Protective effects of hydrogen-rich saline in preeclampsia rat model

Abstract

Hydrogen has been reported as a novel antioxidant to selectively reduce levels of toxic reactive-oxygen species (ROS). We investigated the effects of hydrogen-rich saline on the prevention of oxidative injuries in N(omega)-nitro-l-arginine methyl ester (l-NAME) induced rat model of preeclampsia (PE). Sprague–Dawley rats (n = 50) were randomized into five groups: non-pregnant; normal pregnancy; pregnancy + hydrogen saline, 5 ml/kg, intraperitoneal (i.p.); pregnancy + l-NAME, 60 mg/kg (i.p.); pregnancy + l-NAME + hydrogen saline rats. Terminations of pregnancy were performed on day 22 of gestation, when the placentas and kidneys were microscopically inspected; tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and malonyldialdehyde (MDA) were assessed; and the mean systolic BP, level of proteinuria, resorptions, and pups birth weights were recorded. It was found that the pups of hypertensive gravid rats treated with hydrogen-rich saline presented fewer number of resorptions than those of the group of pregnancy + l-NAME, 60 mg/kg i.p. (P < 0.05). Additionally, hydrogen-rich saline treatment decreased the blood and placental MDA, proteinuria and the pro-inflammatory cytokine TNF-α, IL-1β in the placental tissues compared with those in L-NAME-treated rats (all P < 0.05). The mean systolic BP showed no significant difference except on day 22 of gestation (P < 0.05). The preventive administration of hydrogen significantly attenuated the severity of PE, which might be ascribed to a reduction in inflammation response and oxidative stress. It could be concluded that hydrogen can be an effective antioxidant in the management of PE.

Introduction

Preeclampsia (PE) is estimated to affect 5–8% of all pregnancies, as the leading cause of death and a major contributor to maternal and fetal morbidity and mortality in the developing countries. The pathogenesis of PE is not completely known, but growing evidence of the endothelial dysfunction suggests that the disease results from systemic inflammatory reaction to apoptotic or necrotic debris shed to maternal blood from the placenta [1]. Recently, accumulated evidence indicates that generation of placental oxidative stress, secondary to deficient spiral artery remodeling, is a key intermediary event triggering the secretion of a mixture of placental factors that culminate in an enhanced maternal inflammatory response [2].

Several attempts were made to prevent PE via antioxidant therapy [3], [4], [5], [6], [7], but the question remains as to whether exogenous antioxidant such as vitamin C and E provides beneficial effects in the prevention of PE. Some studies observed positive results [3], [4], [8], [9] but others failed to support routine antioxidant supplementation during pregnancy to reduce the risk of PE [5], [6], [10], possibly because of such barriers to the utilization of exogenous antioxidant as low membrane permeability and high toxicity, which thus constrain the administration of supplementants to a narrow window of therapeutic dosage [11]. Therefore, it is imperative that more effective and safer antioxidants be demanded for PE.

Recently, molecular hydrogen (dihydrogen, H₂) saturated physiological saline, called hydrogen-rich saline, was proposed as a novel antioxidant that selectively reduces levels of toxic reactive-oxygen species such as hydroxyl radicals (OH) without affecting the other signal ROS [12]. Many studies have reported that H₂ can exert beneficial effects in diverse animal models of oxidative stress including ischemia-reperfusion (I/R) [13], inflammation [14] and neurological disease [15], proposing that H₂ possesses potential as an antioxidant for preventive and therapeutic applications. Therefore, we investigated whether administration of hydrogen-rich saline would exert protective effects in an N (omega)-nitro-l-arginine methyl ester (l-NAME) induced PE rat model.