CREB signaling (Desfrere et al , ; De Sá Lima et al , ) and AMPA receptor turnover (Zhang et al , ). In addition, α3‐NKA is also enriched at presynaptic terminals where it controls the probability and precision of firing following post‐tetanic hyperpolarization (Kim et al , ) as well as the availability of readily releasable pool of vesicles (Taruno et al , ).…”

Section: Discussionmentioning

confidence: 99%

α‐synuclein assemblies sequester neuronal α3‐Na⁺/K⁺‐ATPase and impair Na⁺ gradient

et al. 2015

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Extracellular a-synuclein (a-syn) assemblies can be up-taken by neurons; however, their interaction with the plasma membrane and proteins has not been studied specifically. Here we demonstrate that a-syn assemblies form clusters within the plasma membrane of neurons. Using a proteomic-based approach, we identify the a3-subunit of Na + /K + -ATPase (NKA) as a cell surface partner of a-syn assemblies. The interaction strength depended on the state of a-syn, fibrils being the strongest, oligomers weak, and monomers none. Mutations within the neuron-specific a3-subunit are linked to rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). We show that freely diffusing a3-NKA are trapped within a-syn clusters resulting in a3-NKA redistribution and formation of larger nanoclusters. This creates regions within the plasma membrane with reduced local densities of a3-NKA, thereby decreasing the efficiency of Na + extrusion following stimulus. Thus, interactions of a3-NKA with extracellular a-syn assemblies reduce its pumping activity as its mutations in RDP/AHC.

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“…Although no studies make direct associations between ouabain and IL-3, certain studies have shown that ouabain interferes with other interleukin pathways (41,42) and that IL-3 activates Na + /K + -ATPase, which is the main target of ouabain, in macrophages (43). Therefore, the possibility that ouabain regulates the synthesis or secretion of IL-3, which could result in augmented number of basophils and reduced number of monocytes in peripheral circulation, cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Ouabain-induced alterations in ABCB1 of mesenteric lymph nodes and thymocytes of rats and mice

2016

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Abstract. Ouabain is a glycoside with immunomodulating properties, and recent studies have suggested its use in adjuvant therapy for cancer treatment. Ouabain is known to modulate the immune system in vitro, and previous studies have revealed that ouabain can modulate the expression and activity of ABCB1, a protein associated with multidrug resistance present in immune system. Therefore, the present study investigated alterations in the expression and activity of ABCB1 in the thymi, peripheral blood monocytes and lymph nodes of Wistar rats and Swiss mice treated acutely or chronically with ouabain. A decrease of almost 45% in the monocyte count and an increase of 55% in the basophil count were observed. A significant decrease (75% reduction) in the amount of cells with ABCB1 activity was found in the thymocytes of ouabain-treated rats and mice. The possible implications of these results for cancer treatment are discussed.

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Ouabain activates NFκB through an NMDA signaling pathway in cultured cerebellar cells

Cited by 39 publications

References 54 publications

Alpha 2 Na+,K+-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells

Alpha 2 Na+,K+-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells

α‐synuclein assemblies sequester neuronal α3‐Na⁺/K⁺‐ATPase and impair Na⁺ gradient

Ouabain-induced alterations in ABCB1 of mesenteric lymph nodes and thymocytes of rats and mice

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Ouabain activates NFκB through an NMDA signaling pathway in cultured cerebellar cells

Cited by 39 publications

References 54 publications

Alpha 2 Na+,K+-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells

Alpha 2 Na+,K+-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells

α‐synuclein assemblies sequester neuronal α3‐Na+/K+‐ATPase and impair Na+ gradient

Ouabain-induced alterations in ABCB1 of mesenteric lymph nodes and thymocytes of rats and mice

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α‐synuclein assemblies sequester neuronal α3‐Na⁺/K⁺‐ATPase and impair Na⁺ gradient