Effects of Danshensu on maternal syndrome in phosphatidylserine/phosphatidylcholine microvesicle induced-mouse model: is it a candidate for preeclampsia remedy?
BACKGROUND
Up to date, there is few satisfactory pharmacotherapy, except for aspirin and heparin, to stop the preeclampsia progression. Although the mechanism of preeclampsia is poorly understood, it has been proven to be associated with coagulation activation. Researches on prophylactic and therapeutic application of anticoagulants may benefit the clinical aspects of preeclampsia individuals. This study aimed to evaluate the effects of Danshensu on maternal syndrome in phosphatidylserine/phosphatidylcholine (PS/PC) microvesicle induced-mouse model.


METHODS
Sixty-six preeclampsia-like pregnant mice, induced by PS/PC microvesicle administration, were randomly divided into six groups. From days 5.5 to 16.5 of pregnancy, each group was respectively treated as follows: a) mice in group C (n = 12, control group) were injected with 100 microl of filtered phosphate-buffered saline into the tail vein every day; b) group PE (n = 15, preeclampsia model group) were injected in the same way with 100 microl of filtered PS/PC vesicle suspension; c) group H (n = 9, group treated with heparin) were injected with 1 unit heparin together with PS/PC vesicle suspension; d) group A (n = 10, group treated with aspirin) were injected with 20 microg/g aspirin-DL lysine as well; e) group LD (n = 10, group treated with low-dose Danshensu) were injected with 10 microg/g Danshensu; and f) group HD (n = 10, group treated with high-dose Danshensu) were injected with 30 microg/g Danshensu. Systolic blood pressure, total urinary protein levels, blood tests for some hemostatic function parameters (mean platelet counts, plasma antithrombin III activity (AT-III), D-D dimmer levels, and thrombin time), fibrin deposition by phosphotungstic acid hematoxylin staining, and thrombomodulin expression by immunohistochemistry staining in placentas were examined as indices for maternal syndrome.


RESULTS
Heparin showed significant effects on maternal syndrome of preeclampsia such as hypertension and proteinuria, and different doses of Danshensu also presented the certain effects. High-dose Danshensu and aspirin all demonstrated better effects than low-dose Danshensu on decreasing blood pressure to normal level, while high-dose Danshensu demonstrated better effects than aspirin and low-dose Danshensu on decreasing proteinuria to normal level. As to Danshensu's effects on hemostatic function, high- and low-dose Danshensu's marked effects on increasing the plasma AT-III activity were the same as that of aspirin and inferior to that of heparin. High-dose Danshensu's better effect on elevating the platelet counts was superior to low-dose Danshensu and aspirin. Low-dose Danshensu's obvious effect on decreasing D-D levels was close to heparin and superior to high-dose Danshensu and aspirin. High- and low-dose Danshensu's significant effects on reduced thrombin time level are same to heparin. Different anticoagulants all played improvement roles in placental fibrin depositions, but heparin and high-dose Danshensu's roles on lowering thrombomodulin expression in placentas were superior to low-dose Danshensu and aspirin. However, anticoagulant function of high-dose Danshensu was still inferior to heparin. We found long-term use of heparin and aspirin, in spite of low-dose administration, could raise the risk of bleeding such as placental abruption and intestinal hemorrhage. But no any side effect was observed in mice treated with different doses of Danshensu in our study.


CONCLUSIONS
Danshensu has proven to be effective and safe in ameliorating the prognosis of maternal syndrome in a preeclampsia mouse model. We suggest long-term provision of low-dose Danshensu in pregnancy, leading to an improvement of preeclampsia syndrome with considerable maternal safety.
Shen
Yang
Y
Department of Obstetrics and Gynecology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, China.
Hu
Ya-Li
YL
Zhang
Yan
Y
Wang
Jing-Mei
JM
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006493:Heparin / Q000627:therapeutic use; D007773:Lactates / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D010713:Phosphatidylcholines / Q000009:adverse effects*; D010718:Phosphatidylserines / Q000009:adverse effects*; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000139:chemically induced* / Q000517:prevention & control*; D011247:Pregnancy; D011897:Random Allocation; D018180:Thrombomodulin / Q000378:metabolism
D000925:Anticoagulants; D007773:Lactates; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D018180:Thrombomodulin; C035055:3,4-dihydroxyphenyllactic acid; D006493:Heparin; D001241:Aspirin