Inhibitory effects of benzodiazepines on the adenosine A2B receptor mediated secretion of interleukin-8 in human mast cells

Hoffmann, Kristina; Xifró, Rosa Altarcheh; Hartweg, Julia Lisa; Spitzlei, Petra; Meis, Kirsten; Molderings, Gerhard J.; Kügelgen, Ivar von

doi:10.1016/j.ejphar.2012.12.003

Cited by 17 publications

(8 citation statements)

References 31 publications

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“…Interestingly, the benzodiazepine class of medications at the core of treatment of anxiety and panic also addresses inhibitory mast-cell-surface benzodiazepine receptors. [29,30] Physicians (e.g., psychiatrists and emergency physicians) challenged by patients with recurrent idiopathic presentations of anxiety and panic might find more satisfying explanations for these problems in diagnostic assessments for MCAS. Sleep apnea, almost always obstructive, is found in 15% of MCAS patients and curiously occurs not uncommonly in non-obese patients, raising questions of mechanisms which might include airways narrowed by edema, hypertrophy, fibrosis, or excessive mucus, or excessive loss of airway muscular tone in sleep.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Mast Cell Activation Syndrome

Afrin

Self

Menk

et al. 2017

The American Journal of the Medical Sciences

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Background Mast cell activation syndrome (MCAS), a recently recognized non-neoplastic mast cell (MC) disease driving chronic multisystem inflammation ± allergy, appears prevalent and thus important. We report the first systematic characterization of a large MCAS population. Method Demographics, comorbidities, symptoms, family histories, and physical exam and laboratory findings were reviewed in 298 retrospective and 115 prospective MCAS patients. Blood samples from prospective subjects were examined by flow cytometry for clonal MC disease and tested for cytokines potentially driving the monocytosis frequent in MCAS. Results Demographically, white females dominated. Median ages at symptom onset/diagnosis were 9/49 years (ranges 0–88/16–92); median time from symptom onset to diagnosis was 30 years (range 1–85). Median numbers of comorbidities/symptoms/family medical issues were 11/20/4 (ranges 1–66/2–84/0–33). Gastroesophageal reflux, fatigue, and dermatographism were the most common comorbidity, symptom, and exam finding. Abnormalities in routine labs were common and diverse but typically modest. The most useful diagnostic markers were heparin, prostaglandin D2, histamine, and chromogranin A. Flow cytometric and cytokine assessments were unhelpful. Conclusions Our study highlights MCAS’s morbidity burden and challenging heterogeneity. Recognition is important given good survival and treatment prospects.

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Section: Discussionmentioning

confidence: 99%

Characterization of Mast Cell Activation Syndrome

Afrin

Self

Menk

et al. 2017

The American Journal of the Medical Sciences

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“…The TSPO-selective BDZ Ro5-4864 was shown to inhibit concanavalin A-induced serotonin release from as well as 45 Ca uptake into rat MCs, whereas the GABA A -receptor-selective BDZ clonazepam only had a slight impact on serotonin release and did not affect 45 Ca uptake [11]. In addition, diazepam, Ro5-4864, and flunitrazepam were demonstrated to reduce NECA-induced IL-8 production in human MC leukemia cells [20]. Since on the one hand MCs did not express GABA A receptors in previous investigations and on the other hand most BDZs, such as flunitrazepam, diazepam, and midazolam possess considerable affinity for TSPO [7,9,12], it was conceivable that the inhibitory effects of BDZs on MCs may be due to their binding to TSPO in MCs.…”

Section: Introductionmentioning

confidence: 99%

The 1,4-benzodiazepine Ro5-4864 (4-chlorodiazepam) suppresses multiple pro-inflammatory mast cell effector functions

et al. 2013

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Activation of mast cells (MCs) can be achieved by the high-affinity receptor for IgE (FcεRI) as well as by additional receptors such as the lipopolysaccharide (LPS) receptor and the receptor tyrosine kinase Kit (stem cell factor [SCF] receptor). Thus, pharmacological interventions which stabilize MCs in response to different receptors would be preferable in diseases with pathological systemic MC activation such as systemic mastocytosis. 1,4-Benzodiazepines (BDZs) have been reported to suppress MC effector functions. In the present study, our aim was to analyze molecularly the effects of BDZs on MC activation by comparison of the effects of the two BDZs Ro5-4864 and clonazepam, which markedly differ in their affinities for the archetypical BDZ recognition sites, i.e., the GABAA receptor and TSPO (previously termed peripheral-type BDZ receptor). Ro5-4864 is a selective agonist at TSPO, whereas clonazepam is a selective agonist at the GABAA receptor. Ro5-4864 suppressed pro-inflammatory MC effector functions in response to antigen (Ag) (degranulation/cytokine production) and LPS and SCF (cytokine production), whereas clonazepam was inactive. Signaling pathway analyses revealed inhibitory effects of Ro5-4864 on Ag-triggered production of reactive oxygen species, calcium mobilization and activation of different downstream kinases. The initial activation of Src family kinases was attenuated by Ro5-4864 offering a molecular explanation for the observed impacts on various downstream signaling elements. In conclusion, BDZs structurally related to Ro5-4864 might serve as multifunctional MC stabilizers without the sedative effect of GABAA receptor-interacting BDZs.

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“…It was also observed that the presence of oxazepine substituent demonstrated good activity against breast cancer cells (26), thus explaining the antiproliferative effect observed with compound 6. Furthermore, the significant antiproliferative activity of compound 4 could stem from the presence of a diazepine molecule in the structure, since diazepine inhibits the adenosine A2B receptor involved in the development of tumors and proliferation (27). In addition, a previous study reported that adenosine A 2B receptors are expressed at high levels in the estrogen-negative MDA-MB-231 cell line but not expressed in the estrogen-positive MCF-7 cell line, which could explain why the antiproliferative effect of compound 4 was observed here only in MDA-MB-231 cells (28).…”

Section: Discussionmentioning

confidence: 99%

Effects of Spiro-bisheterocycles on Proliferation and Apoptosis in Human Breast Cancer Cell Lines

Ramdani

Talhi

Taïbi

et al. 2016

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Spiro-bisheterocyclic compounds 2-7 were chemically synthesized. Cell proliferation was assessed by resazurin assay. Annexin V-FITC/ PI apoptosis assays was performed in order to demonstrate apoptotic effects of spiro-bisheterocyclic In breast cancer cell lines.Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to analyze the wild-type p53, MDM2, BAX and caspase 3 gene expression levels.

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Inhibitory effects of benzodiazepines on the adenosine A2B receptor mediated secretion of interleukin-8 in human mast cells

Cited by 17 publications

References 31 publications

Characterization of Mast Cell Activation Syndrome

Characterization of Mast Cell Activation Syndrome

The 1,4-benzodiazepine Ro5-4864 (4-chlorodiazepam) suppresses multiple pro-inflammatory mast cell effector functions

Effects of Spiro-bisheterocycles on Proliferation and Apoptosis in Human Breast Cancer Cell Lines

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