Drugs for neuroprotection after birth asphyxia: Pharmacologic adjuncts to hypothermia
Open accessAbstract
An adverse outcome is still encountered in 45% of full-term neonates with perinatal asphyxia who are treated with moderate hypothermia. At present pharmacologic therapies are developed to be added to hypothermia. In the present article, these potential neuroprotective interventions are described based on the molecular pathways set in motion during fetal hypoxia and following reoxygenation and reperfusion after birth. These pathways include excessive production of excitotoxins with subsequent over-stimulation of NMDA receptors and calcium influx in neuronal cells, excessive production of reactive oxygen and nitrogen species, activation of inflammation leading to inappropriate apoptosis, and loss of neurotrophic factors. Possibilities for pharmacologic combination therapy, where each drug will be administered based on the optimal point of time in the cascade of destructive molecular reactions, may further reduce brain damage due to perinatal asphyxia.
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The drugs may act beneficially on the pathways triggered by fetal or neonatal hypoxia.
“These drugs might have a beneficial role in the pathways set in motion after fetal or neonatal hypoxia 91 and may reduce damage induced by reoxygenation and reperfusion of the brain.”
From Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease (2017) · cites this paper as [91]
The drugs may lessen brain damage caused by reoxygenation and reperfusion.
“These drugs might have a beneficial role in the pathways set in motion after fetal or neonatal hypoxia 91 and may reduce damage induced by reoxygenation and reperfusion of the brain.”
From Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease (2017) · cites this paper as [91]
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Self-citationTetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain
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Pathophysiology of Perinatal Asphyxia in Humans and Animal Models
Mota‐Rojas, D., Villanueva‐García, D., Solimano, A. J., Muns, R., Ibarra‐Ríos, D., & Mota-Reyes, A. (2022) · Biomedicines · doi:10.3390/biomedicines10020347 · Cited by 96 · see citing works
“A complete review of these topics may be found in several recent publications [54,55].”
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“Abbreviations: AT-MSCs, adipose tissue-derived mesenchymal stem cells; ATP, adenosine triphosphate; BAG5, BCL2-associated athanogene 5; BAX, Bcl-2-associated X protein; BDNF, brain-derived neurotrophic factor; BMSCs, bone marrow-derived stem cells; DC, dendritic cells; ES, embryonic stem cells; H2O2, hydrogen peroxide…”
BackgroundInfluentialfor the ALBINO Study Group, Maiwald, C. A., Annink, K. V., Rüdiger, M., Benders, M. J. N. L., van Bel, F., Allegaert, K., Naulaers, G., Bassler, D., Klebermaß-Schrehof, K., et al. (2019) · BMC Pediatrics · doi:10.1186/s12887-019-1566-8 · Cited by 70 · see citing works
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“Hypoxic–ischemic brain injury is not a single event, evoked by the actual asphyxia, but rather an ongoing process that leads to significant neuronal cell death over hours to days after the initial insult (9, 10).”
InfluentialSelf-citationNeuroprotective strategies following perinatal hypoxia-ischemia: Taking aim at NOS
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“The latency period between the hypoxia-ischemia insult and the secondary energy failure [51,52] creates a temporary therapeutic window during which pharmacological interventions and remote ischemic postconditioning (RIPoC) can be applied in order to reduce neurological brain damage [53] (Fig.”
BackgroundSelf-citationAnnink, K. V., de Vries, L. S., Groenendaal, F., Eijsermans, R. M. J. C., Mocking, M., van Schooneveld, M. M. J., Dudink, J., Straaten, H. L. M. V., Benders, M. J. N. L., Lequin, M. H., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-83982-8 · Cited by 51 · see citing works
Self-citationRepair of neonatal brain injury: bringing stem cell‐based therapy into clinical practice
Wagenaar, N., Nijboer, C. H. A., & van Bel, F. (2017) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.13528 · Cited by 51 · see citing works
“Pharmacological neuroprotective therapies have been explored in animal models and may be promising in improving outcome in newborn infants in the future.(4) However, current therapeutic possibilities are limited and no treatment is available that leads to restoration of hypoxic-ischaemic brain injury in newborn infant…”
BackgroundSelf-citationA narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy
Korf, J. M., McCullough, L. D., & Caretti, V. (2023) · Translational Pediatrics · doi:10.21037/tp-23-253 · Cited by 45 · see citing works
“During the reperfusion stage, hypoxanthine is subsequently catabolized by xanthine oxidase into free radicals and superoxide, known to be toxic for the developing brain (124,182).”
Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y., Oka, A., & Itoh, M. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01048-w · Cited by 44 · see citing works
“Despite many animal experiments and clinical trials, the pathophysiology is still not clear and an effective therapy has yet to be established [24, 25].”
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“This plethora of compounds include antioxidants [42], bioactive molecules such as chemokines [43], growth factors [44] and hormones [45], as well as drugs and steroidal and non-steroidal anti-inflammatory agents (NSAIDS) [46,47].”
BackgroundAllopurinol: Old Drug, New Indication in Neonates?
Annink, K. V., Franz, A. R., Derks, J. B., Rüdiger, M., van Bel, F., & Benders, M. J. N. L. (2018) · Current Pharmaceutical Design · doi:10.2174/1381612823666170918123307 · Cited by 39 · see citing works
“This leads to the release of excitatory neurotransmitters as glutamate, which results in the over-activation of the NMDA receptors and failure of the Na-K-ATPase pump (22-24).”
BackgroundInfluentialSelf-citationErythropoietin as a Neuroprotective Drug for Newborn Infants: Ten Years after the First Use
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“This period offers an initial therapeutic window to limit further neuronal damage [34].”
BackgroundCosta, F. G., Hakimi, N., & van Bel, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105389 · Cited by 23 · see citing works
Self-citationFavié, L. M. A., de Haan, T. R., Bijleveld, Y. A., Rademaker, C. M. A., Egberts, T. C. G., Nuytemans, D. H. G. M., Mathôt, R. A. A., Groenendaal, F., & Huitema, A. D. R. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1917 · Cited by 22 · see citing works
Self-citationStegeman, R., Nijman, M., Breur, J. M. P. J., Groenendaal, F., Haas, F., Derks, J. B., Nijman, J., van Beynum, I. M., Taverne, Y. J. H. J., Bogers, A. J. J. C., et al. (2022) · Trials · doi:10.1186/s13063-022-06098-y · Cited by 19 · see citing works
“The development of neuroprotective drugs targeting specific steps in this cascade of events might have the potential to limit hypoxic-ischemic brain lesions [14].”
BackgroundSelf-citationParfenova, H., Pourcyrous, M., Fedinec, A. L., Liu, J., Basuroy, S., & Leffler, C. W. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00140.2018 · Cited by 19 · see citing works
“It frequently leads to hypoxia-ischemia encephalopathy (HIE) in survivors and an elevated risk of cerebral palsy, stroke, developmental delay, intellectual disabilities, mental retardation, and physical disabilities (7, 29, 42, 45, 46).”
BackgroundFavié, L. M. A., Peeters‐Scholte, C. M. P. C. D., Bakker, A., Tjabbes, H., Egberts, T. C. G., van Bel, F., Rademaker, C. M. A., Vis, P., & Groenendaal, F. (2019) · Pediatric Research · doi:10.1038/s41390-019-0587-1 · Cited by 17 · see citing works
Self-citationAntenatal prevention of cerebral palsy and childhood disability: is the impossible possible?
Ellery, S. J., Kelleher, M. A., Grigsby, P. L., Burd, I. D., Derks, J. B., Hirst, J. J., Miller, S., Sherman, L. S., Tolcos, M., & Walker, D. W. (2018) · The Journal of Physiology · doi:10.1113/jp275595 · Cited by 17 · see citing works
Chu, W., Annink, K. V., Nijstad, A. L., Maiwald, C. A., Schroth, M. A., el Bakkali, L., van Bel, F., Benders, M. J. N. L., van Weissenbruch, M. M., Hagen, A., et al. (2021) · Clinical Pharmacokinetics · doi:10.1007/s40262-021-01068-0 · Cited by 16 · see citing works
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Brain-Oriented Strategies for Neuroprotection of Asphyxiated Newborns in the First Hours of Life
Cannavò, L., Perrone, S., & Gitto, E. (2023) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2023.02.015 · Cited by 11 · see citing works
Zitta, K., Peeters‐Scholte, C. M. P. C. D., Sommer, L., Gruenewald, M., Hummitzsch, L., Parczany, K., Steinfath, M., & Albrecht, M. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00971 · Cited by 11 · see citing works
“However, about 45% of infants continue to have an adverse outcome despite this treatment (Bel, 2016) and adjunct therapies on top of hypothermia are urgently needed to reduce the harmful effects of HIE.”
BackgroundFrom vulnerability to resilience: unraveling the role of oxidative stress in preterm brain injury
Jiang, Q., Wen, J., Ding, Y., & Cui, H. (2025) · The Italian Journal of Pediatrics/Italian journal of pediatrics · doi:10.1186/s13052-025-02079-4 · Cited by 10 · see citing works
“Theoretically, hypothermia extends the therapeutic window by reducing metabolic demand, suppressing inflammation, and decreasing apoptosis [170], antioxidant drugs like melatonin and NAC may exert their protective effects against OS at different stages by scavenging FRs, restoring cellular…”
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Samaiya, P. K., Narayan, G., Kumar, A., & Krishnamurthy, S. (2018) · Neurotoxicity Research · doi:10.1007/s12640-018-9873-7 · Cited by 10 · see citing works
“Thus, identification of novel targets for pharmacological intervention is required to treat anoxia (Bel and Groenendaal 2016).”
BackgroundIndole‐3‐carbinol ameliorated the neurodevelopmental deficits in neonatal anoxic injury in rats
Ramakrishna, K., & Krishnamurthy, S. (2022) · International Journal of Developmental Neuroscience · doi:10.1002/jdn.10234 · Cited by 10 · see citing works
“Therefore, novel targets and chemical entities are sought for anoxia treatment (van Bel & Groenendaal, 2016).”
Backgroundvan Hoogdalem, E., Peeters‐Scholte, C. M. P. C. D., Leufkens, P., Hartstra, J., van Lier, J. J., & de Leede, L. G. J. (2019) · Current Clinical Pharmacology · doi:10.2174/1574884714666191017111109 · Cited by 7 · see citing works
“Since still 45% of neonates affected by HIE have an unfavorable neurodevelopmental outcome at the age of 2 years old, additional neuroprotective strategies in combination with hypothermia are needed [1, 2, 6].”
Cardozo, V., Vaamonde, L., Parodi‐Talice, A., Zuluaga, M. J., Agrati, D., Portela, M. M., Lima, A. E., Blasina, F., Dajas, F., & Bedó, G. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105064 · Cited by 7 · see citing works
Ziąbska, K., Gewartowska, M., Frontczak‐Baniewicz, M., Sypecka, J., & Ziemka‐Nałęcz, M. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04591-w · Cited by 6 · see citing works
Neuroprotective effect of Src kinase in hypoxia-ischemia: A systematic review
Christidis, P., Vij, A., Petousis, S., Ghaemmaghami, J., Shah, B. V., Koutroulis, I., & Kratimenos, P. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1049655 · Cited by 6 · see citing works
Alderliesten, T., Parmentier, C. E. J., Benders, M. J. N. L., de Vries, L. S., Vijlbrief, D. C., Dudink, J., Tataranno, M. L., Lemmers, P. M. A., Groenendaal, F., & van Bel, F. (2025) · Neonatology · doi:10.1159/000548127 · Cited by 3 · see citing works
“Early information about the severity of brain damage after birth asphyxia in term neonates is important to timely decide whether future additional pharmacological interventions during TH or redirection of care are indicated [2, 3].”
Self-citationGebala, P., Janowska, J., & Sypecka, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262010200 · Cited by 3 · see citing works
“This reperfusion results in further brain damage occurring within hours after birth and can impact significantly larger areas of brain tissue, compared to those initially affected during the event [61,62].”
Gao, H., & Jiang, H. (2024) · Medicine · doi:10.1097/md.0000000000038993 · Cited by 3 · see citing works
Islas-Fabila, P., Orozco-Gregorio, H., Roldán-Santiago, P., Waytula, M., González-Hernández, M., Vega-Manríquez, X., Jiménez-Collado, C. A., & Bonilla‐Jaime, H. (2022) · Veterinární Medicína · doi:10.17221/43/2021-vetmed · Cited by 2 · see citing works
Jongruk, P., Soontaravarapas, N., Angkurawaranon, S., Kosarat, S., Khuwuthyakorn, V., Tantiprabha, W., Manopunya, S., Boonchooduang, N., Louthrenoo, O., Likhitweerawong, N., et al. (2024) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2024.10.003 · Cited by 2 · see citing works
Brainstem and Spinal Cord Disruptions
Folkerth, R. D. (2021) · Cambridge University Press eBooks · doi:10.1017/9781316671863.034 · Cited by 1 · see citing works
Opportunities of cerebroprotection in children in cardiac surgery (review of literature)
Александрович, И. А., Геннадьевич, Б. Д., Borisenko, D. V., & Grigoryev, E. V. (2023) · Messenger of Anesthesiology and Resuscitation · doi:10.24884/2078-5658-2023-20-1-89-96 · Cited by 1 · see citing works
Physiology and Development of the Term and Preterm Neonate
Brett, C. M., & Robinowitz, D. L. (2023) · Springer eBooks · doi:10.1007/978-3-031-25358-4_2 · Cited by 1 · see citing works
Translation from animal to clinical studies, choosing the optimal moment
Favié, L. M. A., Peeters‐Scholte, C. M. P. C. D., Bakker, A., Tjabbes, H., Egberts, T. C. G., van Bel, F., Rademaker, C. M. A., Vis, P., & Groenendaal, F. (2020) · Pediatric Research · doi:10.1038/s41390-020-0820-y · Cited by 1 · see citing works
Self-citationYalçın, S. E., Sezi̇k, M., Yavuz, A., Savran, M., Aşçı, H., & Özmen, Ö. (2021) · Fetal and Pediatric Pathology · doi:10.1080/15513815.2021.1945174 · Cited by 1 · see citing works
“including cell death via excitotoxicity, oxidative stress, inflammation, necrosis, and apoptosis, which leads to long-term neurological sequelae [26].”
BackgroundPERINATAL ASPHYXIA: PREDICTING AND IMPROVING OUTCOME
Annink, K. V. (2020) · doi:10.33540/67
Itoh, M., Aoki, Y., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y., & Oka, A. (2020) · doi:10.21203/rs.3.rs-100349/v1
Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y.-I., Oka, A., & Itoh, M. (2024) · Figshare · doi:10.6084/m9.figshare.26593571
Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y.-I., Oka, A., & Itoh, M. (2024) · Figshare · doi:10.6084/m9.figshare.26593574
Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y.-I., Oka, A., & Itoh, M. (2024) · Figshare · doi:10.6084/m9.figshare.26593553
Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y.-I., Oka, A., & Itoh, M. (2024) · Figshare · doi:10.6084/m9.figshare.26593556
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Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y.-I., Oka, A., & Itoh, M. (2024) · Figshare · doi:10.6084/m9.figshare.26593562
Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y.-I., Oka, A., & Itoh, M. (2024) · Figshare · doi:10.6084/m9.figshare.26593550
Aoki, Y., Dai, H., Furuta, F., Akamatsu, T., Oshima, T., Takahashi, N., Goto, Y.-I., Oka, A., & Itoh, M. (2024) · Figshare · doi:10.6084/m9.figshare.26593541
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Palma, S., Pongers, S. N., Ivens, M., Pachocki, C. J., Vann, S. D., Annink, K. V., van der Aa, N. E., Groenendaal, F., Benders, M. J. N. L., Hoebeek, F. E., et al. (2026) · Journal of the American Heart Association · doi:10.1161/jaha.125.047034
“…or administration of neurotrophic factors such as erythropoietin, IGF-1 (insulin-like growth factor 1), or BDNF (brain-derived neurotrophic factor), 45 or supplementation of melatonin to reduce oxidative stress, in combination with MSC therapy to support neurogenesis could be a future option to…”
Self-citationXue, X.-Y., Sun, L., Yu, M., Li, M.-X., Tian, Q.-Y., Ren, J., Miao, P., Xu, L.-X., Feng, C., Li, M., et al. (2026) · World Journal of Pediatrics · doi:10.1007/s12519-026-01093-8
“Advance-ments in neonatal diagnostic technologies have increased the recognition of PA-induced brain injury but there is an urgent need for novel diagnostic and prognostic targets [10].”
- Authors
- Bel, F. V., & Groenendaal, F.
- Affiliations
- University Medical Center Utrecht (NL)
- Corresponding author
- Bel, Frank van
- Venue
- Seminars in Perinatology
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 40
- Issue
- 3
- Pages
- 152-159
- ISSN
- 0146-0005 (ISSN-L)
- OpenAlex
- W2285862104
- Cited by
- 58
- References
- 102
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 15 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 3 · 2016: 1
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- Locations
- Seminars in Perinatology (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- perinatal asphyxia, neuroprotection, therapeutic hypothermia, combination therapy, excitotoxicity, NMDA receptor, calcium influx, reactive oxygen species, reactive nitrogen species, neuroinflammation, apoptosis, neurotrophic factors, ischemia-reperfusion injury, term infants, brain damage
- MeSH terms
- Neuroprotection, Asphyxia Neonatorum, Humans, Hypothermia, Induced, Infant, Newborn, Metabolism, Neuroprotective Agents, Hypoxia-Ischemia, Brain, Term Birth
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