Fetal Neuroprotective Strategies: Therapeutic Agents and Their Underlying Synaptic Pathways

Synaptic signaling is integral for proper brain function. During fetal development, exposure to inflammation or mild hypoxic-ischemic insult may lead to synaptic changes and neurological damage that impairs future brain function. Preterm neonates are most susceptible to these deleterious outcomes. Evaluating clinically used and novel fetal neuroprotective measures is essential for expanding treatment options to mitigate the short and long-term consequences of fetal brain injury. Magnesium sulfate is a clinical fetal neuroprotective agent utilized in cases of imminent preterm birth. By blocking N-methyl-D-aspartate receptors, magnesium sulfate reduces glutamatergic signaling, which alters calcium influx, leading to a decrease in excitotoxicity. Emerging evidence suggests that melatonin and N-acetyl-L-cysteine (NAC) may also serve as novel putative fetal neuroprotective candidates. Melatonin has important anti-inflammatory and antioxidant properties and is a known mediator of synaptic plasticity and neuronal generation. While NAC acts as an antioxidant and a precursor to glutathione, it also modulates the glutamate system. Glutamate excitotoxicity and dysregulation can induce perinatal preterm brain injury through damage to maturing oligodendrocytes and neurons. The improved drug efficacy and delivery of the dendrimer-bound NAC conjugate provides an opportunity for enhanced pharmacological intervention. Here, we review recent literature on the synaptic pathways underlying these therapeutic strategies, discuss the current gaps in knowledge, and propose future directions for the field of fetal neuroprotective agents

Development of prenatal biomarkers for the prediction of neurological impairment at early stages of life

El proyecto se enmarca en el área de la Medicina Materno-Fetal, un área de investigación emergente que ocupa un amplio lugar en Salud Pública, dado el impacto a corto y largo plazo las alteraciones producidas en vida fetal.La mejor comprensión de las causas responsables de los grandes síndromes obstétricos así como el estudio de biomarcadores nos permiten mejorar o prevenir eventos postnatales adversos.Nuestro proyecto se centra en tres de las patología más importantes que tienen lugar en la gestación, la restricción del crecimiento fetal, la amenaza de parto pretérmino y la encefalopatía neonatal, las cuales pueden condicionar importantes consecuencias neurológicas posnatales. La mejor comprensión de estas consecuencias nos permite establecer intervenciones específicas para cada problema y para cada población de alto riesgo.Nuestro grupo ha demostrado en estudios previos daño neuronal y alteraciones neurológicos en niños con retraso de crecimiento y en este proyecto demostramos como las anomalías de la retina, especialmente las células ganglionares complejas y las capas plexiformes internas (GCL-IPL), pueden ser consideradas como biomarcadorespotenciales del daño neuronal cerebral en la edad escolar en niños que nacieron con bajo peso al nacer.Además, este es el primer estudio que realiza una valoración del neurodesarollo en los niños de madres que sufrieron una amenaza de parto pretérmino durante el embarazo. Dentro de este proyecto también estudiamos algunos biomarcadores de inflamación y angiogénesis que podrían estar relacionados con la amenaza de parto pretérmino con el fin de tratar de descubrir los mecanismos biológicos responsables de esa patología . Nuestros resultados demuestran que patrones similares de expresión génica de inflamación y angiogénesis afectan tanto a los recién nacidos prematuros como a los recién nacidos a término que sufrieron una amenaza de parto prematuro. Además este episodio de amenaza de parto prematuro debe considerarse un factor de riesgo para alteración del desarrollo neurológico en la primera infancia. Este mejor conocimiento es realmente importante para prevenir y mejorar su manejo durante el embarazo.El retraso de crecimiento fetal y la "amenaza de parto prematuro" normalmente se consideran patologías benignas que no requieren ningún seguimiento. Sin embargo, nuestros estudios demuestran que estas patologías están asociadas a anormalidades en los tejidos neuronales de la retina y el cerebro y a alteraciones en el neurodesarrollo. Por eso consideramos importante la detección prenatal de estas patologías para promover un seguimiento postnatal específico que ayude en la focalización de las intervenciones educativas específicas. Finalmente, nuestro último objetivo fue detectar precozmente una de las patologías perinatales con las consecuencias más graves, la encefalopatía neonatal. Para ello, diseñamos un estudio que pretende analizar la capacidad de predicción de esa patología mediante un biomarcador: óxido nítrico sintasa 1 (NOS1). ) Nuestro estudio demostró que el NOS1 es un buen biomarcador para la identificación temprana de encefalopatía neonatal que se puede utilizar para su diagnóstico junto con las manifestaciones clínicas para mejorar la detección, lo que permite una mejor información pronostica y comenzar las intervenciones de forma más precoz.<br /

Umbilical Cord Blood NOS1 as a Potential Biomarker of Neonatal Encephalopathy

BackgroundThere are no definitive markers to aid in diagnosis of neonatal encephalopathy (NE). The purpose of our study was (1) to identify and evaluate the utility of neuronal nitric oxide synthase (NOS1) in umbilical cord blood as a NE biomarker and (2) to identify the source of NOS1 in umbilical cord blood.MethodsThis was a nested case–control study of neonates &gt;35 weeks of gestation. ELISA for NOS1 in umbilical cord blood was performed. Sources of NOS1 in umbilical cord were investigated by immunohistochemistry, western blot, ELISA, and quantitative PCR. Furthermore, umbilical cords of full-term neonates were subjected to 1% hypoxia ex vivo.ResultsNOS1 was present in umbilical cord blood and increased in NE cases compared with controls. NOS1 was expressed in endothelial cells of the umbilical cord vein, but not in artery or blood cells. In ex vivo experiments, hypoxia was associated with increased levels of NOS1 in venous endothelial cells of the umbilical cord as well as in ex vivo culture medium.ConclusionThis is the first study to investigate an early marker of NE. NOS1 is elevated with hypoxia, and further studies are needed to investigate it as a valuable tool for early diagnosis of neonatal brain injury

Feto-maternal trafficking of exosomes in murine pregnancy models

Timing and initiation of labor are well-orchestrated by signals communicated between the fetal and maternal compartments; however, how these signals are communicated is not completely understood. Fetal exosomes, intercellular signaling vesicles, may play a key role in the process. The objective of this study was to evaluate exosome trafficking in vivo from fetal to maternal compartments. Pregnant CD-1 mice were intra-amniotically injected on gestational day 16 and 17 with exosomes isolated from primary human amnion epithelial cells fluorescently labeled with the lipophilic dye 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR). All our analyses were performed on samples collected on Day 18. After 24 h, mice were imaged using Bruker MS FX PRO In vivo Imager and tissues were collected. In vivo imaging of mouse showed fluorescence in the uterus, on the exosome-injected side whereas the uterine tissues from the uninjected side and saline and dye alone injected animals remained negative. Histological analysis of placenta showed exosome migration from the fetal to the maternal side of the placenta. Fluorescence released from exosomes was seen in maternal blood samples as well as in maternal uterus and kidneys. This study demonstrates that exosomal cargo can be carried through systemic route from the fetal to the maternal side of the uterine tissues during pregnancy, supporting the idea that fetal signals can be delivered via exosomes

Genome-wide approach identifies a novel gene-maternal pre-pregnancy BMI interaction on preterm birth

Preterm birth (PTB) contributes significantly to infant mortality and morbidity with lifelong impact. Few robust genetic factors of PTB have been identified. Such ‘missing heritability’ may be partly due to gene × environment interactions (G × E), which is largely unexplored. Here we conduct genome-wide G × E analyses of PTB in 1,733 African-American women (698 mothers of PTB; 1,035 of term birth) from the Boston Birth Cohort. We show that maternal COL24A1 variants have a significant genome-wide interaction with maternal pre-pregnancy overweight/obesity on PTB risk, with rs11161721 (PG × E=1.8 × 10−8; empirical PG × E=1.2 × 10−8) as the top hit. This interaction is replicated in African-American mothers (PG × E=0.01) from an independent cohort and in meta-analysis (PG × E=3.6 × 10−9), but is not replicated in Caucasians. In adipose tissue, rs11161721 is significantly associated with altered COL24A1 expression. Our findings may provide new insight into the aetiology of PTB and improve our ability to predict and prevent PTB.HSN268200782096CHHSN268201200008I20-FY02-56, #21-FY07-605R21ES011666R21HD0664712R01HD041702101-2314-B-400-009-MY2103-2314-B-400-004-MY32016YFC02065079164320121477087NICHD R24HD04285

Prenatal Beginnings for Better Health

Pregnancy has significant short- and long-term health impacts for mother and child, which may lead to pediatric- and adult-onset diseases. Understanding these gestational origins of disease and currently existing platforms for prenatal care has resulted in significant advances to detect and prevent adverse maternal and fetal outcomes. Existing and emerging prenatal interventions that are instituted at critical times in gestation take advantage of unique therapeutic windows and provide an opportunity to modify the risks. This research topic encompasses a variety of approaches and interventions, such as maternal screening for fetal disease, advanced fetal imaging, biomarker development, stem cell or gene therapies, and others

An appraisal of ultrasound fetal biometry in the first trimester

Lily K Pemberton, Irina Burd, Eileen WangDivision of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USAAbstract: We evaluate the current available literature on first trimester measurement references, how critically these data have been evaluated in subsequent studies, and the generalizability of the standards across different populations. We will then discuss the significance of first trimester dating for genetic screening tests and how growth in the first trimester may predict later pregnancy outcomes, which could lead to future research to modify these outcomes.Keywords: biometry, crown-rump length, pregnancy datin

Journey to the Center of the Fetal Brain: Environmental Exposures and Autophagy

Fetal brain development is known to be affected by adverse environmental exposures during pregnancy, including infection, inflammation, hypoxia, alcohol, starvation, and toxins. These exposures are thought to alter autophagy activity in the fetal brain, leading to adverse perinatal outcomes, such as cognitive and sensorimotor deficits. This review introduces the physiologic autophagy pathways in the fetal brain. Next, methods to detect and monitor fetal brain autophagy activity are outlined. An additional discussion explores possible mechanisms by which environmental exposures during pregnancy alter fetal brain autophagy activity. In the final section, a correlation of fetal autophagy activity with the observed postnatal phenotype is attempted. Our main purpose is to provide the current understanding or a lack thereof mechanisms on autophagy, underlying the fetal brain injury exposed to environmental insults