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Int. J. Devl Neuroscience 37 (2014) 8–14

Contents lists available at ScienceDirect

International Journal of Developmental Neuroscience

j ourna l ho me pa g e: www.elsev ier .com/ locate / i jdevneu

eview

eurotrophins: Role in adverse pregnancy outcome

adhavi Dhobaleharati Vidyapeeth University, Pune 411043, India

r t i c l e i n f o

rticle history:eceived 22 March 2014eceived in revised form 12 June 2014ccepted 12 June 2014

eywords:rain derived neurotrophic factorerve growth factor

a b s t r a c t

Proper placental development is essential during pregnancy since it forms the interface between thematernal–foetal circulations and is critical for foetal nutrition and oxygenation. Neurotrophins such asnerve growth factor (NGF), brain derived neurotrophin (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) are naturally occurring molecules that regulate development of the placenta and brain.BDNF and NGF also involved in the regulation of angiogenesis. Recent studies suggest that the levelsof BDNF and NGF are regulated by docosahexaenoic acid (DHA) which is an important omega-3 fattyacid and is a structural component of the plasma membrane. Oxidative stress during pregnancy may

reterm deliveryngiogenesiseto-placental unit

lower the levels of DHA and affecting the fluidity of the membranes leading to the changes in the levelsand expression of BDNF and NGF. Therefore altered levels and expression of NGF and BDNF may leadto abnormal foetal growth and brain development that may increase the risk for cardiovascular disease,metabolic syndromes and neurodevelopmental disorders in children born preterm. This review discussabout the neurotrophins and their role in the feto-placental unit during critical period of pregnancy.

© 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82. Types of neurotrophins and their structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

2.1. Nerve growth factor (NGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.2. Brain derived neurotrophic factor (BDNF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.3. Neurotrophin-3 (NT-3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.4. Neurotrophin-4/5 (NT-4/5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3. Role of neurotrophins in the development of feto-placental unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94. Neurotrophins in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

4.1. Intrauterine growth restriction (IUGR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104.2. Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104.3. Small for gestational age (SGA), appropriate for gestational age (AGA), large for gestational age (LGA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104.4. Preterm delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

5. Interaction between micronutrients, oxidative stress, docosahexaenoic acid and neurotrophins (BDNF and NGF) in preterm pregnancy . . . . . . . 115.1. Micronutrients, docosahexaenoic acid (DHA) and neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115.2. Oxidative stress and neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115.3. Angiogenesis and neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

6. Altered levels of neurotrophins and their implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

. Introduction

The placenta is known to make adaptations to ensure optimaloetal growth during pregnancy. It has been suggested that the

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ttp://dx.doi.org/10.1016/j.ijdevneu.2014.06.005736-5748/© 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

placenta hold clues for predicting the individuals who would beat risk of developing chronic diseases in childhood or in adult life(Faye-Petersen, 2008). Studies also reports that children born with

preterm delivery, low birth weight, intra uterine growth restriction(IUGR) and preeclampsia have been associated with metabolic andneurodevelopmental disorders. However, the mechanisms are notclearly understood.

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M. Dhobale / Int. J. Devl

Growth factors like neurotrophins and cytokines are known toct in paracrine and/or autocrine manner through their receptorsn the cell for the development of feto-placental unit (Guzeloglu-ayisli et al., 2009). Neurotrophins are a family of polypeptiderowth factors that influence proliferation, differentiation, survivalnd death of neuronal and non neuronal cells (Kim et al., 2004). Thetructure and function of these neurotrophins are described below

. Types of neurotrophins and their structures

There are four major types of neurotrophins i.e. nerve growthactor (NGF), brain derived neurotrophin (BDNF), neurotrophin-3NT-3) and neurotrophin-4/5 (NT-4/5). Amongst these, BDNF andGF are suggested to play an important role in placental and foetalrowth and development (Zheng and Shao, 2012; Mayeur et al.,010; Nico et al., 2008; Toti et al., 2006).

.1. Nerve growth factor (NGF)

The biologically active NGF consists of a dimer of 13-kDaolypeptide chains, each of which has three intrachain disulfideridges. The crystal structure of NGF has been resolved (McDonaldt al., 1991). The NGF gene is located on human chromosome onend is expressed as two major splice variants (Edwards et al.,988). NGF has two known receptors, receptor tyrosine kinase ATrkA) and p75NTR (Gigante et al., 2003). Upon binding of NGFo TrkA, the receptor is subjected to a series of events that char-cterize Trk signalling. These include receptor dimerization andransphosphorylation of tyrosines leading to activation of kinasectivity, followed by autophosphorylation of tyrosines outsidef the activation loop. Subsequent phosphorylation and activa-ion of accessory proteins lead to the generation of a cascadef receptor-independent signalling pathways (Ras (Rat Sarcoma),hosphoinositide 3-kinase (PKC), Phospholipase C (PI3) kinaseathway) (Sofroniew et al., 2001).

.2. Brain derived neurotrophic factor (BDNF)

The human BDNF gene has seven noncoding exons that are asso-iated with distinct promoters and one coding exon that encodehe mature BDNF proteins (Liu et al., 2005). BDNF protein sharesbout 50% amino acid identity with NGF, NT-3 and NT-4/5. Itontains a signal peptide following the initiation codon and aro-region containing an N-linked glycosylation site (Binder andcharfman, 2004). It also shares a distinctive three-dimensionaltructure containing two pairs of antiparallel �-strands and cys-eine residues in a cystine knot motif. Human BDNF transcripts areighest in the brain and several alternative BDNF mRNAs showedelatively high expression levels in nonneural tissues. For exam-le, expression levels of transcripts containing exons VI and IXabcdere high in the heart, placenta, and prostate (Pruunsild et al.,

007).BDNF binds to its specific receptor i.e. Trk B, although some

onselective binding also occurs (Thoenen, 1995). Ligand inducedeceptor dimerization results in kinase activation; subsequenteceptor autophosphorylation creates specific binding sites forntracellular target proteins (PLC-�1 (phospholipase C), p85 (theoncatalytic subunit of PI-3 kinase) and Shc (SH2-containing

equence)), which bind to the activated receptor via SH2 domainsPatapoutian and Reichardt, 2001; Barbacid, 1995). This activationan then lead to a variety of intracellular signalling cascades suchs the Ras-MAP (mitogen-activated protein) kinase cascade andhosphorylation of cyclic AMP-response element binding proteinCREB) (Segal, 2003; Patapoutian and Reichardt, 2001).

science 37 (2014) 8–14 9

2.3. Neurotrophin-3 (NT-3)

NT-3 is also a member of neurotrophin family and playsan essential role in the development of both the neural-crest-derived peripheral nervous system and the central nervous system(Chalazonitis, 2004). NT-3 has a high affinity for TrkC as achemokine receptor (Chen et al., 2013) and also binds to TrkA andTrkB with low affinity (Skaper, 2008). It also has the same structurelike other neurotrophins that contain a tertiary fold and cysteineknot. The NT3 promoter contributes to the dimer to form het-erodimers (Robinson et al., 1995). The gene encoding human NT-3(gene symbol designated NTF3) to chromosome 12 (Maisonpierreet al., 1991). The distribution of NT-3 messenger RNA and its biolog-ical activity on a variety of neuronal populations clearly distinguishNT-3 from NGF and BDNF.

2.4. Neurotrophin-4/5 (NT-4/5)

A fourth neurotrophin is NT-4/5 (also known as NT-4, NT-5) hasbeen molecularly cloned from Xenopus (Ip et al., 1992). NT-4/5 con-tain six cysteine residues and also includes an insertion of sevenamino acids between its second and third cysteines (Ip et al., 1992;Berkemeier et al., 1991) and its encoded gene is located on chro-mosome 19 in human. NT-4/5 shares a 95% amino-acid-sequenceidentity with BDNF and it is the only family member that has atruncated precursor region. NT-4/5 bind to the TrkB receptor cor-responds with the onset of neurogenesis in the neural tube duringbrain development and is differentially regulated in later develop-ment (Bartkowska et al., 2010).

There are very limited studies that report the role of these neu-rotrophins in the development of the placenta.

3. Role of neurotrophins in the development offeto-placental unit

BDNF, NGF, NT-3 and NT-4/5 play a vital role during pregnancyin the mother, placenta and foetus (Fig. 1).

BDNF regulate the cytotrophoblast differentiation, proliferationand survival of the placenta (Kawamura et al., 2009, 2011; Mayeuret al., 2010). BDNF plays a key role in the regulation of angiogen-esis and is reported to protect the endothelial progenitor cells byincreasing the expression of superoxide dismutase (He and Katusic,2012; Jiang et al., 2011). Changes in levels of neurotrophins canproduce long lasting effects on neurotrophic processes (neuronnumber, synapse), which alter neuronal maturation and plastic-ity in later life (Vicario-Abejón et al., 2002). BDNF/TrkB-stimulatedintracellular signalling is critical for neuronal survival, morphogen-esis and plasticity (Numakawa et al., 2010).

It has been reported that both foetal and maternal tissues (tro-phoblast, amnion/chorion and maternal deciduas) express the NGFmRNA both in early gestation and at term (Toti et al., 2006). Role ofNGF in mouse placentation during the post implantation period hasbeen described (Kanai-Azuma et al., 1997). Furthermore, NGF andits receptors are suggested to play an important role during organo-genesis (Miralles et al., 1998). NGF acts as an angiogenic factor bycontributing to the maintenance, survival and function of endothe-lial cells by autocrine and/or paracrine mechanisms (Nico et al.,2008). In addition, NGF has been associated with functional activi-ties of cells that include immune and endocrine systems and act asan inflammatory mediator (Berry et al., 2012).

There are very few studies, which have discussed the role of

NT-3 and NT-4 in the development of the feto-placental unit. It hasbeen hypothesized that NT-3 function in the regulation of placentaland foetal brain development and for the maternal inflammatoryresponses (Casciaro et al., 2009). Kawamura et al. (2009) have

10 M. Dhobale / Int. J. Devl Neuroscience 37 (2014) 8–14

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ig. 1. Role of neurotrophins in pregnancy. DHA: docosahexaenoic acid; NGF: neeurotrophin 4/5 tyrosine kinase receptor

emonstrated the expression of neurotrophin 4/5 and their recep-ors TrkB in trophoblast cells and placentas during different stagesf pregnancy in mice. The altered level and expression of these neu-otrophins have been also indicated in complicated pregnanciesuch as intrauterine growth restriction (IUGR), preeclampsia andreterm delivery.

. Neurotrophins in pregnancy

Many studies have reported that alterations in the levels ofeurotrophins (NGF, BDNF, NT-3, NT-4/5) in mother, cord, amni-tic fluid and placenta in pregnancy complications and haveeen suggested their role in placental and foetal developmentMalamitsi-Puchner et al., 2004, 2007; Toti et al., 2006; Marx et al.,999).

It has been suggested that BDNF and NGF could be a marker forhe presence of central nervous system abnormalities, infectiousnsults in utero or both (Marx et al., 1999). Further the expres-ion and localization of NGF has been observed in the trophoblast,ecidua and foetal membranes and support the concept that humanlacenta is a potent neuroendocrine organ throughout gestationToti et al., 2006). Chouthai et al. (2003) demonstrated lower cordDNF levels might have an implications for neural maturity in theremature infants.

However, very few studies have examined the levels and expres-ion of NT-3 and NT-4 in pregnancy. Study suggests that NT-3ay be playing a regulatory function on placenta and foetal brain

evelopment and maternal inflammatory response. It has beeneported that the circulating NT-3 levels increased in early neona-al life, possibly due to exposure to various stimuli soon after birthMalamitsi-Puchner et al., 2007). NT-3 and NT-4 have been doc-mented to act at early stages of neuronal development and toecrease after hypoxia-ischaemia (Nikolaou et al., 2006).

.1. Intrauterine growth restriction (IUGR)

There are very few studies, which have reported the levels ofhese neurotrophins and their role in IUGR complicated pregnan-ies. Malamitsi-Puchner et al. (2007) showed no differences in theirculating levels of BDNF, NT-3 and NT-4 in IUGR pregnancies.GF was the only neurotrophin that higher in the maternal and

oetal plasma and further positively correlated with the infants’entiles and birth weights. This no change in the neurotrophinsould possibly be attributed to the activation of the brain-sparingffect (Malamitsi-Puchner et al., 2006). One of the rat IUGR animal

rowth factor; BDNF: brain derived neurotrophin; NT-3: neurotrophin-3; NT-4/5:

model showed less expression of BDNF and NT-3 in the cerebralcortex than controls. These alterations may be related in delay ofneuronal migration (Fukami et al., 2000).

4.2. Preeclampsia

Lower maternal and higher cord BDNF levels were indicatedin women with preeclampsia when compared to normotensivewomen and suggested a possible role for BDNF in the patho-physiology of preeclampsia (D’Souza et al., 2014). BNDF levelswere significantly higher in umbilical cord blood from preeclamp-tic pregnancies (Bienertova-Vasku et al., 2013). The expression ofBDNF and its receptor TrkB, have been shown to be expressedin membranous chorion and villous tissue and was significantlyhigher in maternal plasma in preeclampsia than in controls (Fujitaet al., 2011). Casciaro et al. (2009) have observed the expressionof NT-3 in the human placenta during normal pregnancy and inpreeclampsia. NGF levels are differently regulated in preeclamp-tic and normotensive mothers delivering low birth weight babies(Kilari et al., 2011).

4.3. Small for gestational age (SGA), appropriate for gestationalage (AGA), large for gestational age (LGA)

BDNF levels in the SGA groups was significantly higher than thatin the AGA and LGA groups suggesting the BDNF is correlating withbirth weight (Wang and Ye, 2008). Further, NGF levels have shownto be higher in the AGA compared to the IUGR group and were asso-ciated with the birth weight of the infants (Malamitsi-Puchner et al.,2006). Nikolaou et al. (2006) have examined the pattern of perina-tal changes in NGF, BDNF, NT-3, and NT-4 in AGA full-term foetusesand neonates by determining their circulating levels. The data sug-gested that a gradual decrease of NT-3 and NT-4 from umbilicalcord (UC) to neonates day 4 (N4), while levels of NGF and BDNFwere decreasing suggesting NT3 and NT-4 have been documentedto act at early stages of neuronal development and to decrease afterhypoxia-ischaemia while NGF and BDNF to increase.

4.4. Preterm delivery

There are very few studies, which have reported the levels

of neurotrophins in preterm deliveries (Malamitsi-Puchner et al.,2004; Haddad et al., 1994). Higher levels of BDNF were observed inwomen delivering full term neonates as compared with pretermneonates suggesting that BDNF levels may reflect the mature

M. Dhobale / Int. J. Devl Neuro

Fig. 2. Association of DHA and neurotrophins in cell membrane. DHA: docosahe-xtr

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aenoic acid; NGF: nerve growth factor; BDNF: brain derived neurotrophin; Trk:yrosine kinase receptor; TrkA: tyrosine kinase receptor A; Trk B: tyrosine kinaseeceptor B

ervous and immune systems of mothers (Malamitsi-Puchner et al.,004). Maternal NGF levels were lower in the mothers deliveringreterm babies as compared with full term babies (Haddad et al.,994). Cord NT-3 levels were significantly decreased in the pres-nce of placental inflammation preterm infants (Kumar et al., 2011).T-3 levels were decreased in preterm birth and suggested to play

role in neuronal growth and differentiation (Matoba et al., 2009).The alterations in the levels and expression of these neu-

otrophins during pregnancy could be due to their interactionith biomolecules such as micronutrients (folic acid, vitamin B12)

nd long chain polyunsaturated fatty acid (docosahexaenoic acid)hich is explained in the following section.

. Interaction between micronutrients, oxidative stress,ocosahexaenoic acid and neurotrophins (BDNF and NGF)

n preterm pregnancy

Proper growth and development of the placenta is determinedy maternal nutrition and plays a critical role in foetal growth andevelopment. The peri or post conceptional period represents a par-icularly sensitive window for feto-placental development duringhich, suboptimal maternal micronutrients may alter the expres-

ion of the foetal genome leading to lifelong consequences. Theseeurotrophins may involve in the preterm delivery through differ-nt mechanisms which are discussed below.

.1. Micronutrients, docosahexaenoic acid (DHA) andeurotrophins

Micronutrients like folic acid and vitamin B12 have a majorole in the one carbon metabolism since they are required for theransfer of methyl groups for methylation of DNA, RNA, proteinsnd membrane phospholipids. Studies carried out on humans andnimals have extensively discussed the interaction of folic acid,itamin B12 and DHA in the one carbon cycle (van Wijk et al.,012; Kulkarni et al., 2011a,b; Kale et al., 2010). Deficiency of theseicronutrients lead to increased homocysteine levels which are

ssociated with reduced DNA methylation potential (Zijno et al.,003). Further, it has been discussed that when DHA levels are low,

nflux of methyl groups may be diverted towards histone and DNA,esulting in altered methylation patterns (Kale et al., 2010).

The levels of BDNF are known to be regulated by omega 3 fatty

cids like DHA (Balogun and Cheema, 2014; Wu et al., 2004). DHAs a structural component of the plasma membrane and reductionsn DHA can have a direct influence on membrane function (Fig. 2).isruptions in membrane fluidity due to DHA deficiency have been

science 37 (2014) 8–14 11

suggested to lower the levels of BDNF in the rat brain (Bhatia et al.,2011).

Animal studies have also demonstrated altered levels andexpression of BDNF and NGF in the brain of the offspring at birthand in later life because of altered maternal micronutrients (Sableet al., 2011, 2012, 2014). These studies highlight the importanceof altered early life nutrition serving as a predisposition to non-communicable diseases like cardiovascular diseases, diabetes andneurodevelopmental disorders in adult life.

Recent human studies have demonstrated the associationbetween altered maternal micronutrients like folate and vitaminB12; reduced DHA levels; increased homocysteine and oxidativestress in preterm deliveries (Dhobale et al., 2011, 2012a,b). Basedon this, we have recently hypothesized that increased oxidativestress and decreased DHA may alter the levels and expression ofneurotrophins in preterm deliveries, since balance between neu-rotrophins and oxidative stress is critical for normal growth anddevelopment (Dhobale and Joshi, 2012).

5.2. Oxidative stress and neurotrophins

Reactive oxygen species and antioxidant defence mechanismplay a vital role in placental growth and development in the normalpregnancy (Al-Gubory et al., 2010). Increased oxidative stress maydisrupt collagen and further lead to preterm delivery (Wall et al.,2002). Gardiner et al. (2009) suggested that increased oxidativestress can lead to down regulation of neurotrophins.

We have observed higher oxidative stress with lower mater-nal and cord plasma NGF levels in preterm deliveries (Dhobaleet al., 2012c; Joshi et al., 2008). Further, this increased oxidativestress was negatively associated with maternal and cord plasmaMDA implying that oxidative stress may play a role in determiningthe levels of NGF. The maternal plasma NGF levels were also pos-itively associated with baby weight suggesting the role of NGF indetermining the foetal growth that support to an earlier study inIUGR infants (Malamitsi-Puchner et al., 2007). This altered levelsof NGF in preterm deliveries could be due to increased oxidativestress that may disturb the membrane fluidity which will affectNGF signalling cascade (Fig. 3A and B). These changes in the levelsof NGF mRNA and protein may lead to poor foetal/placental growthand development in preterm deliveries.

5.3. Angiogenesis and neurotrophins

The process of new vessel growth from the pre-existing ones iscommonly called angiogenesis (Potente et al., 2011). NGF, BDNF andNT-3 might have the potential to greatly increase angiogenesis inpathological situations (Blais et al., 2013; Jadhao et al., 2012). Dur-ing the embryonic development, vessel formation and maturationis a very dynamic process, involving growth factors like vascu-lar endothelial growth factor (VEGF), BDNF that widely modulatesendothelial proliferation and migration (Koch and Claesson-Welsh,2012; Kermani and Hempstead, 2007). NGF is reported to inducea potent angiogenic response in the developing chick embryo(Cantarella et al., 2002).

It has been observed that BDNF and NGF process angiogenicactivity through crucial signalling pathways such as mitogen-activated protein kinases/extracellular signal-regulated kinases(MAPK/ERK) and protein kinase B (PKB) pathways (Jadhao et al.,2012; Julio-Pieper et al., 2009; Wang et al., 2008; Lazarovici et al.,2006). One of an animal study has reported the role of TrkB in

embryonic blood vessel development (Wagner et al., 2005). Fur-ther, Nakamura et al. (2006) has suggested TrkB increases HIF-1�through BDNF that stimulate VEGF expression in neuroblastomacells.

12 M. Dhobale / Int. J. Devl Neuroscience 37 (2014) 8–14

F erm and (B) preterm birth.D eptor; MDA: malondialdehyde, arrows indicate the direction of change

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Fig. 4. Cross talk between neurotrophins and angiogenic factor in the placenta.DHA: docosahexaenoic acid; NGF: nerve growth factor; BDNF: brain derived neu-rotrophic factor; Trk: tyrosine kinase receptor; TrkA: tyrosine kinase receptor A;Trk B: tyrosine kinase receptor B; VEGF: vascular endothelial growth factor; VEGF-R1: vascular endothelial growth factor receptor-1; PI3K: phosphoinositide 3-kinase;

ig. 3. (A and B) Possible association of oxidative stress and NGF in pregnancy (A) tHA: docosahexaenoic acid; NGF: nerve growth factor; TrkA: tyrosine kinase A rec

The lower maternal VEGF, BDNF and NGF levels were reportedn women with preeclampsia (D’Souza et al., 2014; Kulkarni et al.,010; Kilari et al., 2010). VEGF which is representative of angio-enesis can be a new and useful predictor of preterm delivery (Kimt al., 2013). Interestingly, we have observed lower maternal NGFDhobale et al., 2012c), higher placental TrkB levels which was theesponse to the higher levels of its ligand i.e. BDNF in preterm deliv-ry (Dhobale et al., 2012b). The lower placental BDNF and NGFRNA levels in the preterm deliveries suggesting that the lowerRNA levels of BDNF and NGF may possibly be a result of altered

pigenetic mechanisms (Dhobale et al., 2013).From these studies one of the postulated mechanisms for angio-

enesis through neurotrophins could be that BDNF/NGF-TrkB/TrkAignalling casacade increases hypoxia-inducible factor 1-alphaHIF-1�) and may regulate VEGF through mitogen-activated pro-ein kinases/extracellular signal-regulated kinases (MAPK/ERK)nd protein kinase B (PKB) pathways in the placenta in early preg-ancy (Fig. 4).

. Altered levels of neurotrophins and their implications

The altered levels of folate, vitamin B12 and homocysteine maypigenetically regulate the levels and expression neurotrophinseeded for the development of the feto-placental unit and mayesult in preterm delivery. Children born to preterm mothers maye at an increased risk for neurodevelopmental disorders in later

ife (Johnson and Marlow, 2011; Lindström et al., 2011).These altered levels of BDNF and NGF may be a consequence of

ltered gene expression and promoter methylation due to changesn the one carbon cycle. It is likely that these changes in the onearbon cycle influence epigenetic programming of the placenta anday have implications for micronutrient mediated foetal program-ing of diseases in adult life. The lower levels of cord BDNF andGF in preterm pregnancies may provide clues to predict cognitiveeficits in children. Identification of these genes can be of use inlucidating the molecular basis of the pathology and may further

lso lead to identify suitable disease early biomarkers in pregnancy.

Preterm birth is a multifactorial aetiology and therefore rolef these components discussed in this review will throw light innderstanding the mechanisms that leading to preterm delivery.

AKT: protein kinase B; Raf: rapidly accelerated fibrosarcoma; ERK: extracellularsignal-regulated kinases; RAS-MAPK: mitogen-activated protein kinases; HIF-1�:hypoxia-inducible factor 1-alpha.

Further, it may be likely that these neurotrophins influences birthoutcome and neurodevelopmental risk through two mechanismsi.e. angiogenesis and cellular growth, survival and maturation. Theirlevels may be regulated by prenatal epigenetic and foetal program-ming suggesting a need to examine these issues. Understanding thelevels of these neurotrophins in the cord blood may be useful in pre-dicting the consequences of central nervous system abnormalitieswhile in utero.

In future there is need to analyze the levels of neurotrophins inearly pregnancy in order to understand their role in preterm deliv-eries. Children born preterm need to be followed up to assess therisk for cognitive and behavioural disorders to better understand

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he possible role of altered levels of BDNF and NGF at birth. Animaltudies need to be carried out to understand the synergistic effect ofaternal micronutrients and omega 3 fatty acid supplementation

n brain neurotrophins and cognitive performance in the offspring.

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