Preclinical evidence of the anti-inflammatory effect and toxicological safety of aryl-cyclohexanone in vivo

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY Fundamental & Clinical Pharmacology Pub Date : 2024-08-18 DOI:10.1111/fcp.13035

Tainá Larissa Lubschinski, Luiz Antonio Escorteganha Pollo, Paula Giarola Fragoso de Oliveira, Luigi Arruda Nardino, Eduarda Talita Bramorski Mohr, Ziliani da Silva Buss, Louis Pergaud Sandjo, Maique Weber Biavatti, Felipe Perozzo Daltoé, Eduardo Monguilhott Dalmarco

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Abstract

Background

Respiratory distress syndrome is a complex inflammatory condition defined by the presence of acute hypoxemia and cellular infiltration with diffuse alveolar injury following a tissue injury, such as acute lung injury. The inflammatory process involved in this pathology is a defense mechanism of the body against infectious agents and/or tissue injuries. However, when the condition is not reversed, it becomes a significant cause of tissue damage, sometimes leading to loss of function of the affected organ. Therefore, it is essential to understand the mechanisms underlying inflammation, as well as the development of new therapeutic agents that reduce inflammatory damage in these cases. Aryl-cyclohexanone derivatives have previously shown significant anti-inflammatory activity linked to an immunomodulatory capacity in vitro and may be good candidates for therapies in which inflammation plays a central role.

Methods

Was evaluated the anti-inflammatory capacity of a synthesized molecule aryl-cyclohexanone in the murine model of lipopolysaccharide (LPS)-induced acute lung injury. The assessment of acute oral toxicity follows the Organization for Economic Co-operation and Development (OECD) guideline 423.

Results

The results demonstrated that the studied molecule protects against LPS-induced inflammation. We observed a decrease in the migration of total and differential leukocytes to the bronchoalveolar lavage fluid (BALF), in addition to a reduction in exudation, myeloperoxidase (MPO) activity, nitric oxide metabolites, and the secretion of pro-inflammatory cytokines (alpha tumor necrosis factors [TNF-α], interleukin-6 [IL-6], interferon-gamma [IFN-γ], and monocyte chemoattractant protein-1 [MCP-1]). Finally, aryl cyclohexanone did not show signs of acute oral toxicity (OECD 423).

Conclusions

The results prove our hypothesis that aryl-cyclohexanone is a promising molecule for developing a new, safe anti-inflammatory drug.

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关于芳基环己酮的抗炎作用和体内毒理学安全性的临床前证据。

背景：呼吸窘迫综合征是一种复杂的炎症，表现为急性低氧血症和细胞浸润，以及组织损伤（如急性肺损伤）后的弥漫性肺泡损伤。这种病理变化所涉及的炎症过程是机体对感染性病原体和/或组织损伤的一种防御机制。然而，如果病情得不到逆转，就会成为组织损伤的重要原因，有时甚至会导致受影响器官功能的丧失。因此，了解炎症的内在机制以及开发新的治疗药物以减少这些情况下的炎症损伤至关重要。芳基环己酮衍生物曾在体外显示出与免疫调节能力相关的显著抗炎活性，可能是炎症起核心作用的疗法的良好候选物：方法：在脂多糖（LPS）诱导的急性肺损伤小鼠模型中，评估了合成分子芳基环己酮的抗炎能力。对急性口服毒性的评估遵循了经济合作与发展组织（OECD）准则 423：结果表明，所研究的分子对 LPS 诱导的炎症有保护作用。除了减少渗出、髓过氧化物酶（MPO）活性、一氧化氮代谢物和髓过氧化物酶活性外，我们还观察到支气管肺泡灌洗液（BALF）中白细胞总数和差异性迁移的减少、一氧化氮代谢物，以及促炎细胞因子（α 肿瘤坏死因子 [TNF-α]、白细胞介素-6 [IL-6]、γ 干扰素 [IFN-γ] 和单核细胞趋化蛋白-1 [MCP-1]）的分泌。最后，芳基环己酮未显示出急性口服毒性迹象（OECD 423）：这些结果证明了我们的假设，即芳基环己酮是一种很有希望开发出新型安全消炎药的分子。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.