Phlorotannins from edible marine seaweed Ecklonia stolonifera disrupt USP5-Cav3.2 calcium channel interactions and reverse chronic inflammatory pain

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-06-10 DOI:10.1016/j.taap.2025.117440

Md Yousof Ali , Vinicius M. Gadotti , Flavia T.T. Antunes , Agustin Garcia-Caballero , Hyun Ah. Jung , Jae Sue Choi , Gerald W. Zamponi

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引用次数: 0

Abstract

Ecklonia stolonifera is an edible marine seaweed that contains a high amount of phlorotannins, including phlorofucofuroeckol A (PFFA) and dieckol that have a range of pharmacologic effects. Here we report that these two phlorotannins block the interactions between the deubiquitinase USP5 and the Cav3.2 T-type calcium channel which we previously identified as a unique molecular target for pain. PFFA and dieckol delivered intrathecally (10 μg/i.t.) or intragastrically (30 mg/kg, p.o.) inhibited both phases of formalin-induced nocifensive behaviors and eliminated thermal hyperalgesia in a chronic inflammatory pain model induced by administering complete Freund's adjuvant (CFA) to the hind paws of male and female mice. Dieckol but not PFFA lost its analgesic effects in Cav3.2 null mice treated with CFA, suggesting that Cav3.2 channels are not essential for the in vivo actions of PFFA, but are required for those exerted by dieckol. Overall, our results suggest that phlorotannins derived from edible marine seaweeds, particularly PFFA, could be a novel class of analgesics that target the Cav3.2/USP5 interaction.

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可食用海草Ecklonia stolonifera中的绿单宁破坏USP5-Cav3.2钙通道相互作用并逆转慢性炎性疼痛

绿藻（Ecklonia stolonifera）是一种可食用的海洋海藻，含有大量的绿藻素，其中包括具有一系列药理作用的间苯二酚a （PFFA）和二酚。在这里，我们报道了这两种紫单素阻断了去泛素酶USP5和Cav3.2 t型钙通道之间的相互作用，这是我们之前确定的疼痛的独特分子靶点。在用完全弗氏佐剂（CFA）诱导的慢性炎症性疼痛模型中，经鞘内（10 μg/ t）或灌胃（30 mg/kg, p.o）给药的PFFA和二聚氰胺均能抑制福尔马林诱导的两期伤害行为，并消除热痛觉过敏。在经CFA处理的Cav3.2缺失小鼠中，Dieckol而非PFFA失去了其镇痛作用，这表明Cav3.2通道不是PFFA体内作用所必需的，而是Dieckol发挥作用所必需的。总的来说，我们的研究结果表明，从可食用的海洋海藻中提取的叶绿素单宁，特别是PFFA，可能是一类针对Cav3.2/USP5相互作用的新型镇痛药。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.