Article

Pharmacological actions of miltirone in the modulation of platelet function

Authors: Wei Song1,2, Yuan-yuan Ma1,2, Shuo Miao1,2, Ru-ping Yang1,2, Ying Zhu1,2, Dan Shu1,2, Meng Lu1,2, Rong Ma1,2, Zhang-yin Ming1,2,3
1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China
2 The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, 13Hangkong Road, Wuhan 430030, China
3 The Institute of Brain Research, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan 430030, China
Correspondence to: Zhang-yin Ming: zyming@hust.edu.cn,
DOI: 10.1038/s41401-018-0010-1
Received: 4 October 2017
Accepted: 25 January 2018
Advance online: 23 May 2018

Abstract

Salvia miltiorrhiza Bunge contains various active constituents, some of which have been developed as commercially available medicine. Moreover, some other ingredients in Salvia miltiorrhiza play roles in anti-platelet activity. The aim of the present study was to investigate the effects and the underlying mechanism of miltirone, a lipophilic compound of Salvia miltiorrhiza Bunge. The ability of miltirone to modulate platelet function was investigated by a variety of in vitro and in vivo experiments. Platelet aggregation and dense granule secretion induced by various agonists were measured with platelet aggregometer. Clot retraction and spreading were imaged by digital camera and fluorescence microscope. Ferric chloride-induced carotid injury model and pulmonary thromboembolism model were used to check miltirone antithrombotic effect in vivo. To elucidate the mechanisms of anti-platelet activity of miltirone, flow cytometry and western blotting were performed. Miltirone (2, 4, 8 µM) was shown to suppress platelet aggregation, dense granule, and α granule secretion in a dose-dependent manner. Meanwhile, miltirone inhibited the clot retraction and spreading of washed platelets. It reduced the phosphorylation of PLCγ2, PKC, Akt, GSK3β and ERK1/2 in the downstream signal pathway of collagen receptor. It also reduced the phosphorylation of Src and FAK in the integrin αIIbβ3-mediated “outside-in” signaling, while it did not suppress the phosphorylation of β3. In addition, miltirone prolonged the occlusion time and reduced collagen/epinephrine-induced pulmonary thrombi. Miltirone suppresses platelet “inside-out” and “outside-in” signaling by affecting PLCγ2/PKC/ERK1/2, PI3K/Akt, and Src/FAK signaling. Therefore, miltirone might represent a potential anti-platelet candidate for the prevention of thrombotic disorders.
Keywords: miltirone; anti-platelet; glycoprotein VI pathway; integrin αIIbβ3

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