Hypoxiaischemia in the immature brain
1 Department of Pediatrics, Columbia University, New York, NY 10032,
USA
2 Perinatal Center, Sahlgrenska Academy, Goteborg, Sweden
* Author for correspondence (e-mail: sv2020{at}columbia.edu)
Accepted 30 April 2004
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Summary |
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Key words: brain injury, development, excitotoxicity, apoptosis
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Introduction |
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The majority of these experimental studies have utilized a model of
unilateral hypoxicischemic brain damage in the immature rat
(Rice et al., 1981;
Vannucci and Vannucci, 1997
;
Vannucci et al., 1996
), more
recently extended to the immature mouse
(Sheldon et al., 1998
). This
methodology consists of unilateral common carotid artery ligation followed by
a period of systemic hypoxia produced by inhalation of 8% oxygen/balance
nitrogen. 7-day postnatal rat pups can survive up to 2.53 h before
significant mortality occurs. During the course of hypoxic exposure, the pups
demonstrate hypoxemia combined with hypocapnia, produced by hyperventilation;
the hypocapnia compensates for the metabolic acidosis produced by lactic
acidemia, and systemic pH is not different from control pups
(Vannucci et al., 1995
). Mean
systemic blood pressure decreases by 2530% during hypoxia, and cerebral
blood flow is reduced by 4060% of the control rate in the hemisphere
ipsilateral to the ligation (Vannucci et
al., 1988
). Cerebral blood flow is restored to control values
immediately upon return to normoxic conditions, although the period of
hyperemia characteristic of reperfusion following cerebral ischemia in adult
models is not observed in the immature rat model
(Mujsce et al., 1990
).
Hypoxicischemic brain damage, ranging from selective neuronal death to
infarction, or a combination of both, is a near universal finding in the
ligated rat pups surviving a 23 h exposure to hypoxia. The damage is
usually restricted to the hemisphere ipsilateral to the ligation and is
primarily observed in the cerebral cortex, subcortical and periventricular
white matter, striatum/thalamus and hippocampus. Such neuropathological damage
is rarely seen in the contralateral hemisphere and never in pups rendered
hypoxic without carotid artery ligation
(Towfighi et al., 1995
;
Vannucci and Vannucci, 1997
).
Thus using this model, we and others have studied the effects of perinatal
hypoxiaischemia on cerebral energy metabolism, glutamate
excitotoxicity, generation of reactive oxygen species and apoptotic cell
death.
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Energy metabolism and nutrient transport in the immature brain |
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Glutamate excitotoxicity and the developmental regulation of NMDA receptors |
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NMDA receptor activation can be especially devastating in the immature
brain. Glutamate is an important trophic factor for the immature brain and
NMDA receptors mediate normal brain development and function by promoting
proliferation and migration of neuronal precursors, and synaptic development
and plasticity (Komuro and Rakic,
1993; McDonald and Johnston,
1990
). Appropriate to these developmental functions, the
composition and activity of the immature NMDA receptors differ from that
observed in the adult brain, resulting in a period of enhanced sensitivity to
excitotoxic insults (see Johnston,
1995
, and references therein). NMDA receptors are hetero-oligomers
consisting of NR1 subunits (of which there are eight possible splice
variants), NR2, which has four subtypes (2A2D), and NR3 subunits
(Ciabarra et al., 1995
;
Moriyoshi et al., 1991
;
Nishi et al., 2001
;
Sucher et al., 1995
). Whereas
the NR1 subunit is essential for the formation of functional ligand-gated ion
channels, the specific pharmacological and biophysical properties are
determined by the component NR2 (or NR3) subunits
(Cull-Candy et al., 2001
;
Dingledine et al., 1988
;
Sucher et al., 1996
). During
development, the expression of the NR2 subunits changes from a relatively high
level of subtype 2B during the first 2 postnatal weeks in the rat, to a
predominance of the 2A subunit in the adult
(Gurd et al., 2002
;
Sheng et al., 1994
;
Zhong et al., 1995
). This
developmentally regulated alteration in the ratio of NR2A:NR2B is reflected in
altered receptor properties, including increased Ca2+ flux on
glutamate activation, which may contribute to the increased sensitivity of the
neonatal brain to hypoxicischemic injury
(Johnston, 1995
).
Functional characteristics of NMDA receptors are further regulated by
phosphorylation of the component subunits
(Raymond et al., 1994;
Swope et al., 1999
). Tyrosine
phosphorylation of NR2 subunits activates the receptor ion channel
(Kohr et al., 1994
;
Wang and Salter, 1994
) and can
also impact on interactions with associated postsynaptic density (PSD)
proteins and downstream signaling molecules
(Gurd, 1997
;
Takagi et al., 1999
).
Increases in synaptic tyrosine kinase activity occur during normal cerebral
maturation (Cudmore and Gurd,
1991
; Gurd and Bissoon,
1990
) and have been associated with developmentally related
increases in tyrosine phosphorylation of the NMDA receptor
(Gurd et al., 2002
). Although
levels of NR2A relative to P21 are low in the P7 rat, there is a higher level
of basal phosphorylation, which would contribute to the increased excitability
of the NMDA receptor supporting normal cerebral development at this stage but
also render it more vulnerable to H/I damage
(Gurd et al., 2002
).
Recruitment of tyrosine kinases to the post-synaptic density is an early
response of the adult brain in ischemia
(Cheung et al., 2001
), and H/I
induced changes in NR2A and NR2B are specific to the developmental stage of
the brain (Gurd et al., 2002
).
At P7, H/I induced a selective and rapid loss of NR2A, but not NR2B, levels,
although phosphorylation of the latter was increased early in reperfusion. In
contrast, tyrosine phosphorylation of both NR2A and 2B subunits was increased
following H/I in the P21 rat, with no decline in levels of NR2A and a delayed
decrease in NR2B at 24 h of reperfusion. The relationship between subunit
composition, phosphorylation changes, and NMDAR channel properties and
downstream signaling is complex. However, the demonstration of such specific
age-related differences in the response to H/I suggests a basis for the
changing sensitivity of the developing brain to excitotoxicity at the time of
the insult, and could have longer lasting effects of synaptic events involved
in recovery at different ages.
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Oxidative stress and hypoxicischemic injury in the immature brain |
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Two features of the immature brain that render it especially sensitive to
oxidative damage relative to the mature brain are poor antioxidant
capabilities and a high concentration of free iron. Endogenous antioxidant
enzymes in the brain include superoxide dismutase (SOD), which exists as
Cu,Zn-SOD (SOD1) in the cytoplasm and Mn-SOD (SOD2) in the mitochondria. Both
of these enzymes actively scavenge oxygen free radicals by converting them to
H2O2, which can then be effectively detoxified by the
action of catalase or glutathione peroxidase and eliminated as H2O.
Glutathione peroxidase simultaneously catalyzes the conversion of reduced
glutathione to oxidized glutathione, which can then be reduced by glutathione
reductase, at the expense of NADPH. Thus this regeneration system for the
maintenance of antioxidant protection is dependent on the cellular energy
state. Clearly, when these systems fail, as in hypoxiaischemia, the
brain suffers the consequences of oxidative damage to cellular macromolecules
and death. Experimental studies designed to limit oxidative damage following
stroke, including genetic overexpression of SOD1, have been shown to be
protective in the adult nervous system
(Chan, 1996). However,
overexpression of SOD1 in the context of neonatal H/I actually exacerbated
tissue damage, highlighting another significant difference between immature
and adult brains (Ditelberg et al.,
1996
). The reason for this, as well as the increased vulnerability
of the immature brain to oxidative stress, was subsequently explained by an
inability to detoxify accumulated H2O2, due to a limited
capacity of antioxidant enzymes, especially glutathione peroxidase
(Fullerton et al., 1998
).
Additionally, the accumulation of H2O2 is more damaging
to the immature brain due to the higher levels of free iron in the immature,
relative to the adult, nervous system, and the consequent generation of the
hydroxyl radical via the Fenton reaction. Reducing the level of free
iron with the chelator deferoxamine (DFO) has neuroprotective effects on both
wild-type and SOD-overexpressing neonatal mice after H/I
(Sarco et al., 2000
).
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Apoptotic mechanisms in the immature brain |
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Most data suggest, however, that apoptosis as a result of
hypoxiaischemia is morphologically different from developmental
apoptosis, and that many hybrid necroticapoptotic phenotypes are seen
(Leist and Jaattela, 2001;
Martin et al., 1998
).
Biochemically, by contrast, most studies agree that apoptotic processes are
involved in hypoxiaischemia. Indeed, key elements of apoptosis, such as
caspase-3 (Blomgren et al.,
2001
; Cheng et al.,
1998
; Hu et al.,
2000
), APAF-1 (Ota et al.,
2002
), Bcl-2 (Merry et al.,
1994
) and Bax (Vekrellis et
al., 1997
) are upregulated in the immature as compared to the
adult brain and could be expected to have a prominent role in pathological
situations also.
Apoptosis in most mammalian cells involves a family of cysteine proteases,
the caspases, which are proenzymes activated in a highly regulated proteolytic
cascade leading to the downstream activation of Caspase-3, -6 or -7. Caspase-3
appears to be the key executioner in the CNS and its activation leads to
cleavage of hundreds of substrates in the cell that are vital for cell
survival (Cohen, 1997). These
substrates include the nuclear chaperone, inhibitor of caspase-activated DNase
(ICAD), which is cleaved, and caspase-activated DNase (CAD), which is induced,
leading to DNA fragmentation (Enari et
al., 1998
). Caspase-3 can be activated either through intrinsic or
extrinsic (receptor-mediated) pathways
(Hengartner, 2000
). Intrinsic
mechanisms involve the release of cytochrome c and formation of the
`apoptosome' and, subsequently, caspase-9 activation. The extrinsic pathway
includes the binding of the Fas-ligand to its receptor, which leads to
caspase-8 cleavage and activation of caspase-3.
There are several lines of evidence that the caspase system is activated in
the immature brain in response to hypoxiaischemia. The activities of
Caspase-3, -8 and -9 all increase (Blomgren
et al., 2001; Cheng et al.,
1998
; Northington et al.,
2001
; Zhu et al.,
2003
) and their downstream substrates ICAD and
poly(ADP-ribose)polymerase are cleaved
(Wang et al., 2001
).
Furthermore, caspase-3 activity and hypoxicischemic brain injury can be
significantly reduced either by the administration of a `broad-spectrum'
inhibitor (Cheng et al., 1998
)
or through transgenic upregulation of the endogenous caspase-inhibitor `XIAP'
(Wang et al., 2003
,
2004
).
Recent data suggest that another protein, apoptosis inducing factor (AIF),
can be released from mitochondria under some conditions. AIF is an
oxidoreductase with the ability to induce chromatin condensation and DNA
fragmentation in a non-caspase-dependent manner
(Susin et al., 1999).
Poly(ADP-ribose)polymerase-dependent cell death has been shown to depend on
mitochondrial release of AIF (Yu et al.,
2002
), and this protein was also translocated from mitochondria to
the nucleus in neurons of the immature brain in the early phase of reperfusion
after hypoxiaischemia (Zhu et al.,
2003
). Future studies must clarify the relative importance of
caspase-dependent and caspase-independent pathways in various pathological
situations.
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Conclusion |
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Acknowledgments |
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