Elsevier

The Journal of Pediatrics

Volume 160, Issue 4, April 2012, Pages 544-552.e4
The Journal of Pediatrics

Commentary
Which Neuroprotective Agents are Ready for Bench to Bedside Translation in the Newborn Infant?

https://doi.org/10.1016/j.jpeds.2011.12.052Get rights and content

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Methods

A systematic PubMed search up to June 2011 was undertaken to identify medications with evidence of neuroprotection in pre-clinical studies when given either antenatally or postnatally after perinatal hypoxia-ischemia. For antenatal treatments, each medication was scored to a manual score of 60 by using 6 questions, each ranked 1 to 10: (1) placental transfer; (2) ease of administration; (3) knowledge about starting dose; (4) adverse effects; (5) teratological or toxic effects; and (6) overall

Results

Thirteen neuroprotective medications were identified. The possible mechanisms of action are shown in the Figure. They were classified as US Food and Drug Administration (FDA)-approved (adenosine A2A receptor antagonist, allopurinol, erythropoietin [Epo], melatonin, memantine, N-acetylcysteine [NAC], resveratrol, topiramate, vitamins C & E, tetrahydrobiopterin [BH4]) and non-FDA-approved (Epo-mimetic peptides, neuronal nitric oxide synthase [nNOS] inhibitors, xenon).

Discussion

The opinions expressed in this review are meant to generate further discussion and to promote international co-ordination; they are not meant as firm recommendations. Both the choice of agent and the scores are subjective, but are informed by the authors’ earlier experience and knowledge. We acknowledge that many new promising drugs, some of which target specific pathways,156 have been left out. However, this is an ongoing process, and the study group plans to continuously update the priority

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References (158)

  • M. Bouslama et al.

    Melatonin prevents learning disorders in brain-lesioned newborn mice

    Neuroscience

    (2007)
  • J. Chen et al.

    The localization of neuronal nitric oxide synthase may influence its role in neuronal precursor proliferation and synaptic maintenance

    Dev Biol

    (2004)
  • J. Perlman

    Intervention strategies for neonatal hypoxic-ischemic cerebral injury

    Clin Ther

    (2006)
  • M. Willmot et al.

    Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: a systematic review

    Free Radic Biol Med

    (2005)
  • J. Adams et al.

    Nitric oxide synthase isoform inhibition before whole body ischemia reperfusion in pigs: vital or protective?

    Resuscitation

    (2007)
  • C.P. Petzelt et al.

    Participation of the Ca(2+)-calmodulin-activated Kinase II in the control of metaphase-anaphase transition in human cells

    Cell Biol Int

    (2001)
  • M. Coburn et al.

    Randomized controlled trial of the haemodynamic and recovery effects of xenon or propofol anaesthesia

    Br J Anaesth

    (2005)
  • J.L. Martin et al.

    Asynchronous administration of xenon and hypothermia significantly reduces brain infarction in the neonatal rat

    Br J Anaesth

    (2007)
  • G.D. Williams et al.

    Allopurinol preserves cerebral energy metabolism during perinatal hypoxia-ischemia: a 31P NMR study in unanesthetized immature rats

    Neurosci Lett

    (1992)
  • W.D. Johnson et al.

    A randomized controlled trial of allopurinol in coronary bypass surgery

    Am Heart J

    (1991)
  • N. Marlow et al.

    Neuropsychological and educational problems at school age associated with neonatal encephalopathy

    Arch Dis Child Fetal Neonatal Ed

    (2005)
  • A. Edwards et al.

    Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data

    BMJ

    (2010)
  • M. Carroll et al.

    Protection against hippocampal CA1 cell loss by post-ischaemic hypothermia is dependent on delay of initiation and duration

    Metab Brain Dis

    (1992)
  • A. Gunn et al.

    Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep

    Pediatrics

    (1998)
  • N. Badawi et al.

    Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study

    BMJ

    (1998)
  • S.M.L. Lehnardt et al.

    Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway

    PNAS

    (2003)
  • S. Eklind et al.

    Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury

    Eur J Neurosci

    (2001)
  • N. Badawi et al.

    Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study

    BMJ

    (1998)
  • K.P. Williams et al.

    Comparison of intrapartum fetal heart rate tracings in patients with neonatal seizures vs. no seizures: what are the differences?

    J Perinat Med

    (2004)
  • S. Vijgen et al.

    Cost-effectiveness of cardiotocography plus ST analysis of the fetal electrocardiogram compared with cardiotocography only

    Acta Obstet Gynecol Scand

    (2011)
  • J.T. Madsen et al.

    Tetrahydrobiopterin precursor sepiapterin provides protection against neurotoxicity of 1-methyl-4-phenylpyridinium in nigral slice cultures

    J Neurochem

    (2003)
  • R.H. Fabian et al.

    Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia

    Am J Physiol Heart Circ Physiol

    (2010)
  • J. Vásquez-Vivar et al.

    Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain

    Ann Neurol

    (2009)
  • S. Kaufman et al.

    Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain

    Pediatrics

    (1982)
  • M. Giżewska et al.

    Maternal tetrahydrobiopterin deficiency: the course of two pregnancies and follow-up of two children in a mother with 6-pyruvoyl-tetrahydropterin synthase deficiency

    J Inherit Metab Dis

    (2009)
  • F.K. Trefz et al.

    Long-term follow-up of patients with phenylketonuria receiving tetrahydrobiopterin treatment

    J Inherit Metab Dis

    (2010)
  • W. Endres et al.

    Atypical phenylketonuria due to biopterin deficiency. Early treatment with tetrahydrobiopterin and neurotransmitter precursors, trials of monotherapy

    Helv Paediatr Acta

    (1982)
  • R. Koch et al.

    Tetrahydrobiopterin and maternal PKU

    Mol Genet Metab

    (2005)
  • J. Fink et al.

    Tetrahydrobiopterin administration in biopterin-deficient progressive dystonia with diurnal variation

    Neurology

    (1989)
  • M. Segawa et al.

    Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease)

    Ann Neurol

    (2003)
  • A. Altun et al.

    Melatonin: therapeutic and clinical utilization

    Int J Clin Pract

    (2007)
  • R. Hardeland

    Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance

    Endocrine

    (2005)
  • F. Luchetti et al.

    Melatonin signaling and cell protection function

    FASAB J

    (2010)
  • Y. Okatani et al.

    Maternal-fetal transfer of melatonin in pregnant women near term

    J Pineal Res

    (1998)
  • S. Reppert et al.

    Maternal-fetal transfer of melatonin in the non-human primate

    Pediatr Res

    (1979)
  • D. Sadowsky et al.

    Lack of effect of melatonin on myometrial electromyographic activity in the pregnant sheep at 138-142 days gestation (term = 147 days gestation)

    Endocronology

    (1991)
  • P. Vitte et al.

    Plasma, cerebrospinal fluid, and brain distribution of 14C-melatonin in rat: a biochemical and autoradiographic study

    J Pineal Res

    (1988)
  • G. Mistraletti et al.

    Pharmacokinetics of orally administered melatonin in critically ill patients

    J Pineal Res

    (2010)
  • I. Husson et al.

    Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge

    Ann Neurol

    (2002)
  • G. Jahnke et al.

    Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats

    Toxicol Sci

    (1999)
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    The authors declare no conflicts of interest.

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