联合CB1拮抗剂AM6545和NOP激动剂SCH221510加重dss诱导的小鼠结肠炎。

IF 2.1 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Adam Fabisiak, Maria R Maryniak, Fabiana Piscitelli, Roberta Verde, Vincenzo Di Marzo, Marta Zielińska, Weronika Machelak, Ewa Małecka-Wojciesko
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引用次数: 0

摘要

背景:尽管肠道炎症有广泛的治疗选择,但由于当前治疗方法的有效性随着时间的推移而递减,开发新的治疗方法仍然是必不可少的。内源性大麻素系统(ECS)和痛感肽/孤儿蛋白FQ肽(NOP)受体都与肠道炎症相关疾病的发病机制有关,突出了它们作为治疗靶点的潜力。目的:我们假设大麻素受体1和2 (CB1和CB2)与NOP受体之间存在相互作用,这可能与结肠炎的治疗有关。材料和方法:本研究采用3种选择性配体:CB1拮抗剂(AM6545)、CB2拮抗剂(AM630)和NOP激动剂(SCH221510)对3%葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎模型进行治疗。利用western blot分析对几种次级信使蛋白进行定量分析。采用实时定量聚合酶链反应(qPCR)评估结肠组织中CB1的表达水平,采用液相色谱-质谱法(LC-MS)评估内源性大麻素及相关脂质介质的浓度。结果:我们观察到,与单独使用SCH221510治疗相比,AM6545和SCH221510治疗的炎症小鼠宏观评分有统计学意义的增加,微观评分无统计学意义的增加。此外,与仅使用sch221510治疗组相比,联合治疗组细胞外信号调节激酶1/2 (ERK1/2)水平显著降低,磷酸化蛋白激酶B (p-AKT)和β-阻滞蛋白水平显著升高。结论:我们的研究为ECS和NOP受体之间的相互作用提供了新的见解,这可能为结肠炎等炎症疾病的新治疗策略的发展提供信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Combined CB1 antagonist AM6545 and NOP agonist SCH221510 worsen DSS-induced colitis in mice.

Background: Despite the broad range of treatment options available for intestinal inflammation, the development of novel therapeutics remains essential due to the diminishing effectiveness of current therapies over time. Both the endocannabinoid system (ECS) and nociceptin/orphanin FQ peptide (NOP) receptors have been implicated in the pathogenesis of diseases associated with intestinal inflammation, highlighting their potential as therapeutic targets.

Objectives: We hypothesized that an interaction exists between cannabinoid receptors 1 and 2 (CB1 and CB2) and the NOP receptor, which may hold therapeutic relevance for the treatment of colitis.

Material and methods: In this study, we used 3 selective ligands: a CB1 antagonist (AM6545), a CB2 antagonist (AM630) and a NOP agonist (SCH221510) in a mouse model of colitis induced by 3% dextran sulfate sodium (DSS). Quantification of several secondary messengers was conducted using western blot analysis. Real-time quantitative polymerase chain reaction (qPCR) was employed to assess CB1 expression levels in colonic tissue, while liquid chromatography-mass spectrometry (LC-MS) was used to evaluate the concentrations of endocannabinoids and related lipid mediators.

Results: We observed a statistically significant increase in the macroscopic score and a nonsignificant increase in the microscopic score in inflamed mice treated with both AM6545 and SCH221510 compared to those treated with SCH221510 alone. Additionally, the combination-treated group exhibited significantly lower levels of extracellular signal-regulated kinases 1/2 (ERK1/2) and significantly higher levels of phosphorylated protein kinase B (p-AKT) and β-arrestin relative to the SCH221510-only group.

Conclusions: Our study offers novel insights into the interaction between the ECS and the NOP receptor, which may inform the development of new therapeutic strategies for inflammatory conditions such as colitis.

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来源期刊
Advances in Clinical and Experimental Medicine
Advances in Clinical and Experimental Medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.70
自引率
4.80%
发文量
153
审稿时长
6-12 weeks
期刊介绍: Advances in Clinical and Experimental Medicine has been published by the Wroclaw Medical University since 1992. Establishing the medical journal was the idea of Prof. Bogumił Halawa, Chair of the Department of Cardiology, and was fully supported by the Rector of Wroclaw Medical University, Prof. Zbigniew Knapik. Prof. Halawa was also the first editor-in-chief, between 1992-1997. The journal, then entitled "Postępy Medycyny Klinicznej i Doświadczalnej", appeared quarterly. Prof. Leszek Paradowski was editor-in-chief from 1997-1999. In 1998 he initiated alterations in the profile and cover design of the journal which were accepted by the Editorial Board. The title was changed to Advances in Clinical and Experimental Medicine. Articles in English were welcomed. A number of outstanding representatives of medical science from Poland and abroad were invited to participate in the newly established International Editorial Staff. Prof. Antonina Harłozińska-Szmyrka was editor-in-chief in years 2000-2005, in years 2006-2007 once again prof. Leszek Paradowski and prof. Maria Podolak-Dawidziak was editor-in-chief in years 2008-2016. Since 2017 the editor-in chief is prof. Maciej Bagłaj. Since July 2005, original papers have been published only in English. Case reports are no longer accepted. The manuscripts are reviewed by two independent reviewers and a statistical reviewer, and English texts are proofread by a native speaker. The journal has been indexed in several databases: Scopus, Ulrich’sTM International Periodicals Directory, Index Copernicus and since 2007 in Thomson Reuters databases: Science Citation Index Expanded i Journal Citation Reports/Science Edition. In 2010 the journal obtained Impact Factor which is now 1.179 pts. Articles published in the journal are worth 15 points among Polish journals according to the Polish Committee for Scientific Research and 169.43 points according to the Index Copernicus. Since November 7, 2012, Advances in Clinical and Experimental Medicine has been indexed and included in National Library of Medicine’s MEDLINE database. English abstracts printed in the journal are included and searchable using PubMed http://www.ncbi.nlm.nih.gov/pubmed.
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