The protective effect of magnesium sulfate on placental inflammation via suppressing the NF-κB pathway in a preeclampsia-like rat model

Preeclampsia is a common and severe complication of pregnancy characterized by new onset arterial hypertension, proteinuria presenting at or after 20 weeks of gestation, and multiorgan dysfunction including renal damage, liver failure, and neurological abnormalities [1]. Globally, this disorder affects an estimated 5–8% of pregnancies and is an important cause of maternal and neonatal morbidity and mortality [2]. Specifically, severe preeclampsia is responsible for an estimated 38% of maternal deaths among obstetric admissions to the ICU [3].

The precise etiology of preeclampsia remains to be elucidated, but may be explained by dysfunction of trophoblast cells, insufficient remodeling of the uteroplacental spiral arteries, damage to the vascular endothelium, oxidative stress, and the maternal inflammatory response [4]. Interactions between trophoblasts and decidual immune cells, including decidual natural killer (dNK) cells, decidual macrophages (DMs) and decidual T cells regulate trophoblast invasion, vasculogenesis, spiral artery remodeling and immune tolerance [5]. Defects in trophoblast invasion and /or aberrant interactions between trophoblasts and decidual immune cells can alter placental vasculature and restrict placental blood flow. This results in decreased uteroplacental perfusion, damage to the vascular endothelium, microangiopathic thrombosis, oxidative stress, and the activation of multiple maternal inflammatory pathways that contribute to the development of preeclampsia and can exacerbate symptoms [6].

There is an unmet need to explore the role of abnormal maternal inflammation in the pathophysiology of preeclampsia and the possibility of targeting aberrant maternal inflammation as a therapeutic intervention. Clinically, exaggerated activation of maternal inflammatory responses in preeclampsia is evidenced by elevated levels of pro-inflammatory mediators in the blood, including IL-1β, IL-6, IL-8 and TNF-α [7]. TNF-α, IL-6 and MCP-1 levels are increased and TGF-β and IL-10 levels are decreased in placental tissues from patients with preeclampsia compared to normal controls [8], [9], [5]. Our previous research in a rat model of preeclampsia showed pro-inflammatory cytokines exacerbate maternal endothelial dysfunction, impacting multiple organs, and resulting in abnormal pregnancy outcomes [10], [11].

Currently, the only recommended treatment for preeclampsia is delivery of the fetus and placenta. Magnesium sulfate (MgSO4) is considered effective for treating and preventing seizures in women with preeclampsia [12]. By 1929, at one hospital, intramuscular injection of MgSO4 had effectively reduced maternal mortality in preeclampsia from 36% to 7% [13]. Magnesium is an essential element that acts as a cofactor of numerous essential metabolic reactions. Mg deficiency evokes systemic inflammation through several mechanisms, including inhibition of Ca2+ channel opening, activation of phagocytic cells, dysregulation of anti-inflammatory mediators, and upregulation of pro-inflammatory cytokines [14]. Although it is unknown the exact mechanism of the beneficial effects of MgSO4, previous studies supported its anti-inflammatory role. In animal models of endotoxin-induced preterm labor, antenatal MgSO4 injection significantly decreased pro-inflammatory mediator (TNF-α, IL-6) and chemokine (MCP-1, GRO-KC) levels in the maternal and fetal compartments [15]. In our previous research, in a rat model of eclampsia-like seizure, MgSO4 supplementation had anti-neuroinflammatory properties and a neuroprotective effect [11]. In an ex vivo human placental perfusion model, there was an increased secretion of IL-6 into the fetal and maternal circulations of pre-eclamptic placentas compared to placentas from normotensive pregnancies, which was attenuated by MgSO4 [16].

MgSO4 represents a potential therapeutic intervention that targets inflammation to prevent preeclampsia pathogenesis and disease progression. Still, the mechanism of action remains poorly understood. The objective of this study was to investigate the effects of MgSO4 on placental inflammation in a rat model of lipopolysaccharide (LPS)-induced preeclampsia.

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