Signaling function of Na,K-ATPase induced by ouabain against LPS as an inflammation model in hippocampus

Abstract

BackgroundOuabain (OUA) is a newly recognized hormone that is synthesized in the adrenal cortex and hypothalamus. Low doses of OUA can activate a signaling pathway by interaction with Na,K-ATPase, which is protective against a number of insults. OUA has central and peripheral anti-inflammatory effects. Lipopolysaccharide (LPS), via toll-like receptor 4 activation, is a widely used model to induce systemic inflammation. This study used a low OUA dose to evaluate its effects on inflammation induced by LPS injection in rats.MethodsAdult male Wistar rats received acute intraperitoneal (ip) OUA (1.8 μg/kg) or saline 20 minutes before LPS (200 μg/kg, ip) or saline injection. Some of the animals had their femoral artery catheterized in order to assess arterial blood pressure values before and after OUA administration. Na,K-ATPase activity, cytokine mRNA levels, apoptosis-related proteins, NF-κB activation brain-derived neurotrophic factor BDNF, corticosterone and TNF-α levels were measured.ResultsOUA pretreatment decreased mRNA levels of the pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and IL-1β, which are activated by LPS in the hippocampus, but with no effect on serum measures of these factors. None of these OUA effects were linked to Na,K-ATPase activity. The involvement of the inflammatory transcription factor NF-κB in the OUA effect was indicated by its prevention of LPS-induced nuclear translocation of the NF-κB subunit, RELA (p65), as well as the decreased cytosol levels of the NF-κB inhibitor, IKB, in the hippocampus. OUA pretreatment reversed the LPS-induced glial fibrillary acidic protein (GFAP) activation and associated inflammation in the dentate gyrus. OUA also prevented LPS-induced increases in the hippocampal Bax/Bcl2 ratio suggesting an anti-apoptotic action in the brain.ConclusionOur results suggest that a low dose of OUA has an important anti-inflammatory effect in the rat hippocampus. This effect was associated with decreased GFAP induction by LPS in the dentate gyrus, a brain area linked to adult neurogenesis.

Ouabain‐induced changes in MAP kinase phosphorylation in primary culture of rat cerebellar cells

“…There is a number of data indicating that ouabain can induce apoptotic cell death in various cell cultures as well as neurons . On the other hand, a lot of studies show that ouabain can increase the viability of kidney cells, endothelial cells and neurons . Reasons for opposing effects of ouabain remain poorly understood.…”

“…16,17 On the other hand, a lot of studies show that ouabain can increase the viability of kidney cells, [18][19][20] endothelial cells 21 and neurons. [22][23][24][25][26] Reasons for opposing effects of ouabain remain poorly understood. There is evidence that in neurons there are ouabain-triggered signalling cascades associated with mitogen-activated protein kinases (MAP kinases, or MAPK)-p38, JNK and ERK1/2, which are activated by phosphorylation and involved in regulation of cell death.…”

Endogenous hepatic glucocorticoid receptor signaling coordinates sex‐biased inflammatory gene expression

“…2H). It was not surprising to see that the GR pathway was activated after LPS injection, as several rodent models of endotoxemia have shown acute activation of the hypothalamic-pituitary-adrenal axis, leading to an increase in circulating corticosteroids (36)(37)(38)(39)(40). However, we found it intriguing that the GR pathway was ranked 8 on our LPS-regulated pathways in male mice, whereas it was ranked 5 in the females.…”

Mechanistic Insight of Na/K-ATPase Signaling and HO-1 into Models of Obesity and Nonalcoholic Steatohepatitis

“…Hence, ROS-induced activation of Na/K-ATPase signaling and downstream pathways generates further ROS through a feed-forward mechanism and creates an Na/K-ATPase oxidant amplification loop, which has been shown to be critical in a diseased state. While the cellular generation of ROS and the systemic redox imbalance evidently has been linked to the Na/K-ATPase/Src complex, the activation of this signaling mechanism can also be triggered by the release of CTS, like ouabain, which has been implicated in several diseased states [24][25][26][27][28]. Numerous studies have reported that Na/K-ATPase acts as a specific receptor for CTS.…”