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Placenta xxx (2016) 1e8

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Placenta
journal homepage: www.elsevier.com/locate/placenta

Review: Neuroinammation in intrauterine growth restriction


Julie A. Wixey*, Kirat K. Chand, Paul B. Colditz, S. Tracey Bjorkman
The University of Queensland, Perinatal Research Centre, UQ Centre for Clinical Research, Herston, Queensland 4029, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Disruption to the maternal environment during pregnancy from events such as hypoxia, stress, toxins,
Received 30 October 2016 inammation, and reduced placental blood ow can affect fetal development. Intrauterine growth re-
Received in revised form striction (IUGR) is commonly caused by chronic placental insufciency, interrupting supply of oxygen
21 November 2016
and nutrients to the fetus resulting in abnormal fetal growth. IUGR is a major cause of perinatal
Accepted 22 November 2016
morbidity and mortality, occurring in approximately 5e10% of pregnancies. The fetal brain is particularly
vulnerable in IUGR and there is an increased risk of long-term neurological disorders including cerebral
Keywords:
palsy, epilepsy, learning difculties, behavioural difculties and psychiatric diagnoses. Few studies have
Placental insufciency
Growth retardation
focused on how growth restriction interferes with normal brain development in the IUGR neonate but
Inammation recent studies in growth restricted animal models demonstrate increased neuroinammation. This re-
Microglia view describes the role of neuroinammation in the progression of brain injury in growth restricted
Neonatal brain injury neonates. Identifying the mediators responsible for alterations in brain development in the IUGR infant is
key to prevention and treatment of brain injury in these infants.
2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Brain injury in IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Grey and white matter injury in IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Mechanisms of neuronal injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Inflammation in the IUGR brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Proinflammatory cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Systemic proinflammatory cytokines in IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Proinflammatory cytokines in the IUGR brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Activated microglia and reactive astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Activated microglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Reactive astrocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3. Activated microglia and reactive astrocytes in IUGR brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction

* Corresponding author. Perinatal Research Centre, University of Queensland Intrauterine growth restriction (IUGR) is a major cause of peri-
Centre for Clinical Research, Building 71/918, Royal Brisbane and Women's Hospital, natal morbidity and mortality and occurs in approximately 5e10%
Herston Rd, Herston, Queensland 4029, Australia.
of pregnancies [1,2] with even higher rates (21%) reported in the
E-mail address: j.wixey@uq.edu.au (J.A. Wixey).

http://dx.doi.org/10.1016/j.placenta.2016.11.012
0143-4004/ 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: J.A. Wixey, et al., Review: Neuroinammation in intrauterine growth restriction, Placenta (2016), http://
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developing world [3]. IUGR is generally dened as a fetus that fails at 1 year of age have been found to be associated with develop-
to achieve appropriate growth potential due to genetic or envi- mental disabilities [18,20]. These alterations are also evident in
ronmental factors. It is characterised by fetal weight dropping over animal models of growth restriction with demonstrated neuronal
time across growth percentiles; by birth most IUGR infants weigh and white matter disruption [21e30]. Neuronal loss and disruption
less than the 10th percentile for gestational age. Chronic placental are observed in IUGR animal models throughout many regions of
insufciency is a common cause of IUGR. Placental insufciency or the brain including the hippocampus [29,31]. A decrease in prolif-
utero-placental dysfunction results in insufcient blood ow to the eration and differentiation of oligodendrocytes are also evident in
placenta during pregnancy and inadequate supply of nutrients and many growth restricted animal models [21,24,25,27] with some
oxygen to support normal growth of the fetus. Thus, the fetus de- demonstrating postnatal restoration of myelin dependent on the
velops in a chronic hypoxic environment. Placental insufciency severity of injury [25,26,30]. Miller et al. (2014) showed decreased
can result in changes in fetal metabolism, hormones, hematology, myelination with fragmentation and disorganisation of the white
immunology and cardiovascular function. matter tracts in growth restricted sheep [29]. They postulated these
The adverse fetal environment can signicantly affect the abnormal patterns may result in abnormal neuronal activity and
developing brain. In a chronic hypoxic environment, fetal circula- functionality in the IUGR brain. Even though characterisation of
tory redistribution occurs; blood ow is selectively redirected to white matter injury has been a major avenue of investigation in
the brain and away from other organs to maximise oxygen and IUGR animal models, neuronal disruption is also a critical neuro-
nutrient supply. This type of growth restriction is referred to as pathological feature and brain injury in the IUGR neonate is a
brain-sparing or asymmetric IUGR because the body is dispro- combination of white and grey matter injury. As discussed above,
portionately smaller than the head. Asymmetrical IUGR is the most grey matter injury is a predominate neuropathological feature
common form of growth restriction affecting 70e80% of all IUGR observed in human studies [17,18,20], therefore further emphasis
infants with disruption to fetal growth occurring mainly in the on mechanisms of neuronal injury in growth restricted animal
third trimester. Symmetric IUGR accounts for 20e25% of all IUGR models studies are vital.
fetuses and is characterised by a global growth restriction
throughout pregnancy. Brain-sparing has been regarded as a pro- 3. Mechanisms of neuronal injury
tective mechanism in the IUGR fetus to protect and promote brain
development but recent evidence has challenged this idea Few studies have focused on the detailed mechanisms of brain
(reviewed in Ref. [4]). Several studies have demonstrated that injury in the IUGR neonate which is surprising given the high
asymmetric IUGR infants i.e. those with brain-sparing, have worse proportion of IUGR infants who exhibit adverse long-term neuro-
neurodevelopmental outcomes than symmetric IUGR infants logical outcomes [18,19]. There is a considerable paucity of data
[5e10]. from human autopsy tissue of the pathology of the human IUGR
brain. A classical study of six term IUGR infants demonstrated a
2. Brain injury in IUGR reduction in myelin lipids and DNA content (used as an estimate of
cell number) in cerebrum-brainstem and cerebellum fractions [32].
The fetal brain is particularly vulnerable to the effects of IUGR More recently in nine IUGR fetuses a signicant decrease in cell
[11]. Long-term neurological disorders such as cerebral palsy (CP) number in the developmental zones of the cortex has been re-
and epilepsy, as well as learning and attention difculties, neuro- ported [33]. It is extremely challenging to acertain mechanisms of
behavioural disabilities, and other cognitive issues have been IUGR injury from post-mortem human brain tissue. Difculty in
attributed to restricted growth of the fetus [12e15]. A four-to six- estimating the timing of an IUGR insult as well as untangling var-
fold increase in CP has been shown in IUGR neonates [14] with iables of gestational age on brain development, insults such as
others reporting up to a 30-fold increase [16]. The long-term care of pregnancy hypertension and other factors confound intepretation
a child with compromised brain development is associated with from human IUGR autopsy ndings. Therefore animal models of
emotional stress for families and a direct cost on society. Currently IUGR are necessary to adequately explore mechanisms of injury in
there are limited treatments to prevent neurological impairment in the IUGR brain. It is likely that key normal developmental processes
the IUGR neonate. Research is addressing IUGR health problems are affected during the growth of the fetal brain and these may
from different angles; both the preventative aspect in utero as well underlie the adverse neurodevelopmental outcomes in the IUGR
as interventions from birth. As many growth restricted fetuses may infant. Understanding the mechanisms behind grey matter and
not be detected until after birth (especially in the case of asym- white matter loss, and impairment in the IUGR infant is essential to
metric IUGR) it is important to examine the vulnerable IUGR brain identifying therapeutic targets for intervention or prevention of
to best determine treatment options to prevent long-term adverse brain injury. The mechanisms leading to neuronal injury in the
neurological outcomes. IUGR neonatal brain are complex and not well understood.
Although the IUGR fetal brain is often referred to as hypoxic-
2.1. Grey and white matter injury in IUGR ischemic (HI) [34], the IUGR fetal brain is not generally regarded
as globally ischemic as blood ow is actually increased to many
Brain injury in the IUGR infant may be due to a combination of regions of the brain [35e37]. However, the IUGR fetus is relatively
grey matter and white matter disruption and disorganisation in the hypoxic due to chronic placental oxygen deprivation. The chronic
development of the brain. Clinical imaging studies of preterm IUGR IUGR insult leads to a reduction in oxygen delivery to the brain and
infants have demonstrated signicant alterations in white and grey concomitant reduction in delivery of glucose and amino acids with
matter volume and structure [17e19] including decreased cortical potential effects on immature neurons and neuroglia [34]. When
thickness, delayed cortical development and altered brain con- cerebral oxygen is reduced, a cascade of cellular and biochemical
nectivity [17e19] in comparison to non-IUGR preterm infants. In events occurs in the fetal brain causing cellular injury that can lead
IUGR infants cortical grey matter volume is 28% less than that of age to cell death [36]. Many of these events result in mitochondrial
equivalent healthy term-born infants [17]. Reduced cerebral disruption and immediate or delayed cell death [34]. The major
cortical grey matter volume in the term IUGR neonate has been putative mechanisms that may underpin the cellular death and
shown to correlate with attention disorders [17]. Furthermore, such injury in IUGR brains are excitotoxicity, oxidative stress, necrotic
grey matter structural changes in the term IUGR infant that persist and apoptotic degeneration and neuroinammation [34,38].

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4. Inammation in the IUGR brain preterm neonates demonstrated signicantly higher levels of
proinammatory cytokines in the blood during the second post-
Recent studies in animal models of growth restriction have re- natal week; however at birth there was no evidence of this increase
ported increased numbers of activated microglia and astrogliosis, [67]. In umbilical cord serum from IUGR neonates at birth, inter-
indicative of inammatory responses in the IUGR brain (Table 1) feron-g (INF-g) levels have also been reported to be raised and may
[22e27,31,39,40]. Neuroinammation encompasses a number of be related to fetal growth restriction [69]. Furthermore, in mothers
processes including increased numbers of activated microglia, of IUGR infants, stimulation of maternal peripheral blood by
elevated production of proinammatory cytokines (particularly trophoblast antigens showed increased levels of proinammatory
interleukin-1b (IL-1b) and tumour necrosis factor-a (TNF-a)) cytokines, IL-8, INF-g and TNF-a [70] with decreased levels of the
[41e43], decreased production of anti-inammatory cytokines anti-inammatory cytokine IL-10 when compared with mothers of
[44], release of chemokines [44e46], increased production of nitric normally grown infants [70]. Whether the increases in systemic
oxide (NO) [47,48], inltration of leukocytes [45] and astrogliosis proinammatory cytokine expression in these IUGR infants are
[48e52]. However many previous IUGR studies have examined associated with adverse neurological outcome is not yet clear.
only changes at one postnatal time point or changes of only select However we can be guided by a study on small for gestational age
inammatory cytokines. The neuronal damage and loss which re- (SGA) newborns where blood concentrations of inammatory
sults from neuroinammation is a dynamic process and can proteins were examined during the rst two postnatal weeks and
continue for days or even weeks after a neonatal hypoxic insult correlated with mental development at two years of age [68].
[51,53,54]. It is important to focus future studies on the evolving Extremely preterm SGA newborns were at increased risk of lower
impact of inammation on neuronal injury in the IUGR neonate. mental development scores. When these SGA infants presented
Whether the IUGR fetus adapts to this milder chronic HI event such with systemic inammation at two weeks of age, they were at an
that the neuronal damage is not as severe is unclear. However, even greater risk of attaining a lower mental development score at
given the neurodevelopmental disabilities prevalent in these chil- two years of age [68].
dren, these adaptations may be mild. A thorough spatial and tem-
poral examination of inammation and neuronal injury in the IUGR 5.2. Proinammatory cytokines in the IUGR brain
neonate is warranted.
Overproduction of proinammatory cytokines is proposed to be
5. Proinammatory cytokines important in the development of neonatal brain injury [61]. Yet,
few studies have focused on its expression in the IUGR brain. In an
Proinammatory cytokines are shown to play a critical role in IUGR model of chronic hypoxia (chronic fetal hypoxemia; CHX),
acute HI brain injury and may cause and/or exacerbate brain inammatory cytokines are found to be upregulated in the fetal
damage to the fetal and neonatal brain. The on-going presence of brain [22]. TNF-a and IL-1b are increased in response to CHX with
increased levels of proinammatory cytokines contributes to white the elevation in proinammatory cytokines relative to the severity
matter damage as well as neuronal damage after acute neonatal HI of brain injury [22]. Similarly, in a rat model of growth restriction
[41,48,53,55,56]. In the preterm infant, the occurrence of CP has with lipopolysaccharide treatment, a robust increase in cytokine
been attributed, at least partially, to increased levels of proin- macrophage chemoattractant protein-1 (MCP-1) and cytokine
ammatory cytokines in the brain [57]. The long-term conse- induced neutrophil chemoattractant protein-1 (CINC-1) was
quences on neurodevelopment of the IUGR infant may be due to evident in the IUGR rats in comparison to controls [39]. Cytokine
effects of neuroinammation generated by proinammatory cyto- increases are not only evident in the brain of IUGR animals; in a rat
kines in the IUGR brain. model of growth restriction an increase in the proinammatory
Proinammatory cytokines, such as IL-1b, TNF-a, IL-6 and IL-8 cytokines IL-6, TNF-a and IL-1b have also been observed in both the
are small, cell signalling glycoproteins involved in communication amniotic uid and placentas [71]. The increased levels of these
between cells [58] and are secreted in response to cellular injury. cytokines are evident as early as 24 h in the amniotic uid and
Proinammatory cytokines are released by a variety of cells both in placenta after bilateral uterine artery ligation. These studies
the brain and also in the blood in response to hypoxic injury. As conrm not only a systemic inammatory response, but also a
described below, activated microglia are the major source of IL-1b central inammatory response. As an increase in BBB permeability
and TNF-a in the central nervous system (CNS) [59e61]. IL-6 is occurs in the IUGR neonate [40] it is uncertain whether there is an
produced during astrogliosis where an abnormal increase in the inltration of inammatory mediators into the brain of the IUGR
number of astrocytes occurs in the brain. IL-8's release into the neonate or whether inammation is originating from the brain, and
cerebral spinal uid after brain injury has been shown to be asso- the BBB breakdown facilitates brain derived inammatory cells into
ciated with blood brain barrier (BBB) dysfunction [62]. Proin- the blood.
ammatory cytokines promote the progression of injury through
complex interactive networks, such as stimulating the synthesis of 6. Activated microglia and reactive astrocytes
other cytokines and mediators of neuronal injury including NO
synthase, inducing leukocyte inltration and the expression of 6.1. Activated microglia
adhesion molecules, inuencing glial gene expression and
damaging oligodendrocytes [63]. Both TNF-a and IL-1b can also Microglia are the rst inammatory cells that respond to hyp-
activate matrix metalloproteinases (MMP) which leads to the oxic events in the neonatal brain [72]. Microglial cells are resident
disruption of the immature BBB [64,65]. Furthermore, altered BBB macrophages in the brain and are present in large numbers in the
function after HI injury facilitates entry of systemic proin- developing brain. Microglia are involved in cellular pruning during
ammatory cytokines into the brain of the fetus [66]. both normal development and pathological conditions. Resting
(ramied) microglia in the neonate have multiple processes with a
5.1. Systemic proinammatory cytokines in IUGR small cell body [73]. Microglial cells function to defend against
infections or toxic substances released from dying brain cells by
Recent human studies report the presence of systemic inam- scavenging and engulng unwanted pathogens and cellular debris
mation in IUGR neonates [67,68]. Severely growth restricted [74]. Microglia become activated in response to chemical signals

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Table 1
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Glial and inammatory responses in animal models of fetal growth restriction.

IUGR Insult Model Time Frame Brain region Outcomes Other

Insult Examination Microglia Astrocytes Oligos Neurons Cytokines

Pregnant rats exposed Rat E5eE19 P3, P10 and P21 white matter increased decreased Nitric oxide helps
to hypoxic (NO given 12e24 h microglial proliferation and counteract hypoxia by
conditions and nitric prior to delivery activation differentiation decreasing cell death and
oxide inhalation until P5) microglial activation,
(Pham et al., 2015) increasing oligodendroglial
[27] proliferation and improving
myelination.
Chronic placental Rat GR E20; BrSp P3eP21 hippocampus, astrogliosis decreased BrSp alleviated the GR
insufciency with supplement given corpus callosum hippocampus effects of diminished white
broccoli sprout to dams E15-P14 and cingulum neural cells matter, ventricular dilation,
supplement (Black (term is 23 days) astrogliosis, and reduced
et al., 2015) [23] hippocampal neural cells.
Bilateral uterine artery Rat GD18 uids taken post n/a increase in Mg supplements decreased
ligation and delivery cytokines effects of GR. No signicant
magnesium difference in maternal and
supplement (Roman fetal plasma. Signicant
et al., 2013) [71] increases in IL-6, IL-1b,
TNF-a, and CCL2 (MCP-1)
and CSCL1 levels 24 h post-
surgery in amniotic uid
and placenta.
Uteroplacental Rat E19.5 at birth P0 hippocampus changes specic to changes specic to decreased locations GR induces neuronal,
insufciency (Fung gender gender specic to gender astrocytic and immature
et al., 2012) [31] oligodendrocyte decits in
a region and sex specic
manner. GR increased the
amount of dentate gyrus
astrocytes in males only. GR
decreased the amount of
CA3 astrocytes in males
only. GR signicantly
increased amount of CA1
immature oligodendrocytes
in females but decreased
the amount in males.
Maternal uterine artery Rat GD14 P6 whole brain and no difference in no astrogliosis no white matter LPS elevated GR rats with LPS treatment
ligation and entire numbers without without LPS impairment proinammatory demonstrated enhanced
lipopolysaccharide periventricular LPS treatment treatment without LPS cytokines brain damage with
(Campbell et al., white matter treatment increased apoptosis, large
2012) [39] ventricles and impaired
myelination, activated
microglia and astrogliosis.
Transient systemic Rat GD18 (Third GD22 (P1) frontal lobe, loss of loss of neural cells EPO administration rescued
hypoxia-ischemia/ Trimester) coronal sections oligodendrocytes oligodendrocytes and
placental (ventral neural cells.
insufciency (Mazur hippocampal
et al., 2010) [21] commissure-
anterior temporal
horn)
Maternal unilateral Rat E17 E21, birth (P0), P3, white matter microglial astrogliosis loss of White matter lesions were
uterine artery P7, P10, P14, P21 activation oligodendrocytes - smaller in pups with
ligation (Olivier and P60 (in adults) may be restored in moderate GR and larger in
et al., 2007) [25] P14 moderate GR pups with severe GR - rats
pups with severe GR white
matter damage persisted to
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adulthood.
Maternal unilateral Rat E17 E21, birth (P0), P3, white matter increased microglia astrogliosis loss of Defective myelination until
uterine artery P7, P10, P14, P21 oligodendrocytes adulthood.
ligation (Olivier and P60 (in adults)
et al., 2005) [24]
Chronic placental Guinea Pig GD30 (term is 67 GD60e62 subventricular zone no difference in no astrogliosis increase in Blood vessel density
insufciency (Tolcos days) (SVZ) density or neuronal precursor increase with cell
et al., 2015) [85] morphology cells proliferation to counter
effects of CPI.
Chronic placental Guinea Pig GD30 (mid Day of birth (GD 67) cerebral Increase in Increase in oligos reduced in Delay in oligodendrocyte
insufciency (Tolcos gestation) 1 week or 8 weeks hemispheres/ microglial density astrocyte density at GR fetuses - post maturation and
et al., 2011) [26] cerebellum/white at GD60 in WM. No GD60 in WM. No natal recovery myelination in utero is
matter difference at 1 difference at 1 transient. Myelin restored
week of age week of age postnatally.
Chronic fetal Guinea Pig GD46e49 for 14 Days 64e65 hippocampus microglial loss of neuronal increase in Fetal adaptive response to
hypoxemia (Guo days activation cells cytokines chronic hypoxia is
et al., 2010) [22] maladaptive.
Spontaneous growth Guinea Pig GD28e30 (term is P6 medulla no difference Alterations in respiratory
restriction and 66e68 days) between groups and thermoregulatory
unilateral uterine responses with greater
artery ligation effects seen following
(Tolcos et al., 2003) spontaneous GR rather than
[87] experimental GR.
Unilateral uterine Guinea Pig GD30 Day 4e7 hippocampus and decrease in amount Reduced volume of cerebral
artery ligation cerebellum of neurons WM.
(Mallard et al., 2000)
[28]
Maternal unilateral Guinea Pig GD28e30 (term is GD60-62 brainstem regions proliferation of no change Proliferation of astrocytes
uterine artery 66e68 days) astrocytes in the dorsal motor nucleus
ligation (Tolcos and of the vagus, nucleus
Rees 1997) [88] tractus solitarius and
around blood vessels
throughout the brainstem.
Vascular IUGR (Bassan Rabbit GD25 (third GD29 (term is 31 cerebral decline in astrocyte Small fetuses, small body
et al., 2010) [86] trimester) days) hemispheres and index large head, asymmetric GR.
posterior fossa
Chronic placental Lamb GD105e110 (term P1 white matter astrocyte GR lambs demonstrate
insufciency is 145 days) attachment lost reduced vessel density
(Castillo-Melendez within the WM.
et al., 2015) [40] Attachment of astrocytes
and pericytes to blood
vessels is reduced in GR
lambs, which may impact
the integrity of the BBB.
Single umbilical artery Sheep GD105e110 24 h after birth white and grey white matter loss; no consistent loss WM tracts were
ligation and matter: forebrain, hypomyelination of neurons in fragmented and
melatonin treatment hippocampus, cortex; neuronal disorganised in GR brains.
(Miller et al., 2014) thalamus, cerebral degeneration in Cortical organisation and
[29] cortex hippocampus neuronal morphology
altered in some GR brains,
especially within deeper
layers of the cortex.

GD, gestational day; E, embryonic day; LPS, lipopolysaccharide; GR, growth restriction; CPI, chronic placental insufciency; P, postnatal day; BrSp, Brussel sprout; OL/Oligos, oligodendrocyte; WM, white matter; NO, nitrous oxide; Mg,
magnesium; IL-1b, interleukin-1b; TNF-a, tumour necrosis factor-a; MCP-1, macrophage chemoattractant protein-1; CINC-1, cytokine induced neutrophil chemoattractant protein-1.
6 J.A. Wixey et al. / Placenta xxx (2016) 1e8

from injured neurons where they increase in number and migrate a loss of peri-vascular astrocyte attachment. Astrocytes are also
to sites of injury [45,75e78]. Activated microglia are morphologi- essential for the maintenance of the BBB [40] and disruption to this
cally distinct from resting microglia. When activated, their pro- cell type may mitigate the inltration of systemic inammatory
cesses retract to develop a more rounded, amoeboid appearance mediators into the brain.
[73]. Activated microglia increase their tendency to bind lectins, A further study in rat pups with prenatal moderate and severe
up-regulate immunological surface proteins, and release nitric growth restriction induced by unilateral ligation of the uterine ar-
oxide (NO) and proinammatory cytokines [79e81]. Activated tery reported increased activated microglia and astrogliosis in the
microglia are largely responsible for the production of excessive white matter [25]. A notable inammatory response with
levels of the proinammatory cytokines, IL-1b and TNF-a, that are concomitant white matter injury in the severe growth restricted rat
toxic to neurons [45,75,78]. It is unclear whether the injured neu- pup was apparent. Activated microglia were signicantly elevated 2
rons initiate the activation of microglia, or the activated microglia weeks after birth, at a critical time point when white matter
release factors which injure the neurons; regardless, the result is a remodelling and neuronal pruning is occurring, which will have
cyclic pro-inammatory event. long-term consequences on the developing brain [25].
Gender differences have also been reported in several IUGR
6.2. Reactive astrocytes studies. In a model of uteroplacental insufciency in the rat, region
and gender specic changes in astrocytic decits were observed in
Astrocytes, the most abundant glial cells in the brain, are the hippocampus [31]. A signicant increase in the amount of as-
involved in maintenance and support of neurons as well as trocytes in the dentate gyrus was apparent in males with a con-
comprise a signicant component of the BBB. In healthy neural trasting decrease in astrocytes in the CA3 region. As IUGR males
tissue, astrocytes play critical roles in energy provision, regulation demonstrate worse behavioural decits than females, differences
of blood ow, homeostasis of extracellular uid, homeostasis of in astrocyte response to injury and subsequent inammatory re-
ions and transmitters, and regulation of synapse function [82]. sponses in the brain may account for the higher rate of adverse
Astrocytes are critical in fetal development for providing scaf- outcomes in the IUGR male.
folding for migrating neurons to form the layers and substructures
of the brain [83]. Like microglia, the morphology of astrocytes de- 7. Conclusion
pends on the health of the tissue around them. In healthy CNS,
astrocytes exhibit large processes and a distinct star shape. Astro- Chronic deprivation of oxygen and nutrients to the developing
cytes become reactive in response to signals released by injured fetus through altered placental function has dramatic conse-
neurons or activated microglia following an event such as HI injury quences on fetal brain development. Activation of inammatory
[84]. Reactive astrocytes undergo morphological changes where pathways both systemically and in the brain are thought to play a
they divide and become hypertrophic with short and thickened key role in altered brain development and may contribute to the
processes [84]. Reactive astrocytes release various growth factors poor neurodevelopmental outcomes associated with chronic
and cytokines (TNF-a and IL-1b) which exacerbate brain injury. placental insufciency [67,68]. Understanding how the IUGR brain
Reactive astrocytes are also known to physically block neuronal is damaged by examining where inammation is occurring, when it
regeneration and therefore inhibit functional recovery. is occurring and its impact on various cell types and white matter
will facilitate the development of appropriate targeted therapies to
6.3. Activated microglia and reactive astrocytes in IUGR brain improve neurodevelopmental outcomes.

The limited studies examining microglial and astrocytic Funding


response in the IUGR brain have shown varying results. In a
neonatal rat model, antenatal hypoxia-induced IUGR was found to This work was supported by The University of Queensland
be associated with severe neuroinammation and delayed myeli- Medicine and Biomedical Sciences Emerging Leaders grant and
nation. Increased microglial activation was apparent in the devel- Royal Brisbane and Women's Hospital Foundation research grant.
oping white matter at postnatal day 3 and 10 as well as an increased
density of astrocytes in the cingulate white matter of IUGR pups
Conict of interest statement
[27]. In contrast, a guinea pig model of chronic placental insuf-
ciency (CPI) demonstrated no difference between controls and
The authors declare that they have no conict of interest.
IUGR guinea pigs in density or morphology of microglia in the
subventricular zone (SVZ) at 60 days of gestation [85]. In addition,
Acknowledgements
no changes in the density of astrocytes or evidence of reactive
morphology of astrocytes in the SVZ were apparent [85]. Yet the
This review was generated as part of the Queensland Perinatal
SVZ is a site where few activated glia reside. Furthermore neuronal
Consortium Inaugural Conference held on July 15th, 2016 in Bris-
death was not observed in the SVZ but was evident in other regions
bane, Queensland Australia. The conference was supported by an
of the brain [85], therefore this region is likely less affected by
Intra-Faculty Collaborative Workshop grant from the Faculty of
inammation in IUGR neonates. Further regions of the brain war-
Medicine, The University of Queensland. The authors thank Sydney
rant exploration at multiple postnatal time points.
Peterson for assistance with Table 1.
However the majority of studies demonstrate a denitive
astrocytic response in the IUGR brain. A reduced number of mature
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Please cite this article in press as: J.A. Wixey, et al., Review: Neuroinammation in intrauterine growth restriction, Placenta (2016), http://
dx.doi.org/10.1016/j.placenta.2016.11.012