Molecular Indicators of Blood-Brain Barrier Breakdown and Neuronal Injury in Pregnancy Complicated by Fetal Growth Restriction

Abstract

This study evaluated the damage to the endothelial tight junctions (TJs) in pregnancies complicated by fetal growth restriction (FGR) and investigated whether FGR is related to blood–brain barrier disintegration and, subsequently, to the appearance of proteins indicative of neuronal injury in maternal blood. The studied group included 90 pregnant women diagnosed with FGR. The control group consisted of 70 women with an uncomplicated pregnancy. The biochemical measurements included serum neuronal proteins (subunit of the N-methyl-D-aspartate receptor—NR1, nucleoside diphosphate kinase A—NME1, and S100 calcium-binding protein B—S100B), serum TJ proteins (occludin—OCLN, claudin-5—CLN5, zonula occludens—zo-1, and OCLN/zo-1 and CLN5/zo-1 ratios), and placental expression of TJ proteins (OCLN, claudin-4 CLN4, CLN5, zo-1). The significantly higher serum S100B and CLN5 levels and serum CLN5/zo-1 ratio were observed in FGR compared to healthy pregnancies. Moreover, FGR was characterized by increased placental CLN5 expression. Both serum NME1 levels and placental CLN4 expression in FGR pregnancies were significantly related to the incidence of neurological disorders in newborns. Mothers of FGR neonates who developed neurological complications and intraventricular hemorrhage (IVH) had statistically higher NME1 concentrations during pregnancy and significantly lower placental CLN4 expression than mothers of FGR neonates without neurological abnormalities. The serum NME1 levels and placental CLN4 expression were predictive markers of IVH in the FGR group. The blood–brain barrier is destabilized in pregnancies complicated by FGR. Neurological disorders, including IVH, are associated with higher serum concentrations of NME1 and the decreased placental expression of CLN4. The serum NME1 levels and placental CLN4 expression may serve as biomarkers, helpful in predicting IVH in FGR. It may allow for more precise monitoring and influence decision-making on the optimal delivery time to avoid developing neurological complications.

Regulators involved in trophoblast syncytialization in the placenta of intrauterine growth restriction

“…In contrast, Misan et al. reported that ZO-1 levels in both serum and placentas showed no significant difference between IUGR and control groups ( 75 ). Although recent study findings suggest that ZO-1 participates in the trophoblast syncytialization process, there is not sufficient evidence to prove that the occurrence of IUGR is related to the syncytialization deficiency caused by abnormal expression of ZO-1, which may be a new direction for future research.…”

Neural and Onconeural Autoantibodies and Blood–Brain Barrier Disruption Markers in Patients Undergoing Radiotherapy for High-Grade Primary Brain Tumour

“…TJ proteins are the main components of tight junctions between the brain endothelial cells that are crucial to maintaining BBB integrity. Previous studies have shown that these proteins are present in patients with BBB disruption [40][41][42][43]. One study [43] found that OCLN expression in the brain vascular endothelium was significantly higher than in the non-nervous tissue vascular endothelium, which explains why BBB permeability is significantly lower than in other blood tissue barriers.…”

Pathogenesis of Pregnancy-Related Complications

“…Misan et al [ 12 ] described the destabilization of the blood–brain barrier in pregnancies complicated by fetal growth restriction. Neurological disorders in newborns, including intraventricular hemorrhage, were associated with higher serum levels of NME1, nucleoside diphosphate kinase A, and the decreased placental expression of CLN4.…”