Journal Article

DZNE-2023-00586

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Comparing the efficacy in reducing brain injury of different neuroprotective agents following neonatal hypoxia-ischemia in newborn rats: a multi-drug randomized controlled screening trial.

Sabir, H. (First author)DZNE* ; Maes, E.DZNE* ; Zweyer, M.DZNE* ; Schleehuber, Y.DZNE* ; Imam, F. B. ; Silverman, J. ; White, Y. ; Pang, R. ; Pasca, A. M. ; Robertson, N. J. ; Maltepe, E. ; Bernis, M. E. (Last author)DZNE*

2023
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-023-36653-9

Abstract: Intrapartum hypoxia-ischemia leading to neonatal encephalopathy (NE) results in significant neonatal mortality and morbidity worldwide, with > 85% of cases occurring in low- and middle-income countries (LMIC). Therapeutic hypothermia (HT) is currently the only available safe and effective treatment of HIE in high-income countries (HIC); however, it has shown limited safety or efficacy in LMIC. Therefore, other therapies are urgently required. We aimed to compare the treatment effects of putative neuroprotective drug candidates following neonatal hypoxic-ischemic (HI) brain injury in an established P7 rat Vannucci model. We conducted the first multi-drug randomized controlled preclinical screening trial, investigating 25 potential therapeutic agents using a standardized experimental setting in which P7 rat pups were exposed to unilateral HI brain injury. The brains were analysed for unilateral hemispheric brain area loss after 7 days survival. Twenty animal experiments were performed. Eight of the 25 therapeutic agents significantly reduced brain area loss with the strongest treatment effect for Caffeine, Sonic Hedgehog Agonist (SAG) and Allopurinol, followed by Melatonin, Clemastine, ß-Hydroxybutyrate, Omegaven, and Iodide. The probability of efficacy was superior to that of HT for Caffeine, SAG, Allopurinol, Melatonin, Clemastine, ß-hydroxybutyrate, and Omegaven. We provide the results of the first systematic preclinical screening of potential neuroprotective treatments and present alternative single therapies that may be promising treatment options for HT in LMIC.

Keyword(s): Humans (MeSH) ; Infant, Newborn (MeSH) ; Animals (MeSH) ; Rats (MeSH) ; Neuroprotective Agents: pharmacology (MeSH) ; Neuroprotective Agents: therapeutic use (MeSH) ; Animals, Newborn (MeSH) ; Allopurinol: pharmacology (MeSH) ; Melatonin: pharmacology (MeSH) ; Melatonin: therapeutic use (MeSH) ; Caffeine: pharmacology (MeSH) ; Clemastine: pharmacology (MeSH) ; Hedgehog Proteins (MeSH) ; Brain Injuries: drug therapy (MeSH) ; Brain (MeSH) ; Hypothermia, Induced: methods (MeSH) ; Hypoxia-Ischemia, Brain: drug therapy (MeSH) ; Hypoxia: drug therapy (MeSH) ; Hydroxybutyrates: pharmacology (MeSH) ; Asphyxia Neonatorum: drug therapy (MeSH) ; Disease Models, Animal (MeSH) ; Ischemia: therapy (MeSH) ; Neuroprotective Agents ; Allopurinol ; Melatonin ; Caffeine ; Clemastine ; Hedgehog Proteins ; Hydroxybutyrates

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Contributing Institute(s):

1. Neonatal Neuroscience (AG Sabir)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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