Review article
Role of neurotrophins in pregnancy, delivery and postpartum

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Abstract

Neurotrophins (NTs) are a family of polypeptides whose functions have been extensively studied in the past two decades. In particular, Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) play a major role in the development, nutrition and growth of the central and peripheral nervous system and in the pathogenesis of neurodegenerative, cardiometabolic and (auto)immune diseases. However, NGF and BDNF have subtle functions for follicular development, implantation, and placentation. This short narrative review summarizes the existing evidence, published between 2000 and 2019, about the role of NTs in many different conditions that might affect women during and after pregnancy such as preeclampsia, gestational diabetes, obesity, depression, anxiety, smoking and alcohol abuse. Literature suggests that the dysregulation of synthesis and release of NTs may lead to decisive effects on both maternal and fetal health. Some piece of evidences was found about a possible association between NGF/BDNF and breastfeeding. Additional studies on human models are necessary to further characterize the role of NTs in life-changing experiences like labor and delivery.

Introduction

Neurotrophins (NTs) are a family of protein influencing the proliferation, differentiation, survival and death of neuronal and non-neuronal cells [[1], [2], [3]]. This family includes Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3) and Neurotrophin-4/5 (NT-4/5) [4,5]. Since NGF and BDNF play key roles during pregnancy, clinicians are turning their attention to their influence on fetal and placental growth and development [6,7]. Several studies demonstrated that NGF and BDNF are involved in many different maternal pathological conditions such as preeclampsia [8], diabetes [9], depression [[10], [11], [12]], anxiety [13], neurodegenerative diseases [10,14], obesity [[21], [22], [23]], smoking [18,19] and alcohol abuse [20,21]. Furthermore, a few studies suggest a possible association between NTS and breastfeeding [22] or medically assisted procreation techniques [23].

Nerve Growth Factor (NGF), the first neurotrophic factor to be characterized, was discovered in 1951 by Rita Levi-Montalcini, during a search for survival factors on chick embryos [24]. The purified NGF protein is a dimer of two identical subunits linked together by non-covalent bonds [25]. Besides, studies have shown the gene coding for human NGF located on chromosome 1 (p13.2) [26]. The first neurotrophic receptor to be discovered was p75NTR [27], a 75 kDa glycoprotein, that was identified as a low-affinity receptor for NGF, but afterward was shown to bind all neurotrophins. The p75NTR is a member of the tumor necrosis factor (TNF), belonging to a superfamily of cytokine receptors including TNF receptors [[28], [29], [30]]. A second group of NTs receptors are members of the tyrosine kinase receptor (Trk) family and are more selective for NT ligand binding. In particular, TrkA is specific for NGF, a transmembrane tyrosine kinase with a molecular weight of 140 kDa [31]. The stimulation of TrkA is mandatory to elicit a full biological The stimulation of TrkA is mandatory to elicit a full biological response [32]. Indeed, the NGF biological activity depends on the ratio between these two receptor molecules expressed on the surface of target cells. Changes in the ratio of TrkA/p75NTR can contribute to disbalance in the activation of survival and apoptotic pathways in neuronal cells occurring during pathological conditions [32]. The NGF role on massive neuropsychiatric diseases like Alzheimer’s, schizophrenia, autism and major depression has been widely described [10,14] as well the role of NGF in regulating stress, cardiometabolic diseases, brain disruption, metabolic and nutritional diseases [15,16,[33], [34], [35], [36], [37], [38], [39], [40],143].

Brain-derived neurotrophic factor, the second member of the NTs factors, plays a key role in the central nervous system, promoting synaptic plasticity, neurogenesis and neuroprotection. BDNF protein shares about 50 % of the amino acid sequence with NGF, NT-3 and NT-4/5. It also exhibits a distinctive three-dimensional structure containing two pairs of antiparallel β-strands and cysteine residues in a “cystine knot motif” [41]. The gene encoding BDNF in humans is characterized by 7 non-coding nucleotide sequences and one coding exon which program the mature BDNF proteins [42].

The activity of BDNF is mediated by binding to the tyrosine kinase receptor B (TrkB) which was expressed at high levels in the brain [32,43]. The TrkB receptor contains intrinsic tyrosine kinase activity located on the intracellular domain and activation of the receptor causes increased autophosphorylation and leads to interaction with docking proteins that regulate and stimulate different pathways, such as the mitogen-activated protein kinase cascade phospholipase C-γ and phosphatidylinositol-3-kinase. Although mainly expressed in the nervous system with an action similar but wider than NGF [[44], [45], [46], [47], [48], [49], [50], [51], [52], [53]], BDNF and TrkB have been immunolocalized in several regions of the human placenta and exercise important functions during pregnancy as it is important for follicular development, implantation, and placentation within reproductive tissues [[54], [55], [56], [57]]. BDNF plays widespread roles in the regulation of energy homeostasis for both fetuses and mothers, such as controlling patterns of fetal growth [58], adult’s feeding [59], physical activity [49,60], and regulating the glucose metabolism in peripheral tissues [58].

Section snippets

Study selection

Studies examined in this narrative review were obtained searching MEDLINE and ClinicalTrials.gov (last visited Aril 16th, 2019) papers with keywords “neurotrophins pregnancy or neurotrophins gestation”. Two-thousand sixty-three papers were found. Paper were then filtered for species (human) and time range (from 2000 to 2019) obtaining a total of 499 papers. Filtering for titles, the number of works finally included were 47. Other publications included in the review were retrieved through manual

Preeclampsia

Preeclampsia is one of the leading gestational hypertensive disorders, characterize by an increase in blood pressure and by excessive maternal inflammatory response. It has been suggested that altered placental development plays a central role in the pathogenesis of preeclampsia [[61], [62], [63]]. Although much research into mechanism of pre-eclampsia has taken place, its exact pathogenesis remains uncertain. Pre-eclampsia is thought to result from an abnormal placenta, the removal of which

NTs and delivery

Since 2012, researchers of the University of Pennsylvania have been conducting a trial (Clinicaltrials.gov - Identifier NCT01992744) on pregnant women to demonstrate a possible link between BDNF levels in maternal blood samples and birth outcome. Researchers hypothesized that participants with lower levels of BDNF can be at increased risk for poor birth outcomes [132].

NTs and lactation

WHO recommends breastfeeding as the best nutritional choice for the newborns up to 6 months in an exclusive way, and for babies up to 24 months and beyond in a complementary way (https://www.who.int/topics/breastfeeding/en/ last visited April 2019).

Several studies have found that maternal milk is the best source of nutrients and protective components for human infants, particularly during the first months of life [22]. These extensive varieties of bioactive components, including growth factors,

Conclusion

A large number of scientific evidences has proven the fundamental role of NTs in the development of central and peripheral nervous systems. In particular, BDNF and NGF seem to play a vital role in the formation of synaptic bonds. This review summarizes current evidences about the role of NTs in (i) the reproductive biology of women, and (ii) in several pathological conditions commonly affecting pregnancy, such as preeclampsia and gestational diabetes; indeed, BDNF levels were proved to be lower

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

Authors do thank Sapienza University of Rome, Italy for the financial and logistic support

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