Favorable maternal and fetal effects of danshensu in an experimental mice model of preeclampsia.
BACKGROUND
Preeclampsia is a serious pregnancy-specific complication that results in high maternal and neonatal mortality and morbidity worldwide. Till date, there is no satisfactory pharmacotherapeutic treatment, except for aspirin and heparin, to stop the preeclampsia progression. Although the mechanism of preeclampsia is poorly understood, it has proved to be associated with coagulation activation. Researches on prophylactic and remedial application of anticoagulants maybe benefit the clinical aspects of preeclampsia individuals.


METHODS
Sixty-six preeclampsia-like pregnant mice, induced by phosphatidyleserine/phosphatidylcholine (PS/PC) microvesicle administration, were randomly divided into six groups as follows: control group (group C), preeclampsia model group (group PE), group treated with heparin (group H), group treated with aspirin (group A), group treated with low-dose danshensu (group LD), and group treated with high-dose danshensu (group HD). Systolic blood pressure (SBP), proteinuria, mean platelet counts, plasma antithrombin III activity (AT III), D-dimmer levels, thrombin time (TT), fibrin deposition with phosphotungstic acid hematoxylin (PTAH) staining, and thrombomodulin (TM) expression with immunohistochemistry staining in placentas were examined as indices for maternal syndrome. Meanwhile, the number of potentially viable fetuses, weight of fetuses and placentas, weight of fetal brains, nose-breech length, ponderal index (PI), and neurons with hematoxylin-eosin (H/E) and toluidine blue-eosin (Nissl's) staining were all evaluated as indices for fetal syndrome.


RESULTS
Heparin presents significant effects on maternal syndrome of preeclampsia such as hypertension and proteinuria, and different dose danshensu also presents the certain effects. High-dose danshensu and aspirin all process better effects than low-dose danshensu on decreasing blood pressure to normal level, whereas high-dose danshensu process 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 are same as that of aspirin and inferior to heparin. High-dose danshensu's better effect on elevating the platelet counts is superior to low-dose danshensu and aspirin. Low-dose danshensu's obvious effect on decreasing D-dimmer levels is close to heparin and superior to high-dose danshensu and aspirin. High- and low-dose danshensu's significant effects on reduced TT level are same to that of heparin. Different anticoagulants all have the improvement roles on placental fibrin depositions, but heparin and high-dose danshensu's roles on lowering thrombomodulin expression in placentas are superior to low-dose danshensu and aspirin. But anticoagulant function of high-dose danshensu is still inferior to heparin. Furthermore, we found the following changes: increasing fetal body weight and length in every group, obvious overall improvement in group H, greater amelioration equaling to that in heparin group on maternal body weight, fetal nose-breech length and fetal brain weight in group HD, better changes on survival fetal number in group LD than in other groups, and more corrected brain development in group HD than in group A. We found long-term use of heparin and aspirin, in spite of low-dose administration, can raise the risk of bleeding such as placental abruption and intestinal hemorrhage. But no side effect was observed in mice treated with different dose of danshensu in our study.


CONCLUSIONS
Danshensu has proven effective in ameliorating the prognosis of maternal syndrome and fetal syndrome in the PE mouse model. We suggest long-term provision of low-dose danshensu in pregnancy, leading to an improvement of preeclampsia syndrome with considerable maternal safety.
Obstetrics and Gynecology Department, Southeast University Affiliated Zhongda Hospital, Nanjing, China.
Yang
Y
Shen
Yali
Y
Hu
Yan
Y
Zhang
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005333:Fetus / Q000187:drug effects; D006493:Heparin / Q000627:therapeutic use; D007773:Lactates / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D010920:Placenta / Q000187:drug effects; D011225:Pre-Eclampsia; D011247:Pregnancy
D000925:Anticoagulants; D004365:Drugs, Chinese Herbal; D007773:Lactates; C035055:3,4-dihydroxyphenyllactic acid; D006493:Heparin; D001241:Aspirin