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Pharmacotherapeutical reduction of post-hypoxic-ischemic brain injury in the newborn
1Department of Neonatology, Wilhelmina Children's Hospital/University Medical Center, Utrecht, The Netherlands.
Insights
Perinatal hypoxia-ischemia (PHI) causes brain damage during reperfusion. This review categorizes neuroprotective agents for PHI, highlighting the need for clinical trials and combination strategies.
Area of Science:
- Neonatal neurology
- Neuroscience
- Developmental neuroscience
Background:
- Perinatal hypoxia-ischemia (PHI) is a significant cause of newborn morbidity and mortality.
- Brain damage from PHI is exacerbated by reperfusion injury, involving excitotoxicity, oxidative stress, and inflammation.
- While animal models show promise for neuroprotective agents, clinical translation for newborns remains limited.
Purpose of the Study:
- To review and categorize neuroprotective agents investigated for global PHI and reperfusion brain injury in newborns.
- To discuss the modes of action of these agents.
- To identify future research directions, including clinical trials and combination therapies.
Main Methods:
- Literature review focusing on neuroprotective agents for neonatal hypoxia-ischemia.
- Categorization of agents based on their mechanism of action.
- Analysis of evidence from neonatal animal models and limited clinical studies.
Main Results:
- Numerous neuroprotective agents have shown efficacy in animal models of PHI.
- Agents target pathways such as excitotoxicity, oxidative stress, inflammation, and apoptosis.
- Few agents have progressed to clinical trials in term newborns, with limited success reported.
Conclusions:
- Neuroprotective agents hold promise for mitigating PHI-related brain damage.
- Further experimental and clinical research is essential, including long-term follow-up.
- Combination therapies, potentially with brain hypothermia, may offer improved outcomes for reducing newborn brain injury.
Abstract:
Perinatal hypoxia-ischemia (PHI) is a major cause of morbidity and mortality. A substantial part of PHI-related brain damage occurs upon reperfusion and reoxygenation by the excess production of excitatory amino acids, free (pro)radicals and the release of cytokines, triggering programmed cell death. In this respect, several neuroprotective agents have been investigated in neonatal animal models, providing evidence for their usefulness in PHI. Several agents have been shown to be neuroprotective in neonatal animal hypoxia-ischemia models, but only a few agents have been used in clinical studies on term newborns. Although some general information will be provided with respect to focal hypoxia-ischemia and neuroprotective agents, this paper focuses on the investigated neuroprotective agents for global PHI and reperfusion brain injury in the newborn, categorized by their mode of action. Future experimental and clinical trials with promising neuroprotective agents need to be performed, including long-term follow-up to monitor long-term consequences. Moreover, well-designed combinations of neuroprotective agents with or without other neuroprotective strategies such as brain hypothermia should be given consideration for producing the most promising results in reducing post-hypoxic-ischemic reperfusion injury of the newborn brain.