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Pharmacological Strategies For The Prevention of Perinatal Brain Damage
Pharmacological Strategies For The Prevention of Perinatal Brain Damage
Pharmacological Strategies For The Prevention of Perinatal Brain Damage
School of Medicine, The University of Recent clinical studies have confirmed that severe perinataI asphyxial injury is
Auckland, Private Bag 92019, Auckland, associated with delayed development of cerebral energy failure from 6 to 15 h after
New Zealand birth. Reversible hypoxic-ischaemic neural injury precipitates a cascade of injurious
biochemical events, which lead to delayed neuronal death. These damaging mechanisms
however are balanced by endogenous protective mechanisms that may help to limit the
final extent of injury. The delayed evolution of neural damage represents a window of
Key words: Hypoxic-ischaemic opportunity for possible treatment. The present review discusses possible pharmaco-
encephalopathy, perinatal asphyxia, logical interventions, which may act either by directly blocking injurious factors or by
neuroprotection, neuronal rescue, enhancing protective mechanisms. Extensive experimental data show the potential of
neurotrophic factors these agents to treat perinatal asphyxia, stroke, and other forms of acute brain injury.
T a b l e 1. M e c h a n i s m s o f n e u r o n a l cell loss
Calcium cytoaccumulation + + + + ? 4-
M e m b r a n e instability + + + + + + + - +
O x y g e n flee radicals + + + + - i
Excitotoxicity + + + ? - + + +
Apoptosis -- -- + + + + ?+ +
Microglial r e s p o n s e - - - + +
I 1'* lili
m~ 50
m,-t ists seem to have been either partly due to associ-
-~4 4o ated hypothermia [46], or even synergistically
%r~ 30
increased by cooling [47, 48]. More recently it has
~ 20 become clear that prolonged hypothermia of only
2; 10 I to 2°C during the secondary phase may be
0 protective [49, 50], and that this can be produced,
GM-1 Flunarizine MK-801 IGF-1 1-NNA
for example, by anti-excitotoxic agents [51].
Figure 2. Summary of the effects of selective prophylactic
The reciprocal issue arises with mild hyper-
(GM-I and Flunarizine, left) or rescue therapies (MK-80I,
IGF-1 and I-NNA, right) on neuronal damage in the thermia during the secondary phase, which occurs
parasagittal cortex (top panel) or the CA1 subfield of the in several species after stroke; unless this is con-
hippocampus (lower panel), assessed 3 days after 30 rain trolled, it may exacerbate damage and so mask real
cerebral ischaemia in fetal sheep. In general the effect of treatment effects [52]. It is interesting to consider
neuroprophylaxis was greater than that of rescue therapy. whether the inevitable (except in utero) reduction
GM-1 ganglioside [69], and Flunarizine [44], a calcium
channel antagonist, significantly reduced neuronal loss when
in brain temperature as a result of reduced cerebral
given prior to ischaemia. Interestingly, a higher dose of metabolic activity and blood flow during hypoxia-
Flunarizine was not protective, probably because of an ischaemia [53] may in itself be one endogenous
impaired fetal cardiovascular response. Post insult therapy protective factor. The mechanism of action of post
was not effective (unpublished data), Other agents have insult cooling is unclear, but evidence has been
been shown to provide at least partial neuroprotection post
presented to suggest that it acts primarily to block
insult. For example, a single dose of I u g rhlGF-l,
administered i.c.v. 2 h after, ischaemia had a modest effect apoptosis [36]. If this is the case, it is likely that
on damage in the parasagittal cortex with a greater combination therapy of hypothermia with agents
improvement in the hippocampus and lateral cortex [I50]. acting on other pathways will prove to be an
Although MK-80I, a potent highly selective NMDA important modality in the future.
antagonist completely abolished post-ischaemic seizures, it
did not affect parasagittal cortical injury [88]. L-NNA, a
competitive antagonist of NOS attenuated the delayed
luxury perfusion, but tended to worsen the histological Prevention of reperfusion injury
outcome [105]. This adverse effect is likely to be mediated
by inhibition of endothelial NOS and consequent restriction Oxidative metabolism in the mitochondrial elec-
of cerebral blood flow. *P<0.05. **P<0.01. ([--1), control tron chain, as well as other oxidation-reduction
ischaemia; ( • ) , treated.
reactions in the cytoplasm normally produce oxy-
gen free radicals (OFRs), i.e. an oxygen molecule
operative in the brain at the time chosen, but also that contains an uneven number of electrons in
on any other effects of the treatment. Many its outer orbit ('02-). These species are highly
experimental studies have used the approach of reactive, and if not neutralized can lead to degra-
combined hypoxia-ischaemia in the immature rat dation of cell membrane lipids (by peroxidation
to test proposed interventions, since it is much of the unsaturated fatty acids in the lipid bilayer)
more reproducible than systemic asphyxia. Studies [54] with intracellular swelling [55] and impaired
using this type of 'functional' experimental metabolism [56]. In addition, a reciprocal relation-
approach have made critical contributions to our ship between oxygen free radical production and
Prevention of perinatal brain damage 91
The possibility of rescue therapy with such Nitric oxide synthase (NOS) inhibitors
agents remains unclear. Post-asphyxial seizures
have been associated with disproportionate accu- NO is a volatile, rapidly regulated gas which can
mulation of excitotoxins, with a fall in GABA [11]. be produced by NO synthases in endothelial cells
This may in part be related to a greater sensitivity (eNOS), neurons (nNOS) and by neutrophils or
to injury of inhibitory neurons in the primary phase microglia (inducible NOS, or iNOS). Because of
which may contribute to a subsequent loss of failure to take this into consideration the early trials
suppression of excitatory neurons in the second- of non-selective NOS inhibitors produced contra-
ary phase [86, 87]. Both N-methyl-D-aspartate dictory results; as discussed in detail below, the
(NMDA) and the non-NMDA [particularly alpha- available data suggest that prophylactic inhibi-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic tion of nNOS in isolation may reduce neuronal
acid (AMPA)] type receptors have been implicated injury [104] while inhibition of eNOS is likely to
in toxicity. Postasphyxial seizures can for example exacerbate it by impairing cerebral perfusion [105].
be wholly blocked by the NMDA receptor antag- Endothelial NO is a vasodilator which under
onist, Dizocilpine (MK-801) [88]. While there is physiological conditions plays an important role in
some neuroprotective effect of MK-801 when the regulation of CBF, cerebral autoregulation,
given after HI injury [88-90], it is far less effective blood flow-metabolism coupling and the control of
than when administered during the primary phase platelet aggregation and adhesion [106, 107]. In
[91-94]. Although the non-NMDA antagonists the primary phase many studies have shown that
have been proposed to be relatively more protec- during reperfusion there may be reduced NO
tive in the secondary phase, as discussed above production and thus NO mediated cerebrovascular
recent evidence suggests that much of the apparent vasodilatation is impaired [108-111]. There is evi-
protection may have been mediated by a mild but dence to show in the adult that administration of
prolonged fall in systemic temperature [51]. NO donors is cytoprotective and that general NO
inhibition exacerbates neuronal injury probably
by impairing perfusion [107, 108, 112]. NO inhibi-
tion also impairs cerebrovascular autoregulation
Magnesium during moderate hypotension [113]. In the sheep
fetus it has been shown that NO plays a role in
MgSO 4 at high doses is a NMDA receptor maintaining normal fetal vascular tone and NO
antagonist and in experimental paradigms reduces appears to mediate the rises in CBF during hypoxia
excitotoxic injury [95]. It has been reported that [114]. Further, in the secondary phase, in vivo
the use of MgSO 4 for tocolysis and the treatment microdialysis has demonstrated increased NO
of preeclampsia is associated with a reduced inci- synthesis which appears to mediate much of
dence of cerebral palsy [96]. However, recently the secondary hyperaemia [11]. Inhibition of NO
presented alternative analyses suggest the protec- synthetase at this time leads to a reduction in
tive effect of the association with preeclampsia may cerebral blood volume and to greater neuronal loss
be independent of MgSO 4 [97]. Indeed, in prema- [105, 1151.
ture neonates prenatal magnesium exposure does Neuronal NO synthase (nNOS) expression in
not appear to ameliorate subsequent white matter the developing brain correlates with regions of
injury [98]. selective neuronal loss in the developing rat brain.
The levels of Mg 2+ reached after systemic Specific inhibitors of nNOS during or immediately
MgSO 4 therapy, as opposed to intracerebral injec- after the primary phase have recently been shown
tion [99] are not likely to cause significant inhibi- to improve neuronal outcome suggesting that this
tion of Ca 2+ conductances. In recent studies in the component does contribute to reperfusion injury
fetal sheep [100], immature rat [101] and piglet [116, 117]. In vitro, NO also mediates some of the
[102] no protective effect of either prophylactic or cytotoxic actions of excitatory amino acids [118].
rescue (post insult) MgSO 4 could be demonstrated. No studies reported to date have yet examined its
The early multicentre clinical trial of magnesium in role in the secondary phase however.
perinatal asphyxia was thus based on very limited Finally, iNOS, which is inducible by cytokines
evidence of its likely efficacy; it is unfortunate that and released by activated macrophages in very
in the early phase of this trial high dose therapy highly concentrated killing bursts, may contribute
was associated with hypotension [103]. to reperfusion injury [1191. NO can combine with
Prevention of perinatal brain damage 93
superoxide anion to give rise to cytotoxic peroxy- this beneficial outcome might also be related to
nitrite anion. Oligodendrocytes are also highly other systemic effects such as improved pulmonary
sensitive to NO as compared to astrocytes and this function, and so cannot be clearly attributed to a
leads to necrotic death, thought to be a result of neuroprotective effect, but it is a strong induce-
mitochondrial damage [120]. ment to extend experimental investigation of this
approach.
Microglial activation
Microglial activation occurs early in severe injury Endogenous protective
and later in mild injury. The activation is presum- mechanisms
ably a response to tissue injury and altered surface
expression of major histocompatibility complex In devising neuroprotective strategies it is import-
(MHC) antigens on neurons or glial. Activated ant to consider what endogenous mechanisms the
microglia express a number of cytotoxic cytokines CNS itself utilizes to restrict injury. At least four
such as tumour necrosis factor R (TNF-R) and also endogenous protective mechanisms exist: neuro-
the cytotoxic radicals NO and H20 2. Microglial modulators; neurotrophins; cerebrovascular adapta-
reactivity has probably evolved as a protective tions; and cellular factors. A number of possible
response to viral and bacterial infection at the cost interventions have been proposedi primarily based
of retaining a potential neurotoxic role [13]. Most on the first two factors.
of the putative .inhibitors of microglial activation
(e.g. transforming growth factor [3) may have
alternate modes of inducing neuroprotection
[121, 1221. Inhibitory neuromodulators
First, inhibitory neuromodulators such as GABA
Corticosteroids and adenosine may partially antagonize the neural
effects of the EEAs [17]. Microdialysis experiments
In the neonatal 'Levine' rat model of hypoxia- in the fetal sheep suggest that this endogenous
ischaemia, pretreatment with steroids has been response is greatest during the primary phase,
consistently shown to be protective [123], and to a while the endogenous post insult elevation is likely
greater degree than with other modalities including to be limited to the reperfusion phase, and early
OFR antagonists and calcium channel antagonists part of the latent period [11]. Adult species such as
[124]. Although steroid treatment is associated the turtle that are very tolerant to hypoxia, show a
with hyperglycaemia, which is protective in the similarly elevated GABA response to anoxia, which
neonatal rat, the treatment effect was greater than is suggested to reduce cerebral energy consump-
seen with glucose infusions alone [125]. These tion [130]. Consistent with this hypothesis,
results should still be interpreted with some cau- GABAergic agonists have been shown to have
tion, as the data have not been extended to other neuroprotective properties during (but not as yet
species or experimental approaches. Steroid pre- after) ischaemia, both alone and in combination
treatment worsens outcome after ischaemia in adult with NMDA antagonists [131, 132].
rats, because of associated hyperglycaemia [126]. There is evidence that endogenous adenosine
The effect of maturation on the response to hyper- has a significant role in the brain after hypoxia-
glycaemia is related to the comparatively low ischaemia, since theophylline, an adenosine antag-
levels of neuronal glucose transporters in the onist, worsens delayed neuronal death when
neonatal rat [127]. This is unlikely to be the case given post insult [133, 134]. Pre-treatment with
in other species since hyperglycaemia during long acting analogues of adenosine, or upregula-
hypoxia-ischaemia worsens outcome, for example, tion of adenosine receptors has been reported to
in the piglet [128]. reduce neuronal loss, in some [133, 135, 136] but
Despite these caveats, this approach remains of not all studies [17]. Rescue therapy however has
particular interest since administration of dexa- not been consistently effective, and to date the
methasone in premature labour improved neuro- cardiovascular side-effects remain unacceptable
logical function in surviving infants [129]. Clearly [1371.
94 A . J . Gunn & P. D. Gluckman
IGF-1 + IGFBP
Ventricle
Complex
ProteaseBp
=. . . . . . l ......................
f ProteasemF
I
• v
i/
IGF-1 IGF-1
~~ 1 ~ I ~
? I~A--. ?
v ~'" ",g f
Figure 3. This diagram shows the known (filled arrows) and potential (dotted arrows) neurotrophic influences of IGF-1.
Proteases cleave IGFBPs to release IGF-1 which can interact with receptors (R1) on neurons (NA). Glia (GA) have receptors
(RI) which respond to IGF-1 and produce neurotrophins (NTY) which may interact with neuronal receptors (RY). GPE may
be synthesized from IGF-I by protease cleavage and appears to bind to a neuronal (NB) receptor (R2) or binding protein. It
may also interact with a receptor (R2) on glia (GB), stimulating other neurotrophin (NTX) production and receptor (RX)
interactions. N-: Neuron; G =Glia; R1 = IGF-1 receptor; R2 = GPE receptor; NTX,Y= Neurotrophin; RX,Y= Neurotrophin
receptor; Protease BP is specific for IGFBPs; Protease IGF truncates IGFs at the N-terminal tripeptide to produce GPE.
patients resuscitated from an asphyxial episode emission tomography evaluation of cerebral metab-
(particularly birth asphyxia) are destined to develop olism after resuscitation [154]. Active clinical
a secondary phase of injury which can be manipu- research in these areas is needed and will be an
lated. Yet it is only in that group that intervention essential prerequisite to logical introduction of
would be useful. Studies in animals suggest that neuronal rescue therapies.
a variety of biophysical measures (cortical im-
pedance, electrophysiology, magnetic resonance
spectroscopy, near infra-red spectroscopy) can be Conclusions
utilized in the latent phase to predict outcome [14,
24, 33]. Cortical impedance and electrophysiology The development of a rational approach to clinical
are low cost technologies which can be employed intervention in HIE depends on understanding the
at the bedside. At present however, the earliest that multiple mechanisms involved and their temporal
infants with a poor prognosis can be reliably relationship. Neuronal rescue and neuroprophylaxis
identified is approximately 6 h after birth [152]. are highly likely to require distinct therapeutic
Other possible approaches may include biochemi- approaches. A range of strategies have been devel-
cal indices such as CSF lactate [153], or positron oped that are potentially applicable to clinical
96 A . J . Gunn & P. D. Gluckman
practice. While these experimental studies are very 12 Giulian D, Robertson C. Inhibition of mononuclear
promising, a cautious approach to clinical exploita- phagocytes reduces ischemic injury in the spinal cord.
Ann Neurol 1990; 27: 33-42.
tion is still needed, as reviewed elsewhere [155].
13 Lees GJ. The possible contribution of microglia and
We can be optimistic however that the knowledge macrophages to delayed neuronal death after ischemia.
gained over the last decade will ultimately lead to ] Neurol Sci 1993; 114: II9-I22.
effective therapies. 14 Williams CE, Gunn AJ, Gluckman PD. The time course
of intracellular edema and epileptiform activity follow-
ing prenatal cerebral ischemia in sheep. Stroke 199I; 22:
516--521.
Acknowledgements 15 Gunn AJ, Gunn TR, de Haan HH, Williams CE,
Gluckman PD. Dramatic neuronal rescue with prolonged
The authors' work reviewed in this chapter is funded by selective head cooling after ischemia in fetal sheep. J Clin
grants from the Health Research Council of New Zealand and hwest 1997; 99: 248-256.
the National Institutes of Health HD 32752. 16 Giussani DA, Spencer JA, Moore PJ, Bennet L, Hanson
MA. Afferent and efferent components of the cardio-
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