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.
Highlights
Na,K-ATPase (NKA) is a membrane protein that is essential for the survival of the organism
Pretreatment with OUA reduced inducible nitric oxide synthase (iNos), Il-1β, and the Bax/ Bcl2 ratio mRNA levels activated by LPS iNos mRNA levels, an important indicator of inflammation, increased in the LPS group in comparison with the control group as expected
OUA alone had no impact on iNos mRNA level (Figure 2A)
Summary
Na,K-ATPase (NKA) is a membrane protein that is essential for the survival of the organism This enzyme is expressed in all the cells of the human body, having many functions including the maintenance of osmotic balance, cell volume, pH and membrane potential. This occurs by the hydrolysis of an adenosine triphosphate (ATP) molecule leading to the export of three sodium ions and the import of two potassium ions into the cell, which is fundamental for neuronal excitability and cell maintenance [1,2]. This study used a low OUA dose to evaluate its effects on inflammation induced by LPS injection in rats
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