Dimethyl fumarate possesses antiplatelet and antithrombotic properties.
Dimethyl fumarate possesses antiplatelet and antithrombotic properties.
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DOI：
10.1016/j.intimp.2023.110381
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发表时间：
2023-05
影响因子：
5.6
通讯作者：
X. Chu;J Zhang;Y. Li;Ke Yuan;Xue Wang;X. Gui;Yueyue Sun;Chaonan Geng;Wen Ju;Mengdi Xu-Mengdi
中科院分区：
文献类型：
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作者：
X. Chu;J Zhang;Y. Li;Ke Yuan;Xue Wang;X. Gui;Yueyue Sun;Chaonan Geng;Wen Ju;Mengdi Xu-Mengdi
背景富马酸二甲酯（Dimethyl fumarate，DMF）是富马酸的一种甲酯，因其抗炎作用而被批准用于治疗多发性硬化症（multiple sclerosis，MS）和银屑病。血小板与MS的发病机制密切相关。DMF是否影响血小板功能尚不清楚。我们的研究旨在评估DMF对血小板function.Methodswashed人血小板处理不同浓度的DMF（0，50，100和200 μM）在37 °C下1小时，然后通过分析血小板聚集，颗粒释放，受体表达，扩展和凝块收缩。此外，小鼠腹腔注射DMF（15 mg/kg），以评估尾部出血时间，动脉和静脉thrombosis.ResultsDMF显着抑制血小板聚集和释放致密/α颗粒响应胶原相关肽（CRP）或凝血酶刺激剂量依赖性不改变血小板受体αIIbβ3，GPIbα，和GPVI的表达。此外，DMF处理的血小板在胶原蛋白或纤维蛋白原上的铺展和凝血酶介导的凝块收缩显著减少沿着c-Src和PLCγ2的磷酸化水平降低。此外，小鼠给予DMF显著延长了尾部出血时间，并损害了动脉和静脉血栓形成。结论DMF可抑制血小板功能和动、静脉血栓形成，并可抑制NF-κB的活化和ERK 1/2、p38和AKT的磷酸化。考虑到MS中存在血栓形成事件，我们的研究表明，MS患者的DMF治疗可能获得抗炎和抗血栓形成获益。
BackgroundDimethyl fumarate (DMF) is a methyl ester of fumaric acid and has been approved for treating multiple sclerosis (MS) and psoriasis due to anti-inflammatory effect. There is a close association between platelets and the pathogenesis of MS. Whether DMF affects platelet function remains unclear. Our study intends to evaluate DMF’s effect on platelet function.MethodsWashed human platelets were treated with different concentrations of DMF (0, 50, 100 and 200 μM) at 37 °C for 1 h followed by analysis of platelet aggregation, granules release, receptors expression, spreading and clot retraction. In addition, mice received intraperitoneal injection of DMF (15 mg/kg) to assess tail bleeding time, arterial and venous thrombosis.ResultsDMF significantly inhibited platelet aggregation and the release of dense/alpha granules in response to collagen-related peptide (CRP) or thrombin stimulation dose-dependently without altering the expression of platelet receptors αIIbβ3, GPIbα, and GPVI. In addition, DMF-treated platelets presented significantly reduced spreading on collagen or fibrinogen and thrombin-mediated clot retraction along with the decreased phosphorylation of c-Src and PLCγ2. Moreover, administration of DMF into mice significantly prolonged the tail bleeding time and impaired arterial and venous thrombus formation. Furthermore, DMF reduced the generation of intracellular reactive oxygen species and calcium mobilization, and inhibited NF-κB activation and the phosphorylation of ERK1/2, p38 and AKT.ConclusionDMF inhibits platelet function and arterial/venous thrombus formation. Considering the presence of thrombotic events in MS, our study indicates that DMF treatment for patients with MS might obtain both anti-inflammatory and anti-thrombotic benefits.