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A novel isoquinoline derivative exhibits anti-inflammatory properties and improves the outcomes of endotoxemia

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Abstract

Background: Sepsis initiates an inflammatory response that causes widespread injury, and candidates for related myocardial depressant factors include cytokines and nitric oxide (NO). Nuclear factor kappa-B (NF-KB) stimulated by toll-like receptor 4 activation in sepsis mediates the transcription of multiple proinflammatory genes. These inflammatory mediators can cause myocardial dysfunction, which may deteriorate sepsis outcomes. To address this risk, we investigated the potential beneficial effects of a novel isoquinolines derivative, CYY054c, in LPS-induced inflammatory response leading to endotoxemia.

Methods: The effects of CYY054c on cytokine and inflammatory-related protein production were evaluated in lipopolysaccharide (LPS)-stimulated macrophages. To determine whether CYY054c alleviates inflammatory storm-induced myocardial dysfunction in vivo, LPS was injected in rats, and cardiac function was measured by a pressure-volume loop.

Results: CYY054c inhibited LPS-induced NF-KB expression in macrophages and reduced the release of tumor necrosis factor-alpha (TNF-1α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In the animal studies, CYY054c alleviated LPS-upregulated plasma TNF-ct, IL-1β, IL-6, and NO concentrations, as well as cardiac monocyte chemotactic protein-1, iNOS, and COX-2 expression in rats, contributing to the improvement of cardiac function during endotoxemia.

Conclusions: The reduction of NF-KB-mediated inflammatory mediators and the maintenance of hemodynamic performance by CYY054c improved the outcomes during endotoxemia. CYY054c may be a potential therapeutic agent for sepsis.

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  1. Equal Contribution.

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Taitung MacKay Memorial Hospital, Taiwan

    Shih-Yi Lee

  2. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, MacKay Memorial Hospital, Taiwan

    Shih-Yi Lee

  3. Mackay junior College of Medicine, Nursing, and Management, Taipei, Taiwan

    Shih-Yi Lee

  4. School of Pharmacy, Molecular Probes Development Core, Molecular Imaging Center, Taipei, Taiwan

    Ling-Wei Hsin

  5. Center for Innovative Therapeutics Discovery, National Taiwan University, Taipei, Taiwan

    Ling-Wei Hsin

  6. Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Ming-Jai Su & Ching-Chia ChangChien

  7. Department of Life Science, Fujen Catholic University, New Taipei City, Taiwan

    Hui-Chun Ku

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Correspondence to Hui-Chun Ku.

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Lee, SY., Hsin, LW., Su, MJ. et al. A novel isoquinoline derivative exhibits anti-inflammatory properties and improves the outcomes of endotoxemia. Pharmacol. Rep 71, 1281–1288 (2019). https://doi.org/10.1016/j.pharep.2019.06.015

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