Long-term impact of intrauterine neuroinflammation and treatment with magnesium sulphate and betamethasone: Sex-specific differences in a preterm labor murine model

Abstract

Preterm infants are at significantly increased risk for lifelong neurodevelopmental disability with male offspring disproportionately affected. Corticosteroids (such as betamethasone) and magnesium sulphate (MgSO4) are administered to women in preterm labor to reduce neurologic morbidity. Despite widespread use of MgSO4 in clinical practice, its effects on adult offspring are not well known nor have sex-specific differences in therapeutic response been explored. The objective of our study was to examine the long-term effects of perinatal neuroinflammation and the effectiveness of prenatal MgSO4/betamethasone treatments between males and females in a murine model via histologic and expression analyses. Our results demonstrate that male but not female offspring exposed to intrauterine inflammation demonstrated impaired performance in neurodevelopmental testing in early life assessed via negative geotaxis, while those exposed to injury plus treatment fared better. Histologic analysis of adult male brains identified a significant reduction in hippocampal neural density in the injured group compared to controls. Evaluation of key neural markers via qRT-PCR demonstrated more profound differences in gene expression in adult males exposed to injury and treatment compared to female offspring, which largely showed resistance to injury. Prenatal treatment with MgSO4/betamethasone confers long-term benefits beyond cerebral palsy prevention with sex-specific differences in response.

The orphan nuclear receptor Nr4a1 mediates perinatal neuroinflammation in a murine model of preterm labor

“…2-5, 7a, b) support the notion that Nr4a1 ablation does not influence normal development. However, with the addition of an inflammatory instigator there are significant changes that may cause neurodevelopmental deficiencies noted in postnatal animals 36 .…”

“…PCR reactions were conducted with SYBR Green on a Light Cycler 480 II system (both from Roche, Indianapolis, IN, USA). Reactions were performed in triplicate for each gene sample using the following conditions: 95°C × 5 min, then 40 cycles at 95°C × 10 s, 60°C ×10 s, and 72°C × 10 s. The relative expression of each respective target was calculated by ΔCt, normalizing to ribosomal protein 18 s 35,36 . Primer sequences for Foxd1 were generated using NCBI primer-BLAST 37 .…”

Genetic inhibition of PKCε attenuates neurodegeneration after global cerebral ischemia in male mice

“…Male co‐housed Prkce +/+ and Prkce −/− littermates between 2 and 4 months of age were used for the experiments. The decision to use male mice was based on the evidence that sexual dimorphism occurs for cerebral ischemia (Hanamsagar & Bilbo, ; Spychala, Honarpisheh, & McCullough, ; Thagard et al, ). Female mice exhibit attenuated ischemic brain injury as compared to male mice.…”

Protection of brain development by antenatal magnesium sulphate for infants born preterm

“…In a murine model of perinatal neuroinflammation, long‐term sex‐specific benefits were observed in magnesium sulphate/betamethasone‐treated cases relative to a placebo group. The sex‐specific effect favoured males; a minimal injury causing a greater alteration to gene control among females, or a heightened susceptibility to magnesium or betamethasone among males, may account for the sex‐specific discrepancy . Magnesium sulphate can also prevent excitotoxic glutaminergic cell death induced by excess intracellular calcium.…”

“…The sex-specific effect favoured males; a minimal injury causing a greater alteration to gene control among females, or a heightened susceptibility to magnesium or betamethasone among males, may account for the sex-specific discrepancy. 18 Magnesium sulphate can also prevent excitotoxic glutaminergic cell death induced by excess intracellular calcium. The latter is related to a decrease in presynaptic glutamate release: magnesium attaches to an intrachannel site on the N-methyl-Daspartate glutamate receptor, inducing a potentiation of presynaptic adenosine receptors, or a noncompetitive blockade of voltage-gated calcium channels.…”