Effect of edaravone on pregnant mice and their developing fetuses subjected to placental ischemia

Marwa Atallah,Toru Yamashita,Koji Abe

doi:10.1186/s12958-021-00707-2

Abstract

Growing evidence indicates that reduced uterine perfusion pressure (RUPP) triggers the cascade of events leading to preeclampsia. Edaravone is a powerful free radical scavenger used for the treatment of ischemia/reperfusion diseases due to its anti-oxidative stress and anti-inflammatory properties. Here we investigate the effect of edaravone (3 mg/kg) on different maternal and fetal outcomes of RUPP-induced placental ischemia mice model. RUPP surgery was performed on gestation day (GD) 13 followed by edaravone injection from GD14 to GD18, sacrifice day. The results showed that edaravone injection significantly decreased the maternal blood pressure (113.2 ± 2.3 mmHg) compared with RUPP group (131.5 ± 1.9 mmHg). Edaravone increased fetal survival rate (75.4%) compared with RUPP group (54.4%), increased fetal length, weights, and feto-placental ratio (7.2 and 5.7 for RUPP and RUPP-Edaravone groups, respectively) compared with RUPP group. In addition, RUPP resulted in many fetal morphological abnormalities as well as severe delayed ossification, however edaravone decreased the morphological abnormalities and increased the ossification of the fetal endoskeleton. Edaravone improved the histopathological structure of the maternal kidney and heart as well as decreased the elevated blood urea and creatinine levels (31.5 ± 0.15 mg/dl (RUPP), 25.6 ± 0.1 mg/dl (RUPP+edaravone) for urea and 5.4 ± 0.1 mg/dl (RUPP), 3.5 ± 0.1 mg/dl (RUPP+edaravone) for creatinine) and decreased cleaved caspase-3 expression in the maternal kidney. In conclusion, this study demonstrated that our RUPP mice model recapitulated preeclampsia symptoms and edaravone injection ameliorated most of these abnormalities suggesting its effectiveness and potential application in preeclampsia treatment regimes.

Highlights

Reduced placental blood flow leads to placental ischemia, an initiating event in the pathophysiology of preeclampsia [11]
It has been reported that reduced uterine perfusion pressure (RUPP) model is a model of oxidative stress observed during preeclampsia [40]
Injection of edaravone to RUPP pregnant mice resulted in an increase in their body weight and recovery of the initial body weight loss, though still lower than the values of SV group (Fig. 2a, Table 1S) with a final net weight increase of 8.6 at the end of the experiment (Fig. 2b, Table 2S)

Summary

Introduction

Reduced placental blood flow leads to placental ischemia, an initiating event in the pathophysiology of preeclampsia [11]. The pathogenesis of preeclampsia is related to trophoblast invasion suppression leading to incomplete spiral artery remodeling and decreased blood flow to the placenta (Stage 1 of preeclampsia) which. The reduced uterine perfusion pressure (RUPP) model is a well-characterized animal model of preeclampsia [11, 27, 32] which has been reported to manifest symptoms related to preeclampsia such as increased maternal blood pressure, increased serum sFlt-, proteinuria, endotheliosis and decreased fetal weight [17, 23]. It has been reported that RUPP model is a model of oxidative stress observed during preeclampsia [40]. Ushida et al [50] reported that the administration of H2, a novel antioxidant, improved the placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress

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