Abstract
BackgroundAtrial natriuretic peptide (ANP) secreted from atrial myocytes is shown to possess anti-inflammatory, anti-oxidant and immunomodulatory effects. The aim of this study is to assess the effect of ANP on bacterial lipopolysaccharide (LPS)-induced endotoxemia-derived neuroinflammation and cognitive impairment.MethodsLPS (5 mg/kg) was given intraperitoneally to mice. Recombinant human ANP (rhANP) (1.0 mg/kg) was injected intravenously 24 h before and/or 10 min after LPS injection. Subdiaphragmatic vagotomy (SDV) was performed 14 days before LPS injection or 28 days before fecal microbiota transplantation (FMT). ANA-12 (0.5 mg/kg) was administrated intraperitoneally 30 min prior to rhANP treatment.ResultsLPS (5.0 mg/kg) induced remarkable splenomegaly and an increase in the plasma cytokines at 24 h after LPS injection. There were positive correlations between spleen weight and plasma cytokines levels. LPS also led to increased protein levels of ionized calcium-binding adaptor molecule (iba)-1, cytokines and inducible nitric oxide synthase (iNOS) in the hippocampus. LPS impaired the natural and learned behavior, as demonstrated by an increase in the latency to eat the food in the buried food test and a decrease in the number of entries and duration in the novel arm in the Y maze test. Combined prophylactic and therapeutic treatment with rhANP reversed LPS-induced splenomegaly, hippocampal and peripheral inflammation as well as cognitive impairment. However, rhANP could not further enhance the protective effects of SDV on hippocampal and peripheral inflammation. We further found that PGF mice transplanted with fecal bacteria from rhANP-treated endotoxemia mice alleviated the decreased protein levels of hippocampal polyclonal phosphorylated tyrosine kinase receptor B (p-TrkB), brain-derived neurotrophic factor (BDNF) and cognitive impairment, which was abolished by SDV. Moreover, TrkB/BDNF signaling inhibitor ANA-12 abolished the improving effects of rhANP on LPS-induced cognitive impairment.ConclusionsOur results suggest that rhANP could mitigate LPS-induced hippocampal inflammation and cognitive dysfunction through subdiaphragmatic vagus nerve-mediated gut microbiota–brain axis.
Highlights
Studies of both animals and humans have shown a close relationship between systemic inflammation and neuropsychiatric disorders [1,2,3]
Effects of Recombinant human ANP (rhANP) on spleen weight and plasma inflammatory cytokines after LPS injection First, we investigated the effects of rhANP treated in three different protocols on the spleen weight and plasma inflammatory cytokines after LPS injection (Fig. 1a)
A significant attenuation of LPS-induced increase in the plasma levels of IL-6, IL17A, IFN-γ and tumor necrosis factor (TNF)-α was observed in mice received combined prophylactic and therapeutic treatment with rhANP, as compared to that in mice treated with saline (Fig. 1e–h)
Summary
Studies of both animals and humans have shown a close relationship between systemic inflammation and neuropsychiatric disorders [1,2,3]. LPS-challenged animal model to mimic Gram-negative bacterial infection is widely used to study the psychiatric and cognitive consequences of infection and systemic inflammation [8, 9]. It has been shown that systemic LPS-triggered neuroinflammation plays a pivotal role in the pathophysiology of endotoxemia-derived cognitive impairment [4, 10,11,12,13,14,15]. Atrial natriuretic peptide (ANP) secreted from atrial myocytes is shown to possess anti-inflammatory, anti-oxidant and immunomodulatory effects. The aim of this study is to assess the effect of ANP on bacterial lipopolysaccharide (LPS)-induced endotoxemia-derived neuroinflammation and cognitive impairment
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