Elsevier

Pharmacological Research

Volume 149, November 2019, 104468
Pharmacological Research

Review
The brain-placental axis: Therapeutic and pharmacological relevancy to pregnancy

https://doi.org/10.1016/j.phrs.2019.104468Get rights and content

Abstract

The placenta plays a critical role in mammalian reproduction. Although it is a transient organ, its function is indispensable to communication between the mother and fetus, and supply of nutrients and oxygen to the growing fetus. During pregnancy, the placenta is vulnerable to various intrinsic and extrinsic conditions which can result in increased risk of fetal neurodevelopmental disorders as well as fetal death. The placenta controls the neuroendocrine secretion in the brain as a means of adaptive processes to safeguard the fetus from adverse programs, to optimize fetal development and other physiological changes necessary for reproductive success. Although a wealth of information is available on neuroendocrine functions in pregnancy, they are largely limited to the regulation of hypothalamus–pituitary–adrenal/gonad (HPA/ HPG) axis, particularly the oxytocin and prolactin system. There is a major gap in knowledge on systems-level functional interaction between the brain and placenta. In this review, we aim to outline the current state of knowledge about the brain-placental axis with description of the functional interactions between the placenta and the maternal and fetal brain. While describing the brain-placental interactions, a special emphasis has been given on the therapeutics and pharmacology of the placental receptors to neuroligands expressed in the brain during gestation. As a key feature of this review, we outline the prospects of integrated pharmacogenomics, single-cell sequencing and organ-on-chip systems to foster priority areas in this field of research. Finally, we remark on the application of precision genomics approaches to study the brain-placental axis in order to accelerate personalized medicine and therapeutics to treat placental and fetal brain disorders.

Section snippets

Introduction and overview of placenta

Pregnancy establishment and success involve complex cellular, molecular and physiological processes. The fertilized egg divides and develops into a blastocyst which then adheres and nidates into the endometrium. For implantation to occur, an implantation competent blastocyst must be superimposed on a receptive endometrium. Then a precise orchestration of apposition and attachment processes ensues invasion of the trophoblast cells to penetrate the endometrial epithelium and invade into the

Placenta and maternal brain connection

During pregnancy, the maternal brain undergoes temporal changes at different level. Pregnancy changes the maternal brain for at least two years following birth, including enhancement of key hippocampal functions in human [12,13]. Study also suggests that changes in hormone levels during late pregnancy and early postpartum influence specific cognitive abilities in women [14]. During pregnancy, many women experience varying symptoms relating to brain, often referred to as ‘pregnancy brain’,

Placenta and the fetal brain connection

Signaling plays a key role in regulating placental function to the communication between mother and fetus. The classical insulin-like growth factor (IGF) system is a well-studied example of placental role in maternal-fetal communication [62]. Also, the placenta contains a unique microbiome [63] that may have functional roles in pregnancy outcomes. However, several studies have demonstrated that placental regulation of Igf2, Cortisol, Serotonin, and T4/T3 influences neurodevelopmental processes

Animal models and clinical studies

Since the advent of the Barker Hypothesis in 1990, which posits that the intrauterine environment has direct and long-lasting effects on the fetus [101], much attention has been directed towards researching the fetal origins of adult disease. In this pursuit, the brain-placental axis is being dissected to understand the association between the placenta and the fetal brain and more recently the association of the placenta with the maternal brain. Animal models have proven invaluable for studying

Future prospects and research avenues

Understanding the architecture and hormonal links between the placenta and brain requires innovative experiments using both top-down and bottom-up approaches. Though these approaches have been used in research relating to animal physiology and metabolism [127], not much research has been conducted using these methods in the field of neuroendocrinology. An example of the top-down approach will be the establishment of genetic alteration (such as conditional knockout models) or physiological

Concluding remarks

Our current state of knowledge in placental and fetal biology, in general, requires new paradigms to pursue. Though a great deal of achievement has been made in advancing the field, we have not yet succeeded in curing placental insufficiency, hypoxia, preterm birth and fetal brain defects and other birth defects. Research needs to incorporate concepts and techniques from diverse areas including reproductive biology, systems biology, pharmacology, neuroendocrinology and chemical biology to

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported in parts by grant from the University of Missouri (Research Council Grant) to S.K.B and R21 HD076347 and R01 HD096266 from the Eunice Kennedy Shriver National Institute of Child Health and Development to T.E.S.

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