Abstract :
[en] Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal morbidity and mortality and is a common cause of disability with devastating impact on individuals and families.
During the acute phase, HIE is initially characterized by an excitotoxic cascade with hypoxic membrane depolarization, cytotoxic edema, glutamate release and intracellular accumulation of calcium leading to necrotic cell death and production of proinflammatory cytokines through the NF-κB pathway. In a second phase, reperfusion leads to production of free radicals, activation of proteases and phospholipases, exacerbing the damage to cell membrane and DNA and mitochondrial dysfunction causing caspase mediated apoptotic cell death. In a third phase, growth factors and inflammatory cytokines produced during the early phase of HIE attempt to repair damage induced by hypoxia–ischemia.
Although the utility of therapeutic hypothermia induced in the 6 hours following HIE in the reduction of death or major neurodevelopmental disability is now well established in the neonate with moderate or severe encephalopathy, almost half of these children still die or have abnormal outcomes [1]. Protocols attempting to optimize cooling with deeper hypothermia (33.5°C vs 32.0°C) and/or longer duration (72h vs 120h), as well protocols studying neuroprotective effect of late hypothermia (6-24h) or hypothermia for 33-35 week GA preterm babies are currently performed.
Furthermore, experimental data suggest that hypothermia extends the duration of the therapeutic window [2] and that certain drugs given during this time may improve neuroprotection either additively or synergistically.
Xenon is a noble gas with anaesthetic and neuroprotective properties. It inhibits NMDA receptor, promotes cell survival and induces the production of erythropoietin and vascular endothelial growth factor through the hypoxia inducible factor 1 alpha (HIF-1α) pathway. Data from experimental piglet models of hypoxia-ischemia (HI) demonstrate a synergy when Xenon is administered in combination with mild therapeutic hypothermia [3]. In the human newborn, a phase-1 trial recently established that breathing 50% Xenon for up to 18 hours with 72 hours of cooling was feasible, with no adverse effects seen with 18 months’ follow-up [4]. A monocentric phase-3 trial is currently under process in England.
Melatonin is a remarkable natural antioxidant but also exhibits antiapoptotic and anti-inflammatory properties in vitro. In animal models, melatonin administration prior or after the onset of HI significantly reduced infarct volume demonstrating both prophylactic and therapeutic effect [5-6]. When combined with hypothermia, melatonin enhances neuroprotection by reduction of the H–I-induced increase in clinically relevant biomarkers in the deep grey matter of newborn piglets [7]. Clinical studies confirmed its safety profile and its ability to reduce biomarkers level of HI in the human newborn [8]. Recently, a randomized controlled trial showed that the combination of melatonin and hypothermia administered to infants with moderate-to-severe H–I brain injury was efficacious in reducing oxidative stress, neonatal seizures and MRI brain lesions as well as in improving neurological outcomes at 6 months of age [9].
Erythropoietin (EPO) and its receptor are expressed in the developing central nervous system and are required for normal brain development. EPO is up-regulated in umbilical cord blood from babies who have suffered HI, which may be an endogenous repair mechanism. In vitro and in vivo neuroprotection induced by EPO is achieved by several mechanisms such as direct neurotrophic effect, direct antioxidant effects, decreased inflammation or regulation between pro-apoptotic and anti-apoptotic factors. Safety profile of EPO administration during hypothermia for newborns with HIE has been established in Phase I trials [10]. In a randomized prospective pase-2 trial, repeated low-dose rEPO reduced the risk of disability for infants with moderate but not severe HIE at 18 months, without apparent side effects [11]. A double-blind randomized controlled phase-3 trial is currently performed in France.
Allopurinol is a xantine-oxidase inhibitor. In high concentrations it also scavenges hydroxyl radicals and prevents free radical formation. Allopurinol provides neuroprotection in rat and piglets models of HIE. In the human, a systematic review and meta-analysis of three studies on 114 newborns did not reveal statistically difference in the risk of death or a composite of death or severe neurodevelopmental disability between groups [12]. It was hypothesized that postnatal allopurinol treatment started too late to reduce reperfusion-induced free radical surge. However, in a recent study, allopurinol given to mothers during labor with fetal hypoxia did not significantly lower neuronal damage markers in cord blood even if post hoc analysis revealed a potential beneficial treatment effect in girls [13].
Magnesium sulfate (MgSO4) is a naturally occurring NMDA receptor antagonist. MgSO4 given to mothers at risk for preterm birth is associated with a reduced risk of cerebral palsy and gross motor dysfunction in their children. Its role as an adjuvant to therapeutic hypothermia in the asphyxiated term infant remains unclear. A recent review of preclinical studies using MgSO4 in HIE highlights the inconsistent impact between studies related to a lack of temperature control during and after HI, along with variability in the dose, timing of treatment [14]. A metaanalysis of five randomized controlled trials that compared magnesium to control in newborns with HIE showed a significant improvement in short term outcomes but no difference in the composite outcome of death or moderate to severe disability at 18 months [15]. Other NMDA and AMPA antagonist such as topiramate and memantine also exhibited neuroprotective properties in animal models but safety and efficacy in the human newborn with HIE still needs to be clarified [16].
N-acetyl cysteine (NAC) acts as a glutathione precursor with antioxidant, antiapoptotic, and anti-inflammatory properties. In a piglet model of HIE, NAC reduced cerebral oxidative stress, reduced cerebral lactate accumulation and improved cerebral perfusion. When combined with hypothermia in the asphyxiated rodent, NAC decreased infarct volume, improved myelin expression and functional outcomes on a synergistic pattern. NF-κB inhibitors and NO synthase inhibitors are other therapeutic options currently under investigation in in vitro and in vivo preclinical studies.
Moreover, recent research performed at the University of Liege also suggests that Estetrol (E4), an estrogen synthetized exclusively by the human foetus, has neuroprotective properties in a rat model of HIE. Translation to clinical use in humans still needs to be studied [17].
Several therapies have also been suggested in order to improve mechanisms of repair and regeneration observed after the HI insult. Growth factors such as BDNF, IGF-1, EGF or bFGF can improve cell viability, stimulate the growth of new neurons or promotes oligodendroglial differentiation and myelination. Recent advances in regenerative medicine suggest that stem cell transplantation may improve repair of the damaged brain after HIE through the replacement of dead cells as well as through the release of trophic factors [18]. Animal preclinical data are promising. However many questions need to be answered with well-designed controlled trials before clinical application in daily practice.
References
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