The effects of BRL-50481 on ovalbumin-induced asthmatic lung inflammation exacerbated by co-exposure to Asian sand dust in the murine model

Kim, Hong Jo; Song, Jin Yong; Park, Tae Il; Choi, Won Seok; Kim, Jong Heon; Kwon, Oh Seong; Lee, Ji-Yun

doi:10.1007/s12272-021-01367-x

Cited by 10 publications

(6 citation statements)

References 41 publications

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“…As a result, Roflumilast, a selective and long-acting PDE4 inhibitor, was developed as a treatment of inflammatory lung diseases such as asthma and COPD for preventing their exacerbation (Ilango et al 2013). Our previous study also showed that PDE7 inhibitor, BRL-50481, alleviates ovalbumin-induced asthmatic lung inflammation (Kim et al 2022).…”

Section: Introductionmentioning

confidence: 83%

Anti-Inflammatory Effect of Phosphodiesterase 2 Inhibitor in Lipopolysaccharide (LPS)-Stimulated RAW 264.7 Macrophages

Song

Lee

Kwon

et al. 2023

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Although the inflammatory response is an important process in the host defense system, it has been found to cause serious complications in disease in response to various stresses. Cyclic nucleotide monophosphates (cAMP and cGMP) are related to the inflammatory response, however, their mechanism is unclear. Although the antioxidative and neuroprotective mechanisms of the phosphodiesterase 2 (PDE2) inhibitor have been extensively studied in relation to heart failure and neuropsychiatric diseases, the PDE2 inhibitor's role in inflammatory immune responses caused by bacterial endotoxin has not been elucidated. In the present study, the anti-inflammatory effects of the PDE2 selective inhibitor BAY 60-7550 were investigated in the murine macrophage cell line RAW 264.7 after being induced by lipopolysaccharide (LPS). BAY 60-7550 showed no cytotoxicity in RAW 264.7 cells and suppressed the LPS-induced overexpression of oxidative stress factors such as an inducible nitric oxide synthase (iNOS), nitric oxide (NO), and reactive oxygen species (ROS). The oxidative stress-induced activation of the mitogen-activated protein kinase (MAPK) pathway, especially the phosphorylation of the extracellular signal-regulated kinases (ERK)1/2 and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, was also inhibited by the application of BAY 60-7550. Moreover, the expression of COX-2, PGE₂, and pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β was significantly reduced by the application of BAY 60-7550. In conclusion, BAY 60-7550 has an anti-inflammatory effect through the regulation of the ERK1/2-associated MAPK and NF-κB pathways. Thus, this finding shows the potential of the PDE2 selective inhibitor as a new therapeutic candidate for infectious inflammatory diseases.

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Section: Introductionmentioning

confidence: 83%

Anti-Inflammatory Effect of Phosphodiesterase 2 Inhibitor in Lipopolysaccharide (LPS)-Stimulated RAW 264.7 Macrophages

Song

Lee

Kwon

et al. 2023

DTT

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“…A potential solution to the lack of efficacy could be directing drug development efforts to evaluate combinatory regimens, as suggested for PDE 5 inhibitors in ED; combining PDE 5 inhibitors with other therapeutic approaches, such as antioxidants, showed improved outcomes without increasing ADRs (Mykoniatis et al, 2021). A similar strategy is suggested Frontiers in Pharmacology frontiersin.org Alzheimer's disease (Li et al, 2018) BRL-50481 GlaxoSmithKline PDE 7 CNS disorders (Chen et al, 2020), inflammation (Kim et al, 2022) CC-3052 Celgene PDE 4 Tuberculosis , HIV (Guckian et al, 2000;La Maestra et al, 2000) EHNA N/A PDE 2 Cancer (Bernard et al, 2014;Hiramoto et al, 2014;Murata et al, 2019), HIV (Sei et al, 1989) JNJ-42314415…”

Section: Discussionmentioning

confidence: 99%

“…Several agents target novel PDE targets. BRL-50481, a PDE 7 inhibitor, have showed neuroprotector ( Chen et al, 2020 ) and anti-inflammatory properties ( Kim et al, 2022 ) on animal models. Lu AF33241, a dual PDE 2A/PDE 10A inhibitor, was found to attenuate sub-chronic phencyclidine-induced deficits in novel object recognition and displayed antipsychotic-like activity ( Redrobe et al, 2015 ).…”

Section: Phosphodiesterase Inhibitors In Clinical Researchmentioning

confidence: 99%

Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules

et al. 2022

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The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors’ will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.

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“…After the experiment, blood was collected from the inferior vena cava of all mice, and 40 μL 3.2% sodium citrate was used as an anticoagulant for each syringe. The blood samples were centrifuged at 1,500 g and 4°C for 10 min, and the separated serum was stored at −80°C for the determination of OVA-specific immunoglobulin E (IgE) and IgG1 protein levels [24]. Mice were euthanized by intraperitoneal injection of 200 mg/kg pentobarbital sodium, and bronchoalveolar lavage fluid (BALF) was collected from all the mice for cell count and cytokine detection.…”

Section: Establishment Of the Allergic Asthmatic Mouse Model And Grou...mentioning

confidence: 99%

“…The precipitate was collected and resuspended with 250 μL PBS, and the total number of inflammatory cells in BALF was counted using a blood cell counter (Paul Marienfeld GmbH & Co. KG, Lau-da-Konigshofen, Germany). After the cytocentrifuge preparation with Cytospin 2 (Thermo Fisher), differential cell counts were performed using staining images prepared with the Kwik-Dif TM Stain kits based on standard morphological criteria (Thermo Fisher) [24].…”

Section: Balf Collection and Cell Countmentioning

confidence: 99%

miR-146a-5p Attenuates Allergic Airway Inflammation by Inhibiting the NLRP3 Inflammasome Activation in Macrophages

Yang

Huang

et al. 2022

Int Arch Allergy Immunol

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Objective: Asthma is a common inflammatory respiratory disease with increasing incidence worldwide. This study aimed to investigate the mechanism of miR-146a-5p in reducing allergic airway inflammation by inhibiting NLRP3 inflammasome activation in macrophages. Methods: Allergic mouse models were established by ovalbumin stimulation, and mice were treated with miR-146a-5p agomir and oe-TIRAP 3 h before OVA stimulation. The pathological changes of lung tissues were observed by hematoxylin-eosin staining. The airway hyperresponsiveness of mice were examined. The miR-146a-5p level was detected by RT-qPCR. The inflammatory cytokines (IL-18/TNF-α) and anti-inflammatory cytokine IL-10 levels in bronchoalveolar lavage fluid and serum IgE levels were examined by ELISA. Airway inflammation in mice was detected after miR-146a-5p overexpression. The levels of NLRP3/ASC/caspase1 proteins and macrophage M1/M2 surface markers in mouse lung tissues were examined using immunohistochemistry, Western blot, and flow cytometry. The targeting relationship between miR-146a-5p and TIRAP was verified by dual-luciferase assay. The p65 levels in the cytoplasm/nucleus of mouse lung tissue were measured. Results: miR-146a-5p was downregulated in the lung tissues of allergic mice, and miR-146a-5p overexpression alleviated airway inflammation in asthmatic mice. miR-146a-5p suppressed NLRP3 inflammasome activation in macrophages of allergic mice, reduced NLRP3/ASC/caspase1 protein levels in lung tissues, blocked M1 polarization, and promoted M2 polarization. miR-146a-5p targeted TIRAP. TIRAP overexpression partially reversed the promoting effect of miR-146a-5p on M2 polarization. miR-146a-5p can inhibit the activation of the TIRAP/NF-κB pathway. Conclusion: miR-146a-5p inhibited NLRP3 inflammasome activation in macrophages in the lung tissue of allergic mice, prevented pro-inflammatory phenotype M1 polarization, and promoted anti-inflammatory phenotype M2 polarization by targeting the TIRAP/NF-κB pathway, thus alleviating airway inflammation in allergic asthma.

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The effects of BRL-50481 on ovalbumin-induced asthmatic lung inflammation exacerbated by co-exposure to Asian sand dust in the murine model

Cited by 10 publications

References 41 publications

Anti-Inflammatory Effect of Phosphodiesterase 2 Inhibitor in Lipopolysaccharide (LPS)-Stimulated RAW 264.7 Macrophages

Anti-Inflammatory Effect of Phosphodiesterase 2 Inhibitor in Lipopolysaccharide (LPS)-Stimulated RAW 264.7 Macrophages

Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules

miR-146a-5p Attenuates Allergic Airway Inflammation by Inhibiting the NLRP3 Inflammasome Activation in Macrophages

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