Emerging Concepts in
Periventricular White Matter Injury
Stephen A. Back, MD, PhD,* and Scott A. Rivkees, MD†
Approximately 10% of newborns are born prematurely. Of these children, more than 10%
will sustain neurological injuries leading to significant learning disabilities, cerebral palsy,
or mental retardation, with very low birth weight infants having an even higher incidence of
brain injury. Whereas intraventricular hemorrhage was the most common form of serious
neurological injury a decade ago, periventricular white matter injury (PWMI) is now the
most common cause of brain injury in preterm infants. The spectrum of chronic PWMI
includes focal cystic necrotic lesions (periventricular leukomalacia; PVL) and diffuse myelination disturbances. Recent neuroimaging studies support that the incidence of PVL is
declining, whereas diffuse cerebral white matter injury is emerging as the predominant
lesion. Factors that predispose to PVL include prematurity, hypoxia, ischemia, and inflammation. It is believed that injury to oligodendrocyte (OL) progenitors contributes to the
pathogenesis of myelination disturbances in PWMI by disrupting the maturation of myelin–
myelin-forming oligodendrocytes. Other potential mechanisms of injury include activation
of microglia and axonal damage. Chemical mediators that may contribute to white matter
injury include reactive oxygen (ROS) and nitrogen species (RNS), glutamate, cytokines,
and adenosine. As our understanding of the pathogenesis of PWMI improves, it is anticipated that new strategies for directly preventing brain injury in premature infants will
evolve.
Semin Perinatol 28:405-414 © 2004 Elsevier Inc. All rights reserved.
T
he care of premature infants has improved markedly
over the past few decades, resulting in striking improvements in the survival of very low birth weight (VLBW) infants
(⬍1.5 kg). However, improved survival of premature infants
has been accompanied by increasing recognition of longterm neurological deficits. At least 10% of preterm survivors
will develop the spastic motor deficits of cerebral palsy and
up to 50% will be identified with learning disabilities.1-6 Several forms of brain injury are observed in premature infants
that include intraventricular hemorrhage (IVH), intraparenchymal hemorrhage, and PWMI. Whereas medical interventions have resulted in a pronounced decrease in the incidence
of IVH,7,8 the incidence of PWMI is not decreasing.8,9 Thus
PWMI is now the major neurological problem that affects
VLBW infants.
*Department of Pediatrics, Oregon Health Science University, Portland, OR.
†Yale Child Health Research Center, Yale University, New Haven, CT.
Address reprint requests to: Scott A. Rivkees, MD, Director, Yale Child Health
Research Center, Yale Pediatrics, P.O. Box 208081, 464 Congress Avenue,
New Haven, CT 06520. E-mail: Scott.Rivkees@yale.edu
0146-0005/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2004.10.010
Pathological Features
of Periventricular
White Matter Injury
PWMI includes a spectrum of cerebral injury that ranges
from focal injury to extensive cerebral white matter lesions
(diffuse PWMI).8,10 PVL is characterized by focal cystic–necrotic lesions that commonly occur in the subventricular
zone (SVZ) adjacent to the lateral ventricle and involve injury
to all cellular elements.10 Such lesions may be accompanied
by reduction in white matter volume, secondary cyst formation or ventricular enlargement. Multiple neuropathology
studies indicate that diffuse PWMI is characterized by extensive regions in deep cerebral white matter that contain numerous reactive astrocytes (ie, “diffuse gliosis”) and fail to
normally myelinate. Diffuse PWMI may be accompanied by
PVL or occur as an isolated lesion.11-15 Although diffuse gliosis is believed to arise in response to extensive white matter
damage, the injured cell types that provoke this gliosis remain unresolved but are hypothesized to be oligodendrocyte
progenitors,10 because such lesions occur in a similar distribution to regions of myelination disturbance. Recent neuroimaging studies support that the incidence of cystic necrotic
405
406
lesions (PVL) is declining, whereas diffuse cerebral white
matter injury is emerging as the predominant lesion.16-18 In
these recent series, cystic PVL lesions accounted for less than
5% of cases. The ability to recognize neonatal white matter
injury has been greatly facilitated by the use of diffusionweighted imaging (DWI).16 Using DWI, abnormal white matter signals are observed in up to 68% of former preterm
infants when studied at term equivalency. Abnormalities detected with DWI are believed to reflect reduced myelin axonal myelination, but neuropathological confirmation is still
lacking.
Risk Factors for PWMI
Several factors are associated with the development of PWMI,
the most prominent of which is prematurity. Other risk factors include apnea with hypoxia, bradycardia, intrauterine
growth retardation and preeclampsia. The major pathogenetic mechanisms proposed for PVL are maternal–fetal infection19,20 and impaired cerebrovascular autoregulation that
results in cerebral ischemia.21,22 Either mechanism may be
operative during fetal development or in the neonate, and are
not mutually exclusive. Fetal exposure to endotoxins or cytotoxic cytokines occurs in the setting of chorioamnionitis,
and in experimental models these agents can trigger white
matter injury through vasoactive mechanisms that result in
cerebral ischemia.23,24 Although inflammatory-mediated
mechanisms related to maternal fetal infection in near-term
and term infant are strongly correlated with risk for later
cerebral palsy, recent studies have failed to identify a similar
relationship in premature infants by examination of either
intrauterine exposure to infection or inflammatory cytokines
in neonatal blood.25,26
A complex interplay of factors related to cerebrovascular
immaturity appear to predispose preterm human periventricular white matter to injury from ischemia. Vascular end
zones exist in the cerebral white matter that are supplied by
long or short penetrating arteries that arise from the pial
arteries.27,28 Volpe has proposed that the occurrence of severe
or persistent ischemia in vascular end zones of long penetrating arteries that supply the periventricular white matter may
account for the focal cystic-necrotic lesions of PVL.8 The
occurrence of less severe or briefer episodes of ischemia in the
territory of more superficially situated end zones of short
penetrating arteries may account for the more extensive myelination disturbances commonly associated with diffuse
PWMI.8 Ample evidence supports that the propensity for the
premature neonate to exhibit a pressure-passive circulation is
related to disturbances of cerebral autoregulation.29-31 Basal
cerebral blood flow in healthy preterm neonates is markedly
lower than in term infants or adults.32-35 Basal flow to cerebral
white matter was estimated to be less than 20% of gray matter.36 Direct experimental evidence that human periventricular white matter is selectively susceptible to ischemia is, however, lacking. Recently, Tsuji and coworkers provided
indirect evidence with near infrared spectroscopy that impaired cerebrovascular autoregulation was highly correlated
with the development of PVL and germinal matrix-intraven-
S.A. Back and S.A. Rivkees
tricular hemorrhage.37 With the advent of more sensitive modalities to identify the at-risk preterm neonate, it is clear that
an understanding of the vascular basis of preterm white matter injury is needed and will require the application of new
technologies in appropriate animal models (see below) to
measure blood flow to defined regions of vulnerable white
matter.
The Developing
Brain is at High Risk for
Oxidant-Mediated Damage
Oxidative stress resulting from the generation of injurious
reactive species or oxidants is a well-established sequela of
ischemia–reperfusion.38 Several models of perinatal asphyxia
in the term fetus have demonstrated increased free radical
generation in the developing cerebrum. Electron spin resonance studies found that free radical generation is most pronounced during the initial period of reperfusion.39,40 Elevations in lipid peroxidation products, protein carbonyls, and
biomarkers of reactive nitrogen species were detected 8 minutes after the onset of reperfusion in a near term fetal rabbit
model of placental insufficiency. Administration of antioxidants to the mother after the onset of this insult resulted in
decreased brain injury implicating the important role of reactive species in brain injury from hypoxia–ischemia.41,42
The fetal brain is especially prone to lipid peroxidation-mediated injury, because of the abundance of membrane lipids.43,44 The aldehydes formed from lipid hydroperoxides are
most specifically detected in glia by measurement of F2-isoprostanes.45 Increased lipid peroxidation has been observed
in lipid extracts from the entire brain of normal premature
guinea pigs that peaks at around 60% term gestation. Following hypoxia, increased lipid peroxidation was observed in
brains obtained at around 80% term gestation.46 In the preterm human fetus, elevated lipid peroxidation products have
been detected in periventricular white matter.15,47 In the preterm human fetus, antioxidant defenses appear to be underdeveloped compared with the term fetus.48 In guinea pig
brain, most of the antioxidant enzyme systems increase and
attain adult levels in the last 30% of the gestation period.49
The developing brain may be more vulnerable to oxidative
damage due to a lag in the expression of the potentially protective enzymes superoxide dismutases-1 and -2, catalase,
and glutathione peroxidase in the white matter of the human
fetus.50 There is thus little direct information from experimental models about the extent of free radical generation in
the preterm fetus in response to ischemia–reperfusion and
cerebral white matter has not been specifically studied.
Human
Oligodendrocyte Development
and Damage in PVL
OLs develop according to a well-established lineage, defined
by stage-specific antibodies specific for sequentially ex-
Periventricular white matter injury
Figure 1 The four stages of oligodendrocyte development. The antigens expressed at each stages are listed in the bottom panel.
pressed OL cell-surface and myelin-specific epitopes.51,52
The successive OL stages are distinguished by a progressively
more complex morphology (Fig. 1). The OL progenitor is
identified by the A2B5 monoclonal antibody in vitro or by
NG2, in vivo. The preOL is a simple multipolar, mitotically
active late OL progenitor identified with the O4 but not the
O1 monoclonal antibodies. The immature OL is a postmitotic complex multipolar cell identified by the O1 antibody
that binds to galactocerebroside. The mature OL is identified
by myelin-associated markers that include myelin basic protein. It is, thus, feasible to precisely define the timing and
features of OL lineage progression both in vitro and in vivo.
Since the major period of vulnerability for PWMI (23-32
weeks gestation) occurs before the onset of myelination,
Volpe first proposed that the myelination disturbances of
PWMI might arise from targeted death of OL progenitors that
are the source of mature OLs.48 This hypothesis proposes that
the predilection for PWMI is related to a developmentallyregulated susceptibility of more immature stages of the OL
lineage to oxidative stress, a well-established sequela of both
hypoxia–ischemia53 and maternal-fetal infection.20 In support of this hypothesis we found that the developmental window of highest risk for PWMI (ie, about 23-32 weeks
postconceptional age) corresponds to a period in white matter development before the onset of myelination.51 This period coincides with the presence of one major population of
preOLs in cerebral white matter and identifies the preOL as a
target for injury in PWMI. The decline in risk for PWMI
coincides with the onset of a wave of differentiation of preOLs to immature OLs that initiate myelination of periventricular white matter.52 Several lines of evidence in support of
a role for targeted preOL death in the pathogenesis of PWMI
derive from in vitro and in vivo experimental models.
Maturation-Dependent
Vulnerability of
the Oligodendrocyte
Lineage to Oxidative Stress
OL progenitors display maturation-dependent vulnerability
to oxidative stress in vitro and hypoxia–ischemia in vivo.54-59
407
The notion that OL progenitors display enhanced susceptibility to oxidative stress was initially supported by in vitro
studies that compared the susceptibility of successive stages
in the OL lineage to intrinsic and extrinsic sources of oxidative stress. We initially demonstrated that preOLs are markedly more susceptible than mature OLs to intrinsic and extrinsic sources of oxidative stress.54 We defined an oxidative
stress pathway in which intracellular depletion of glutathione
triggered a downstream rise in reactive oxygen species (ROS)
that lead to preOL death. Interestingly, the E2-isoprostanes, a
lipid peroxidation product, are particularly toxic to OL progenitors, but not mature OLs, which suggests that specific
compounds generated endogenously from oxidative stress
might be a potential mechanism for OL degeneration in
PWMI.60 Several recent in vitro studies found that caspasemediated death of OL progenitors occurs and after oxidative
stress in vitro.58,61,62
If targeted death of the preOL is related to the pathogenesis
of PVL, then preOLs should demonstrate enhanced susceptibility to hypoxia–ischemia, a common sequela of critical
illness in the premature neonate. In a perinatal rodent model
of hypoxia–ischemia, we found that preOLs are highly susceptible to hypoxia–ischemia, whereas earlier and later OL
stages are markedly more resistant. The enhanced susceptibility of preOLs was a stage-specific property that was independent of the postnatal age of the animal or the location of
these cells in the forebrain. Hence, targeted death of preOLs
could contribute to the pathogenesis of PWMI across a broad
range of gestational ages and in multiple susceptible regions.
We and others have found that caspase-mediated mechanisms of apoptosis at least partially contribute to preOL death
from hypoxia–ischemia.56,63-65 In summary, multiple experimental studies support a developmental explanation for the
predilection for PWMI to occur during prematurity that is
related to the presence of a susceptible population of preOLs
in the periventricular white matter.
Microglia Induced Cell Injury
The observation that activated microglia are present in the
brains of infants with PVL, raises the possibility that this
inflammatory cell type may contribute to preterm brain injury.14,66,67 Microglia are macrophage-derived cells involved
in the response of the brain to inflammatory and metabolic
insults.68-71 Microglia are present in the fetal brain by midgestation, and are expressed in developing white matter.72,73
Microglia are small, ramified cells with branching processes
and dynamically respond to changes in the microenvironment.68-71 Microglia have membrane receptors for several
neurotransmitters,74,75 including purinergic receptors74 that
are stimulated by ATP and adenosine. Microglia are also responsive to excitatory neurotransmitters including glutamate71 In response to altered levels of neurotransmitters
and/or cytokines, microglia are activated.68,71,76,77 Reactive
microglia are nonramified cells that secrete a variety of cytokines that exert toxic effects on neurons and oligodendrocytes.68,71,76,77 These factors include tumor necrosis factor-␣
(TNF-␣), IL-1␤, interferon-gamma (INF-␥) and superoxide
408
radicals.68,71,76,77 Microglial factors that may project against
cell injury including the cytokines TGF-␤1, IL-4, bFGF and
NGF.68,71,76,77 Nitric oxide production by activated microglia
generates reactive nitrogen species that are toxic to both preOLs and mature OLs in vitro.78-82 In vitro studies also support
the notion that microglial are required to promote the toxicity of inflammatory mediators. Vartanian showed that activation of the microglial Toll-like receptor TLR4 is required for
endotoxin to promote the acute degeneration of oligodendrocyte progenitors in vitro.83
Perinatal Neuronal Injury
Despite the particular predilection of the preterm infant to
white matter pathology, increasing evidence suggests that
neuro-axonal gray matter injury may contribute to the longterm deficits that accompany PWMI in survivors of premature birth. Volumetric MRI studies of infants with PWMI
found reductions in gray matter volumes in several brain
regions that prominently included the cerebral cortex.84
There have been, however, no neuropathological studies to
directly account for the mechanisms underlying the reductions in gray matter volume. Although the cerebral cortex is
typically spared in PWMI, extensive neuronal necrosis, thalamic infarcts and pontosubicular necrosis can be observed
together with PWMI.10
A number of recent experimental findings are consistent
with maturation-dependent susceptibility of developing gray
matter to hypoxia–ischemia. We recently reported that after
hypoxia–ischemia, preterm fetal rabbits sustained injury to
the basal ganglia and anterior thalamus, which are major
components of subcortical motor pathways. At birth, hypertonic motor deficits that resemble early cerebral palsy were
observed in the preterm survivors. These regions are particularly susceptible to hypoxic–ischemic injury in both preterm and term infants.85,86 Likewise, the thalamus and basal
ganglia are particularly susceptible to hypoxia–ischemic injury in preterm and near-term fetal sheep subjected to global
cerebral hypoperfusion87 (Back and Hohimer, unpublished
observations). It, thus, appears that susceptibility of the developing gray matter to injury also will be maturation-dependent and involve preferential injury to particular neuronal
populations. Within the cerebral cortex, fetal rabbits showed
a predilection of apparent subplate neurons to injury consistent with recent observations that hypoxia–ischemia preferentially targets these neurons in the perinatal rat.88
In chronic sublethal hypoxia, reduction in gray matter
volume is observed in several brain regions including the
cerebral cortex, thalamus, and striatum.89 Recent data show
that chronic sublethal hypoxia is associated with reduced
neuronal number (see chapter by Schwartz and colleagues).
In neonatal rats reared in 10% oxygen, H-NMR spectroscopy
reveals lower levels of brain N-acetyl aspartate levels, which
suggests reductions in neuronal number (R. Rao, personal
communication). Levels of glutamate, GABA, and phosphocreatine are also lower than in control animals. Glutamate:
glutamine ratios are higher in hypoxia, which indicates reduced neurotransmitter recycling.
S.A. Back and S.A. Rivkees
Several mediators of neuronal loss in the developing brain
have been identified that include excitatory neurotransmitters, free radicals, and iron.90,91 Evidence recently generated
from our laboratory suggests that the neuromodulator adenosine may contribute to injury in developing neurons by
altering intracellular calcium levels.92 Although not well
characterized in PWMI, it is likely that brain injury may be
associated with altered levels of neurotrophic agents and
other factors that influence axon growth and synaptogenesis.
Potential Chemical Mediators
of Preterm Brain Injury
PWMI causation is complex and will likely involve the action of
different neurochemicals and cytokines. In addition to reactive
oxygen and nitrogen species, other factors considered to play a
role in PWMI include excitatory amino acids, iron deposition,
and inflammatory cytokines.93 Activated microglia release a
number of cytokines that are toxic to OLs. The microglial products TNF-␣ and interferon-␥ (INF-␥) are directly toxic to preOLs and mature OLs94-97 and in combination their toxicity is
synergistic.98 Recently, INF-␥ immunopositive cells were localized in necrotic foci in premature infants with white matter
injury.99 Free iron contributes to the generation of toxic ROS
and is directly toxic to oligodendrocytes. IVH increases the risk
of PWMI and elevated levels of iron can be observed in the spinal
fluid of such infants.
Multiple studies indicate that OLs play a central role in
CNS iron metabolism and, thus, may be at risk for ironmediated oxygen radical toxicity. Within the adult rodent
and human CNS, including the white matter, ferric iron,
ferritin, and transferrin localize primarily to OLs, as well as to
some restricted populations of neurons, microglia and astrocytes.100-103 Myelin deficient rats, in which OLs fail to mature,
show significant reductions in the distribution of iron, transferrin, and the transferrin receptor in the CNS.104-106 Degeneration of preOLs subjected to oxidative stress107 was
prevented by pretreatment with the iron chelator desferrioxamine. A photochemically induced rise in ROS was also
blocked in OLs by desferrioxamine.108 In embryonic cortical
neurons, a broader role for iron chelators was proposed
based on the finding that the protection rendered by such
compounds against oxidative stress-induced apoptosis involves the activation of a collection of hypoxia-responsive
genes.109
Increased release of glutamate and glutamate action has
been implicated in rodent studies of preterm white matter
injury.110-112 It has been suggested that white matter injury is
associated with elevations of extracellular glutamate, possibly
due to axonal injury.8 In addition, with altered brain energy
supply, glutamate uptake is reduced. Glutamate-induced injury to preOLs is mediated by ionotropic glutamate receptors
(iGluRs) of the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate type.55,113-117 Recent data show
that preOLs also express metabotropic glutamate receptors
(mGluRs).112 However, activation of group 1 mGluRs attenuates OL excitotoxicity by controlling downstream oxidative
Periventricular white matter injury
stress after iGluR overactivation.112 Nonreceptor-mediated
mechanisms also can lead to glutamate-induced OL
death.54,107,118 Excessive extracellular glutamate causes glutathione depletion in preOLs with consequent free radical generation.54 This effect is related to activation of a glutamate–
cystine exchange transporter, which results in glutamate
uptake and cystine efflux.119-121 In turn, intracellular cystine
depletion leads to reduced glutathione synthesis, leading to
depletion of free radical scavengers.
Experimental Models of PWMI
Several experimental models have been developed to provide
insight into injury of the developing brain and include studies in rodents, rabbits, sheep and nonhuman primates. Models used to induce injury include ischemia–reperfusion, injection of endotoxin, administration of excitoxic agents, and
rearing in chronic sublethal hypoxia. These models are complementary and it is not clear that any one model is fully
representative of human PWMI.122,123
Rodents have been widely used for studies of neonatal
brain injury. In mice and rats, the first two postnatal weeks
are roughly similar to the last trimester of human gestation.124
To develop a model of perinatal H-I in the rat relevant to the
high-risk period for PWMI in humans, we recently defined
the timing of oligodendrocyte lineage progression in rats and
mice. We identified a period in early rodent cerebral development when the distribution of OL lineage stages coincides
with that of human during the high-risk period for PWMI.125
Each species was found to display a distribution of OL stages
at postnatal day 2 (P2) that was similar to that seen in premature human cerebral white matter. At P2, the cerebral
white matter of rodents, like premature infants,51 contains
predominantly preOLs. These studies also predicted that if
the vulnerable period for white matter injury in the rodent is
centered around P2, then it should decline thereafter, coincident with the onset of oligodendrocyte differentiation and
myelination between P7 and P14.126 We, confirmed that
white matter injury in the rat is maximal at P2 and declines
markedly by P7 when oligodendrocyte maturation occurs.56
It should be emphasized that this model and the widely used
Rice-Vannucci P7 rodent model of focal hypoxia–ischemia127
do not closely reproduce the pathological features of PWMI
in humans. These hypoxia–ischemia models generate extensive cortical and subcortical neuronal necrosis and apoptosis.
The particular value of these models resides, in part, in the
considerable experimental access they provide to questions
related to cellular and molecular mechanisms of injury to
immature cell types in the developing cerebrum. Excitotoxic
agents also have been studied in perinatal rodents to mimic
the effects of severe neonatal hypoxic–ischemic brain injury.
Injection of AMPA or ibotenate in neonatal rodents induces
focal white matter lesions that resemble cystic necrotic
PVL.128-132
Whereas acute hypoxia–ischemia models commonly trigger cortico-neuronal necrosis together with white matter injury, rearing newborn rats or mice in chronic sublethal hypoxia (CSH; 9-10% oxygen) appears to result in diffuse PWMI
409
without focal necrosis.89 CSH results in features similar to
those observed in PWMI, including ventriculomegaly, reduced white and gray matter volumes, and reduced myelination.89,133 Studies suggest that CSH is associated with arrested
oligodendrocyte lineage progression, reduced myelination,
and abnormal axon spouting.134,135
A distinct shortcoming of perinatal rodent models is that
they do not reproduce the many distinct physiological features unique to the premature human infant. For this reason,
a number of investigators are actively studying the pathological features of true fetal models. These studies have principally evaluated fetal rabbits, sheep and nonhuman primates.
Preterm rabbit fetuses subjected to sustained global hypoxia–
ischemia survive and display significant impairment of motor
activity related to hypertonic motor deficits.136 Histopathological studies identified a distinct pattern of acute injury to
subcortical motor pathways that involved the basal ganglia
and thalamus.136 These findings suggest that the rabbit may
provide a unique model for studying cerebral palsy.
The instrumented immature (0.65 gestation) fetal sheep
appears to be the optimal in utero animal model of relatively
specific white matter damage.20 The 0.65 gestation fetal
sheep is similar to human between 24 to 28 weeks in terms of
the completion of neurogenesis, the onset of cerebral sulcation, and the detection of the cortical component of the auditory and somatosensory evoked potentials.137-139 We found
that OL lineage maturation in 0.65 gestation ovine cerebral
white matter is developmentally similar to the 23 to 28 week
human fetus.140 Over the last 20 years there has been extensive in utero study of late-gestation fetal ovine cerebral blood
flow and metabolic rate of oxygen consumption under normal and pathological conditions. Important studies focused
on normal values and the vasodilatory role of hypoxia141,142
and hypercarbia.143 The immature fetus appears to be extremely vulnerable to hypotension and subsequent hypoxia–
ischemia. The immature fetus also has even less autoregulatory capacity than the term fetus.144,145 The immature sheep
fetus has a much lower cerebral blood flow (CBF) than the
late gestation fetus.146-148 Most significantly anatomically undefined cerebral white matter of the immature fetus had only
about 50% of the CBF of the cerebral cortex. These studies,
however, provided no information regarding blood flow specifically to periventricular white matter.
The predilection for periventricular white matter damage
appears to be greater in the preterm fetal sheep. Reddy and
coworkers reported an ovine model of white matter injury
generated by severe brain hypoperfusion imposed by chronic
bilateral ligation of the occipito-vertebral anastomosis and a
30-minute reversible occlusion of the carotid arteries.87 In
the near term (0.9 gestation) fetus, this insult caused primarily selective neuronal loss in the upper layers of the cortex
while in the immature fetus (0.65 gestation) the damage was
primarily to subcortical white matter.149 Chronic placental
insufficiency in the near term fetal sheep resulted in moderate
hypoxemia, cerebral cortical gliosis and myelination disturbances of subcortical but not periventricular white matter.150
Severe hemorrhagic hypotension in the 0.6 gestation sheep
caused periventricular white matter lesions in most (5/6) an-
S.A. Back and S.A. Rivkees
410
imals.151 We are currently defining a model of graded global
cerebral hypoperfusion. With increasing duration of ischemia, we generated graded selective cerebral white matter
injury that replicates the major histopathological features of
the spectrum of acute PWMI.140
Lipopolysaccharide (LPS) exposure in preterm and near
term animals has been used to generate white matter injury in
immature dogs, cats, and fetal sheep, and has been used to
provide insights into inflammatory mechanisms of injury to
the developing brain. LPS and umbilical cord occlusion both
produce white matter injury with quite similar distribution in
sheep about two-thirds through gestation.152 The morphological appearance is associated with pronounced infiltration
of inflammatory cells into the brain and focal collections of
microglia/macrophage.
Of great interest is the potential use of nonhuman primates
in the study of PWMI. As detailed in the chapter by Dr. Inder
and coworkers in this issue, the preterm baboon infant cared
for in a manner similar to human premature infants manifest
many features of PWMI. Also of great interest is the rhesus
macaque model of infection-induced preterm labor that
closely mimics many of the key features of chorioamnionitis
in the preterm infant.153,154 This model holds considerable
promise to clarify the role of maternal-fetal infection in the
pathogenesis of PWMI.
The Role of Adenosine
in White Matter Injury
In the mature brain, adenosine plays an important neuroprotective role.155 However, evidence generated from in vitro and in
vivo studies suggests that adenosine may play a critical role in
the pathogenesis of hypoxia-related brain injury, and possibly
PWMI. Adenosine is a nucleoside that is present in all cells and
is a component of nucleic acids and energy carrying molecules.156 Adenosine levels can rapidly climb more than 100-fold
with ischemia and increased tissue activity, providing a barometer of tissue activity and oxygenation.156 Specific cell surface
receptors transduce adenosine action including A1 adenosine
receptors (A1ARs) that are activated when modest elevations in
adenosine levels occur and are distributed throughout the
brain.157-159 The other cloned adenosine receptor subtypes include A2a, A2b, and A3 adenosine receptors (ARs).160 A1ARs
are found throughout the brain and are enriched in cerebral
white matter tracts. The A1ARs are expressed in brain during
periods of neuronal birth, migration, and axon sprouting.161
A1ARs are expressed by neurons, microglia and oligodendrocytes.162,163
When P3 to P14 rats are treated with A1AR agonists, reductions in cerebral white matter are observed together with
ventriculomegaly, and reduced myelination.164 Quantitative
electron microscopy reveals reductions in total axon volume.
Importantly, neonatal rats treated with A1AR agonists sustain
alterations in cerebral anatomy that are strikingly similar to
those observed in rats reared in chronic sublethal hypoxia.164
We also examined the brains of genetically-engineered mice
that are deficient in the enzyme adenosine deaminase. These
mice have circulating levels of adenosine that are 100-fold
higher than control animals.165,166 In support of the notion
that increased levels of endogenous adenosine induced brain
injury, we observed ventriculomegaly and reduced myelination in ADA-deficient mice. Moreover, we found that deletion of A1ARs prevents hypoxia-induced ventriculomegaly
and myelin loss.133 When mice expressing A1ARs are reared
in 10% oxygen, reduced myelination and ventriculomegaly is
seen, along with elevated brain adenosine levels. Yet, hypoxia-induced ventriculomegaly and myelination disturbances are not observed in A1AR-knockout mice. Further
supporting the notion that adenosine mediated hypoxia-induced brain injury; in preliminary studies we observed that
adenosine antagonist therapy, can also prevent hypoxia-induced delayed myelination and brain injury.135 Caffeine,
which is a nonselective adenosine antagonist, has also been
shown to reduce hypoxic–ischemic injury in neonatal
mice.167
Summary
PWMI continues to be the major form of brain injury in very
low birth weight infants and underlies the chronic spastic
motor deficits of cerebral palsy and cognitive and learning
disabilities. The spectrum of PWMI ranges from the cystic
necrotic lesions of PVL to myelination disturbances that coincide with regions of diffuse gliosis. Factors that predispose
to PWMI include prematurity, hypoxia, ischemia, and inflammation that contribute to degeneration of the progenitors to myelin-forming oligodendrocytes. Mediators contributing to cell injury included reactive oxygen, glutamate,
cytokines, and adenosine. As our understanding of PWMI
pathogenesis improves, it is anticipated that new strategies
for directly preventing brain injury in premature infants will
evolve.
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