Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice

O’Neill, Eoin; Griffin, Éadaoin W.; O'Sullivan, Ruairi; Murray, Carol; Ryan, Lucy; Yssel, Justin; Harkin, Andrew; Cunningham, Colm

doi:10.1016/j.bbi.2020.12.002

Cited by 21 publications

(10 citation statements)

References 54 publications

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“…The increase in nucleotide release resulting from brain injury was shown to be involved in activation of microglial cells as well as in their chemotaxis by acting on purinergic receptor P2Y12 (P2ry12) [42]; the expression of P2ry12 was downregulated in response to both MCAO and LPS in our study. Significant decrease in hippocampal P2ry12 expression was found previously after microglial activation by systemic LPS administration [43]. It has been reported that P2Y12 receptor activation on microglia aggravates ischemic stroke injury [44].…”

Section: Inflammatory Responsementioning

confidence: 90%

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis

et al. 2021

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Acute cerebral ischemia induces distant inflammation in the hippocampus; however, molecular mechanisms of this phenomenon remain obscure. Here, hippocampal gene expression profiles were compared in two experimental paradigms in rats: middle cerebral artery occlusion (MCAO) and intracerebral administration of lipopolysaccharide (LPS). The main finding is that 10 genes (Clec5a, CD14, Fgr, Hck, Anxa1, Lgals3, Irf1, Lbp, Ptx3, Serping1) may represent key molecular links underlying acute activation of immune cells in the hippocampus in response to experimental ischemia. Functional annotation clustering revealed that these genes built the same clusters related to innate immunity/immunity/innate immune response in all MCAO differentially expressed genes and responded to the direct pro-inflammatory stimulus group. The gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses also indicate that LPS-responding genes were the most abundant among the genes related to “positive regulation of tumor necrosis factor biosynthetic process”, “cell adhesion”, “TNF signaling pathway”, and “phagosome” as compared with non-responding ones. In contrast, positive and negative “regulation of cell proliferation” and “HIF-1 signaling pathway” mostly enriched with genes that did not respond to LPS. These results contribute to understanding genomic mechanisms of the impact of immune/inflammatory activation on expression of hippocampal genes after focal brain ischemia.

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Section: Inflammatory Responsementioning

confidence: 90%

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis

et al. 2021

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“…The locus coeruleus noradrenergic (LCNE) pathway has been proven to be involved in regulating a wide range of advanced cognitive functions ( Sara, 2009 ; Betts et al, 2019 ), such as working memory, learning and attention ( Robbins, 1984 ; Aston-Jones and Cohen, 2005 ; Mather et al, 2016 ), memory formation and consolidation ( Gibbs and Summers, 2002 ; Gibbs et al, 2010 ; Hansen, 2017 ), and immunological mechanisms in the brain ( Polak et al, 2011 ; Stowell et al, 2019 ). A few studies have shown that the LCNE pathway contributes to the pathomechanism of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) ( Giorgi et al, 2020 ), and septic encephalopathy ( O’Neill et al, 2020 ), in which neuroinflammation plays an important role. In Termpanit’s study, the losses of LC fibers and noradrenaline (NE) exacerbate spatial learning and memory deficits in transgenic mouse models of AD, accompanied by the activation of microglia and astrocytes in the hippocampus ( Chalermpalanupap et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

A Noradrenergic Lesion Attenuates Surgery-Induced Cognitive Impairment in Rats by Suppressing Neuroinflammation

Wang

Zhou

et al. 2021

Front. Mol. Neurosci.

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Postoperative cognitive dysfunction (POCD) is a common postoperative neurocognitive complication in elderly patients. However, the specific pathogenesis is unknown, and it has been demonstrated that neuroinflammation plays a key role in POCD. Recently, increasing evidence has proven that the locus coeruleus noradrenergic (LCNE) system participates in regulating neuroinflammation in some neurodegenerative disorders. We hypothesize that LCNE plays an important role in the neuroinflammation of POCD. In this study, 400 μg of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected intracerebroventricularly into each rat 7 days before anesthesia/surgery to deplete the locus coeruleus (LC) noradrenaline (NE). We applied a simple laparotomy and brief upper mesenteric artery clamping surgery as the rat POCD model. The open field test, novel objection and novel location (NL) recognition, and Morris water maze (MWM) were performed to assess postoperative cognition. High-performance liquid chromatography (HPLC) was used to measure the level of NE in plasma and brain tissues, and immunofluorescence staining was applied to evaluate the activation of microglia and astrocytes. We also used enzyme-linked immune-sorbent assay (ELISA) to assess the levels of inflammatory cytokines and brain-derived neurotrophic factor (BDNF). Pretreatment with DSP-4 decreased the levels of systemic and central NE, increased the level of interleukin-6 (IL-6) in the plasma at 6 h after the surgery, decreased the concentration of IL-6 in the prefrontal cortex and hippocampus, and decreased the level of interleukin-1β (IL-1β) in the plasma, prefrontal cortex, and hippocampus at 1 week postoperatively. In addition, DSP-4 treatment attenuated hippocampal-dependent learning and memory impairment in rats with POCD, with a downregulation of the activation of microglia and astrocytes in the prefrontal cortex and hippocampus. In conclusion, these findings provide evidence of the effects of LCNE in modulating neuroinflammation in rats with POCD and provide a new perspective in the prevention and treatment of POCD.

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“…On days 7 and 14 before intestinal I/R injury, mice in the DSP-4 + I/R group were administered DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, #C8417, Sigma-Aldrich Corporation, St Louis, MO, USA) at 50 mg/kg IP. The dose and timepoint of DSP-4 have been used in many previous studies [ 36 , 37 ]. Animals in the DSP-4 + DEX + I/R group received DSP-4 and then dexmedetomidine before intestinal I/R, and the dose and time points were the same as those in the DEX + I/R or DSP-4 + I/R groups.…”

Section: Methodsmentioning

confidence: 99%

Dexmedetomidine Ameliorated Cognitive Dysfunction Induced by Intestinal Ischemia Reperfusion in Mice with Possible Relation to the Anti-inflammatory Effect Through the Locus Coeruleus Norepinephrine System

Zhou

Wei

et al. 2022

Neurochem Res

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Cognitive impairment is a common central nervous system complication that occurs following surgery or organs damage outside the nervous system. Neuroinflammation plays a key role in the molecular mechanisms of cognitive impairment. Dexmedetomidine alleviates neuroinflammation and reduces cognitive dysfunction incidence; however, the mechanism by which dexmedetomidine alleviates cognitive dysfunction remains unclear. This study evaluated the effect of dexmedetomidine on attenuation of early cognitive impairment induced by intestinal ischemia–reperfusion in mice and examined whether the locus coeruleus norepinephrine (LCNE) system participates in the anti-inflammatory effect of dexmedetomidine. The superior mesenteric artery was clamped for 45 min to induce intestinal ischemia reperfusion injury. Dexmedetomidine alone or combined with DSP-4, a selective locus coeruleus noradrenergic neurotoxin, was used for pretreatment. Postoperative cognition was assessed using the Morris water maze. Serum and hippocampal levels of IL-1β, TNF-α, norepinephrine (NE), and malondialdehyde (MDA) were assessed by enzyme-linked immunosorbent assay. Immunofluorescence, immunohistochemistry, and hematoxylin and eosin staining were used to evaluate the expression of tyrosine hydroxylase (TH) in the locus coeruleus, hippocampal microglia, and intestinal injury. Pretreatment with dexmedetomidine alleviated intestinal injury and decreased the serum and hippocampal levels of NE, IL-1β, TNF-α, and MDA at 24 h after intestinal ischemia reperfusion, decreased TH-positive neurons in the locus coeruleus, and ameliorated cognitive impairment. Similarly, DSP-4 pre-treatment alleviated neuroinflammation and improved cognitive function. Furthermore, α2-adrenergic receptor antagonist atipamezole or yohimbine administration diminished the neuroprotective effects and improved cognitive function with dexmedetomidine. Therefore, dexmedetomidine attenuated early cognitive dysfunction induced by intestinal ischemia–reperfusion injury in mice, which may be related to its anti-inflammatory effects through the LCNE system.

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Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice

Cited by 21 publications

References 54 publications

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis

A Noradrenergic Lesion Attenuates Surgery-Induced Cognitive Impairment in Rats by Suppressing Neuroinflammation

Dexmedetomidine Ameliorated Cognitive Dysfunction Induced by Intestinal Ischemia Reperfusion in Mice with Possible Relation to the Anti-inflammatory Effect Through the Locus Coeruleus Norepinephrine System

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