The anti-inflammatory and antinociceptive effects of NF-κB inhibitory guanidine derivative ME10092

Dambrova, Maija; Zvejniece, Liga; Skapare, Elina; Vilšķe̅rsts, Reinis; Švalbe, Baiba; Баумане, Л.; Muceniece, Ruta; Liepinsh, Edgars

doi:10.1016/j.intimp.2010.01.006

Cited by 26 publications

(15 citation statements)

References 34 publications

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“…Cell Treatment For studying the effects of HCA ligands on adipogenesis, SGBS cells were treated throughout the differentiation process with 50 µM niacin (NA) to stimulate the HCA2, 9) 50 µM 1-isopropyl-1H-benzotriazole-5-carboxylic acid (IPBT) to stimulate the HCA3, 24) or 100 µM dihydroxybenzoic acid (DHBA) to stimulate the HCA1. 25) For studying the effects of HCA ligands on differentiated THP-1 and SGBS cells, cells were pretreated with ligands for 1 h before the addition of 1 µg/mL LPS for 4 h. Optimal concentrations of HCA ligands were established from preliminary dose response experiments for NA (1 to 100 µM), IPBT (1 to 100 µM) and DHBA (50 to 200 µM).…”

Section: Methodsmentioning

confidence: 99%

Hydroxycarboxylic Acid Receptor Ligands Modulate Proinflammatory Cytokine Expression in Human Macrophages and Adipocytes without Affecting Adipose Differentiation

Mandrika

Tilgase

Petrovska

et al. 2018

Biological & Pharmaceutical Bulletin

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Members of the hydroxycarboxylic acid receptor (HCA1-3) family are mainly expressed in adipocytes and immune cells. HCA2 ligand, niacin, has been used for decades as lipid-modifying drug. Recent studies suggest that HCA ligands can be involved in the modulation of inflammatory processes. In this study, we evaluated the effects of HCA1-3 ligands on adipose differentiation and cytokine expression in human adipocytes and macrophages. Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes were induced to differentiate into adipocytes for 8 d in the presence or absence of HCA ligands and evaluated for lipid accumulation and adipogenic gene expression. The inhibitory effects of the ligands on the expression and production of cytokines were measured in lipopolysaccharide (LPS)-stimulated adipocytes and THP-1 macrophage cells. Preadipocytes treated with HCA ligands showed no changes in the capacity to differentiate into adipocytes and no significant alteration in peroxisome proliferator activated receptor γ (PPARγ) or its target gene expression. HCA2-3 ligands significantly downregulated LPS-induced expression of interleukin (IL)-6 (53-64%), tumor necrosis factor-α (TNF-α) (55-69%) and IL-8 (51-59%) in adipocytes and macrophages. IL-1β inhibition (58-68%) by HCA2-3 ligands was observed only in adipocytes. Furthermore, LPS increased the expression of HCA2-3 in adipocytes and macrophages and this expression was decreased by treatment with their ligands. These results suggest that HCA ligands modulated LPS-mediated pro-inflammatory gene expression in both macrophages and adipocytes without affecting adipogenesis. Therefore, targeting HCA2 and HCA3 would be beneficial in treating inflammation conditions associated with atherosclerosis and obesity.

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Section: Methodsmentioning

confidence: 99%

Hydroxycarboxylic Acid Receptor Ligands Modulate Proinflammatory Cytokine Expression in Human Macrophages and Adipocytes without Affecting Adipose Differentiation

Mandrika

Tilgase

Petrovska

et al. 2018

Biological & Pharmaceutical Bulletin

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“…Quantitative RT-PCR was performed using a previously described method 29 with slight modifications. Total RNA was isolated from brain tissues using an RNA mini kit (Life Technologies, Grand Island, NY) according to the manufacturer's instructions.…”

Section: Quantitative Rt-pcr Analysismentioning

confidence: 99%

Skull Fractures Induce Neuroinflammation and Worsen Outcomes after Closed Head Injury in Mice

Zvejniece

Stelfa

Vāvers

et al. 2020

Journal of Neurotrauma

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The weight-drop model is used widely to replicate closed-head injuries in mice; however, the histopathological and functional outcomes may vary significantly between laboratories. Because skull fractures are reported to occur in this model, we aimed to evaluate whether these breaks may influence the variability of the weight-drop (WD) model. Male Swiss Webster mice underwent WD injury with either a 2 or 5 mm cone tip, and behavior was assessed at 2 h and 24 h thereafter using the neurological severity score. The expression of interleukin (IL)-6, IL-1b, tumor necrosis factor-a, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 genes was measured at 12 h and 1, 3, and 14 days after injury. Before the injury, micro-computed tomography (micro-CT) was performed to quantify skull thickness at the impact site. With a conventional tip diameter of 2 mm, 33% of mice showed fractures of the parietal bone; the 5 mm tip produced only 10% fractures. Compared with mice without fractures, mice with fractures had a severity-dependent worse functional outcome and a more pronounced upregulation of inflammatory genes in the brain. Older mice were associated with thicker parietal bones and were less prone to skull fractures. In addition, mice that underwent traumatic brain injury (TBI) with skull fracture had macroscopic brain damage because of skull depression. Skull fractures explain a considerable proportion of the variability observed in the WD model in mice-i.e., mice with skull fractures have a much stronger inflammatory response than do mice without fractures. Using older mice with thicker skull bones and an impact cone with a larger diameter reduces the rate of skull fractures and the variability in this very useful closed-head TBI model.

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“…AM1030 is a novel 5-HT 2B receptor antagonist that displays binding to and functional inhibition of the human receptor (K i = 0.33 μM; IC 50 = 0.14 μM). Structurally, AM1030 is an aminoguanidine derivative related to a previously published compound with anti-inflammatory properties [ 30 ]. AM1030 is currently in clinical development phase.…”

Section: Introductionmentioning

confidence: 99%

A human and animal model-based approach to investigating the anti-inflammatory profile and potential of the 5-HT2B receptor antagonist AM1030

Palmqvist¹,

Siller²,

Klint³

et al. 2016

J Inflamm

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BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic eczematous lesions that are commonly treated with topical corticosteroids and calcineurin inhibitors. Side-effects and safety concerns associated with these agents restrict their use, and new, safe treatment options are therefore needed. Recent reports suggest that serotonin, i.e. 5-hydroxytryptamine (5-HT) and the 5-HT2 receptor family may contribute to inflammation and pruritus in the skin. The objective of this particular study was to investigate the 5HT2B receptor antagonist AM1030 with respect to its anti-inflammatory profile and potential.MethodsAM1030 was tested in a set of distinct human and rodent in vitro and in vivo models, differing with respect to e.g. T cell involvement, triggering stimulus, main read-outs and route of drug administration. The in vitro systems used were staphylococcal enterotoxin A (SEA)-stimulated human peripheral blood mononuclear cells, lipopolysaccharide (LPS)-stimulated human primary monocytes, LPS-stimulated human THP-1 monocytes and LPS-stimulated mouse primary macrophages. The in vivo systems used were LPS- and SEA-induced cytokine production in the mouse, antigen-induced arthritis in the rat, glucose-6-phosphate isomerase-induced arthritis in the mouse and delayed-type hypersensitivity reaction in the mouse. In addition, different cell populations were analyzed with respect to their expression of the 5-HT2B receptor at the mRNA level.ResultsAM1030 significantly reduced both T cell-dependent and T cell-independent inflammatory responses, in vivo and in vitro. Due to the low or absent expression of the 5-HT2B receptor on T cell populations, the influence of AM1030 in T cell-dependent systems is suggested to be mediated via an indirect effect involving antigen-presenting cell types, such as monocytes and macrophages.ConclusionBased on the wide range of model systems used in this study, differing e.g. with respect to species, T cell involvement, triggering stimuli, route of drug administration and read-outs, our results suggest a broad anti-inflammatory effect of AM1030 and identify the 5-HT2B receptor as a promising future target for anti-inflammatory intervention, e.g. in AD.

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The anti-inflammatory and antinociceptive effects of NF-κB inhibitory guanidine derivative ME10092

Cited by 26 publications

References 34 publications

Hydroxycarboxylic Acid Receptor Ligands Modulate Proinflammatory Cytokine Expression in Human Macrophages and Adipocytes without Affecting Adipose Differentiation

Hydroxycarboxylic Acid Receptor Ligands Modulate Proinflammatory Cytokine Expression in Human Macrophages and Adipocytes without Affecting Adipose Differentiation

Skull Fractures Induce Neuroinflammation and Worsen Outcomes after Closed Head Injury in Mice

A human and animal model-based approach to investigating the anti-inflammatory profile and potential of the 5-HT2B receptor antagonist AM1030

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