Ali Md Yousof, Gadotti Vinicius M, Antunes Flavia T T, Garcia-Caballero Agustin, Jung Hyun Ah, Choi Jae Sue, Zamponi Gerald W
Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N4N1, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1, Canada; Zymedyne Therapeutics, Calgary, AB T2N4G4, Canada.
Department of Clinical Neurosciences, University of Calgary, Calgary, AB T2N4N1, Canada; School of Health Sciences, Graduate Program in Pharmaceutical Sciences, University of Vale do Itajaí (UNIVALI), Itajaí, SC, Brazil.
Toxicol Appl Pharmacol. 2025 Sep;502:117440. doi: 10.1016/j.taap.2025.117440. Epub 2025 Jun 10.
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.
匍枝马尾藻是一种可食用的海洋海藻，含有大量的间苯三酚单宁，包括具有一系列药理作用的岩藻呋喃间苯三酚A（PFFA）和二eckol。在此我们报告，这两种间苯三酚单宁可阻断去泛素化酶USP5与Cav3.2 T型钙通道之间的相互作用，我们之前将该通道确定为疼痛的独特分子靶点。鞘内注射（10μg/鞘内）或胃内给药（30mg/kg，口服）的PFFA和二eckol可抑制福尔马林诱导的伤害性防御行为的两个阶段，并消除在雄性和雌性小鼠后爪注射完全弗氏佐剂（CFA）诱导的慢性炎症性疼痛模型中的热痛觉过敏。在接受CFA治疗的Cav3.2基因敲除小鼠中，二eckol而非PFFA失去了其镇痛作用，这表明Cav3.2通道对于PFFA的体内作用并非必需，但对于二eckol发挥的作用是必需的。总体而言，我们的结果表明，源自可食用海洋海藻的间苯三酚单宁，尤其是PFFA，可能是一类靶向Cav3.2/USP5相互作用的新型镇痛药。
