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• W2149763277 abstract "Neonatal encephalopathy caused by perinatal hypoxia-ischemia in term newborn infants occurs in 1 to 3 per 1000 births1Kurinczuk J. White-Koning M. Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy.Early Hum Dev. 2010; 86: 329-338Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar and leads to high mortality and morbidity rates with life-long chronic disabilities.2Marlow N. Rose A. Rands C. Draper E.S. Neuropsychological and educational problems at school age associated with neonatal encephalopathy.Arch Dis Child Fetal Neonatal Ed. 2005; 90: F380-F387Crossref PubMed Scopus (114) Google Scholar, 3Robertson C.M. Finer N.N. Grace M.G. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term.J Pediatr. 1989; 114: 753-760Abstract Full Text PDF PubMed Google Scholar Although therapeutic hypothermia is a significant advance in the developed world and improves outcome,4Edwards A. Brocklehurst P. Gunn A. Halliday H. Juszczak E. Levene M. 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; 340: C363Crossref PubMed Scopus (237) Google Scholar, 5Gluckman P. Wyatt J. Azzopardi D. Ballard R. Edwards A. Ferriero D. et al.Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.Lancet. 2005; 365: 663-670Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar hypothermia offers just 11% reduction in risk of death or disability, from 58% to 47%. Therefore, there still is an urgent need for other treatment options. Further, there are currently no clinically established interventions that can be given antenatally to ameliorate brain injury after fetal distress. One of the major limitations to progress is what may be called “the curse of choice.” A large number of possible neuroprotective therapies have shown promise in pre-clinical studies.6Kelen D. Robertson N.J. Experimental treatments for hypoxic ischaemic encephalopathy.Early Hum Dev. 2010; 86: 369-377Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 7Cilio M. Ferriero D. Synergistic neuroprotective therapies with hypothermia.Semin Fetal Neonatal Med. 2010; 15: 293-298Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar How should we select from them? There is no consensus at present on which drugs have a high chance of success for either antenatal or postnatal treatment. There are insufficient societal resources available to test them all. Thus, it is imperative to marshal finite resources and prioritize potential therapies for investigation. The authors believe that facilitating discussion of strategy and findings in “competing” laboratories is critical to facilitate efficient progress toward optimizing neuroprotection after hypoxia-ischemia. Few studies have examined possible interactions of medications with hypothermia and whether combination therapies augment neuroprotection. The timing of the administration of medications may be critical to optimize benefit and avoid neurotoxicity (eg, early acute treatments targeted at amelioration of the neurotoxic cascade compared with subacute treatment that can promote regeneration and repair). Intervention early on in the cascade of neural injury is likely to achieve more optimal neuroprotection8Carroll M. Beek O. Protection against hippocampal CA1 cell loss by post-ischaemic hypothermia is dependent on delay of initiation and duration.Metab Brain Dis. 1992; 7: 45-50Crossref PubMed Scopus (108) Google Scholar, 9Gunn A. Gunn T. Gunning M. Williams C. Gluckman P. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep.Pediatrics. 1998; 102: 1098-1106Crossref PubMed Scopus (175) Google Scholar; however, there is frequently little warning of impending perinatal hypoxia-ischemia episodes. Sensitizing factors such as maternal pyrexia,10Badawi N. Kurinczuk J.J. Keogh J.M. Alessandri L.M. O’Sullivan F. Burton P.R. Pemberton P.J. Stanley F.J. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study.BMJ. 1998; 317: 1554-1558Crossref PubMed Google Scholar maternal/fetal infection,11Lehnardt S.M.L. Follett P. Jensen F.E. Ratan R. Rosenberg P.A. Volpe J.J. et al.Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway.PNAS. 2003; 100: 8514-8519Crossref PubMed Scopus (437) Google Scholar, 12Eklind S. Mallard C. Leverin A.L. Gilland E. Blomgren K. Mattsby-Baltzer I. et al.Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury.Eur J Neurosci. 2001; 13: 1101-1106Crossref PubMed Google Scholar and poor fetal growth13Badawi N. Kurinczuk J.J. Keogh J.M. Alessandri L.M. O’Sullivan F. Burton P.R. et al.Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study.BMJ. 1998; 317: 1549-1553Crossref PubMed Google Scholar are well recognized and contribute to the heterogeneity of the fetal response and outcome in neonatal encephalopathy. We include potential antenatal therapy medications in the scoring process; however, electronic fetal monitoring has a low positive predictive value (3%–18%) for identifying intrapartum asphyxia.14Williams K.P. Galerneau F. Comparison of intrapartum fetal heart rate tracings in patients with neonatal seizures vs. no seizures: what are the differences?.J Perinat Med. 2004; 32: 422-425Crossref PubMed Scopus (11) Google Scholar, 15Kumar S. Paterson-Brown S. Obstetric aspects of hypoxic ischemic encephalopathy.Early Hum Dev. 2010; 86: 339-344Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 16Williams K.P. Galerneau F. Intrapartum fetal heart rate patterns in the prediction of neonatal acidemia.Am J Obstet Gynaecol. 2003; 188: 820-823Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 17Westgate J. Wibbens B. Bennet L. Wassink G. Parer J. Gunn A. The intrapartum deceleration in center stage: a physiologic approach to the interpretation of fetal heart rate changes in labor.Am J Obstet Gynaecol. 2007; 197: 236.e1-236.e11Abstract Full Text Full Text PDF Scopus (17) Google Scholar, 18Vijgen S. Westerhuis M. Opmeer B. Visser G. Moons K. Porath M. et al.Cost-effectiveness of cardiotocography plus ST analysis of the fetal electrocardiogram compared with cardiotocography only.Acta Obstet Gynecol Scand. 2011; 90: 772-778Crossref PubMed Scopus (4) Google Scholar At present, therefore, any antenatal intervention potentially involves treatment of many cases that do not need treatment in order to benefit a few at risk of brain injury. In January 2008, investigators from research institutions with a special interest in neuroprotection of the newborn appraised published evidence about medications that have been used in pre-clinical animal models, pilot clinical studies, or both as treatments for: (1) antenatal therapy for fetuses with a diagnosis of antenatal fetal distress at term; and (2) postnatal therapy of infants with moderate to severe neonatal encephalopathy. The aims of this study were to: (1) prioritize potential treatments for antenatal and postnatal therapy; and (2) provide a balanced reference for further discussions in the perinatal neuroscience community for future research and clinical translation of novel neuroprotective treatments of the newborn. 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 benefit and efficacy. For postnatal treatments, each drug was scored to a total possible score of 50 by using 5 questions, each scored 1 to 10: (1) ease of administration; (2) knowledge about starting dose; (3) adverse effects; (4) teratological or toxic effects; and (5) overall benefit and efficacy. The 12 authors represent perinatal neuroscience research groups from The Netherlands, United Kingdom, United States, Sweden, and New Zealand. Two to 3 medications were assigned to each member; each member was asked to evaluate the scientific literature, score the assigned medications, and present this evidence to the group, justifying the scores. General guidance for the scores were: score 0 to 3, no evidence or some significant concerns; score 4 to 5, some evidence or some concerns; score 6 to 8, good evidence or minor concerns; and score 9 to 10, compelling evidence and no significant concerns. Final scores reflected the opinion of the whole group. A total of 5 meetings were held, the first by Skype (Microsoft Skype Division, Luxembourg City, Luxembourg) in January 2009, and the final meeting was held in May 2011. 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). The medication with the highest score was BH4 (score 54/60, 90%), which was chosen for ease of administration, absence of teratological effects, and potential benefit. Melatonin (49/60, 82%) was the second choice, because of ease of administration and placental transfer and benefit. The medications with the lowest scores were topiramate and memantine (6/60, 10%). nNOS inhibitors were ranked third (75%). Xenon scored 42 of 60 (70%) and was ranked fourth; most points were lost in the “ease of administration” category. Allopurinol was ranked fifth (67%), followed by vitamins C and E (39/60, 65%). NAC, Epo-mimetics, Epo, resveratrol, and adenosine A2A receptor antagonists all scored <60% (Table I).Table IPotential antenatal neuroprotective therapies to be given to the mother in whom fetal distress is detectedBH4MelatoninnNOS inhibitorsXenonAllopurinolVitamin C and ENACEpo mimetic peptidesEpoResveratrolAdenosine A2A receptor antagonistMemantineTopiramateEase of administration10101027101010107111Starting dose107108655335111Placental transfer8108101071411111Side effects8767446613111Teratological effects1081810101081010111Benefit87107335674511FDA approvedYesYesNoNoYesYesYesNoYesYesNoYesYesTotal score (maximum 60)544945424039373732301066Rank (% score)1 (90%)2 (82%)3 (75%)4 (70%)5 (67%)6 (65%)7 (57%)7 (57%)8 (53%)9 (50%)10 (17%)11 (10%)11 (10%)Medications are ranked from highest (left) to lowest score (right).Each item is marked out of 10 and totalled to give an overall score of 60.10 = highest; 0 = lowest Open table in a new tab Medications are ranked from highest (left) to lowest score (right). Each item is marked out of 10 and totalled to give an overall score of 60. 10 = highest; 0 = lowest The medication with the highest score was melatonin (45/50; 90%), the medication with the second highest score was Epo (86%), and the medication with the third highest score was NAC (80%). The drugs with the lowest scores were BH4 and nNOS inhibitors (both 10%). Epo-mimetics were ranked fourth (38/50, 76%). Allopurinol was ranked fifth (35/50, 70%), and xenon was ranked sixth (34/50, 68%). Resveratrol, vitamins C and E, memantine, topiramate, and adenosine A2A receptor antagonists scored between 68% (resveratrol) and 44% (adenosine A2A receptor antagonists; Table II).Table IIPotential postnatal neuroprotective therapiesMelatoninEpoNACEpo mimetic peptidesAllopurinolXenonResveratrolVitamins C and EMemantineTopiramateAdenosine A2A receptor antagonistnNOS inhibitorsBH4Ease of administration10101010748934511Starting dose7777865654511Adverse effects108108884665811Teratological/neurodegenerative effects1010107108108109211Benefit8836386433511FDA approvedYesYesYesNoYesNoYesYesYesYesNoNoYesTotal score (maximum 50)454340383634333327252255Rank (% score)1 (90%)2 (86%)3 (80%)4 (76%)5 (72%)6 (68%)7 (66%)7 (66%)8 (54%)9 (50%)10 (44%)11 (10%)11 (10%)Medications are ranked from highest scores (left) to lowest score (right).Each item is marked out, and the total is combined to give the overall score of 50.10 = highest optimal score; 0 = lowest score. Open table in a new tab Medications are ranked from highest scores (left) to lowest score (right). Each item is marked out, and the total is combined to give the overall score of 50. 10 = highest optimal score; 0 = lowest score. The top 6 medications in both the antenatal or postnatal category are reviewed below, because a ranking in the top 6 suggests that these drugs are most likely to reach the clinical arena in the next 5 to 10 years. Putative mechanisms of neuroprotection are summarized in the Figure. BH4 (antenatal therapy, rank 1: score 90%; postnatal therapy, rank 11: score 10%) is an important co-factor for a number of enzymes, such as aromatic amino acid hydroxylases, which convert phenylalanine to tyrosine (phenylketonuria), tyrosine to L-dopa, and tryptophan to 5-hydroxytryptophan and nitric oxide synthase (NOS). It is synthesized de novo from guanosine triphosphate by 3 enzymatic reactions controlled by guanosine triphosphate cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, and sepiapterin reductase. Deficits in these enzymes result in motor disturbances, such as dopa-responsive dystonia. A newly identified defect in sepiapterin reductase causes motor disabilities and mental disturbances in children early in life. BH4 is a developmental factor determining the vulnerability of fetal brain to hypoxia-ischemia. There is evidence that BH4 deficiency can exacerbate oxidative injury19Madsen J.T. Jansen P. Hesslinger C. Meyer M. Zimmer J. Gramsbergen J.B. Tetrahydrobiopterin precursor sepiapterin provides protection against neurotoxicity of 1-methyl-4-phenylpyridinium in nigral slice cultures.J Neurochem. 2003; 85: 214-223Crossref PubMed Google Scholar and that neonatal hypoxia-ischemia can cause relative BH4 deficiency.20Fabian R.H. Perez-Polo J. Kent T.A. Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia.Am J Physiol Heart Circ Physiol. 2010; 295: h1809-h1814Crossref Scopus (30) Google Scholar Maternal treatment with BH4 increased fetal levels in basal ganglia and significantly ameliorated motor deficits and decreased stillbirths.21Vásquez-Vivar J. Whitsett J. Derrick M. Ji X. Yu L. Tan S. Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain.Ann Neurol. 2009; 66: 323-331Crossref PubMed Scopus (7) Google Scholar Transfer of BH4 was demonstrated in mice and also for an BH4 analog in rabbits,21Vásquez-Vivar J. Whitsett J. Derrick M. Ji X. Yu L. Tan S. Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain.Ann Neurol. 2009; 66: 323-331Crossref PubMed Scopus (7) Google Scholar, 22Kaufman S. Kapatos G. McInnes R. Schulman J. Rizzo W. Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain.Pediatrics. 1982; 70: 376-380PubMed Google Scholar but placental transfer is untested in humans. There have been extensive safety trials for the application of BH4 therapy in humans,23Frye R. Huffman L. Elliott G.R. Tetrahydrobiopterin as a novel therapeutic intervention for autism.Neurotherapeutics. 2010; 7: 241-249Crossref PubMed Scopus (11) Google Scholar including human pregnancy.24Giżewska M. Hnatyszyn G. Sagan L. Cyryłowski L. Zekanowski C. Modrzejewska M. 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; https://doi.org/10.1007/s10545-009-1073-4Crossref Scopus (1) Google Scholar From long-term follow-up in humans, BH4 in a wide range of doses has no adverse events.20Fabian R.H. Perez-Polo J. Kent T.A. Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia.Am J Physiol Heart Circ Physiol. 2010; 295: h1809-h1814Crossref Scopus (30) Google Scholar, 25Trefz F.K. Scheible D. Frauendienst-Egger G. Long-term follow-up of patients with phenylketonuria receiving tetrahydrobiopterin treatment.J Inherit Metab Dis. 2010; https://doi.org/10.1007/s10545-010-9058-xCrossref PubMed Scopus (10) Google Scholar Doses of 10 mg/kg per day have been used without problems,24Giżewska M. Hnatyszyn G. Sagan L. Cyryłowski L. Zekanowski C. Modrzejewska M. 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; https://doi.org/10.1007/s10545-009-1073-4Crossref Scopus (1) Google Scholar, 26Endres W. Niederwieser A. Curtius H. Wang M. Ohrt B. Schaub J. Atypical phenylketonuria due to biopterin deficiency. Early treatment with tetrahydrobiopterin and neurotransmitter precursors, trials of monotherapy.Helv Paediatr Acta. 1982; 37: 489-498PubMed Google Scholar, 27Koch R. Moseley K. Guttler F. Tetrahydrobiopterin and maternal PKU.Mol Genet Metab. 2005; 86: S139-S141Crossref PubMed Scopus (17) Google Scholar although for purposes of neuroprotection a higher dose may need to be given. BH4 in the synthetic preparation form sapropterin dihydrochloride, was approved by FDA for use in pregnancy with certain provisos. There are no known adverse effects, but more extensive studies in pregnant women need to be done. No teratological effects have been documented. BH4 levels increase during normal fetal development21Vásquez-Vivar J. Whitsett J. Derrick M. Ji X. Yu L. Tan S. Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain.Ann Neurol. 2009; 66: 323-331Crossref PubMed Scopus (7) Google Scholar and are crucial for brain development. In rabbits, maternal supplementation with sepiapterin can significantly increase the BH4 levels in the fetal brain and decrease the incidence of motor deficits or death after fetal hypoxia-ischemia.21Vásquez-Vivar J. Whitsett J. Derrick M. Ji X. Yu L. Tan S. Tetrahydrobiopterin in the prevention of hypertonia in hypoxic fetal brain.Ann Neurol. 2009; 66: 323-331Crossref PubMed Scopus (7) Google Scholar In addition to disrupting normal neurotransmitter production in the brain, hypoxia-ischemia reduces the availability of BH4 in the brain. Such decreases in BH4 levels with hypoxia-ischemia could contribute to the severity of neurological outcomes from hypoxia-ischemia. Substantial amounts of BH4 can be detected in cerebrospinal fluid when given peripherally to patients with hyperphenylalaninemia caused by defective biopterin synthesis. Treatment with BH4 can ameliorate some cases of dystonia,28Fink J. Ravin P. Argoff C. Levine R. Brady R. Hallett M. et al.Tetrahydrobiopterin administration in biopterin-deficient progressive dystonia with diurnal variation.Neurology. 1989; 39: 1393-1395Crossref PubMed Google Scholar, 29Segawa M. Nomura Y. Nishiyama N. Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease).Ann Neurol. 2003; 54: S32-S45Crossref PubMed Google Scholar further emphasizing the importance of BH4 in the development of motor disturbances. There have been no studies of the combination of BH4 with therapeutic hypothermia after hypoxia-ischemia. It is unknown whether long-term supplementation is required for prevention/amelioration of hypoxia-ischemia injury or whether acute administration at the time of fetal distress would be effective. However, the safety and efficacy profile make BH4 supplementation an excellent candidate for further study. Melatonin (N-acetyl-5-methoxytryptamine; antenatal therapy, rank 2: score 82%; postnatal therapy, rank 1: score 90%) is produced mainly by the pineal gland, allowing the entrainment of circadian rhythms of several biological functions.30Altun A. Ugur-Altun B. Melatonin: therapeutic and clinical utilization.Int J Clin Pract. 2007; 61: 835-845Crossref PubMed Scopus (54) Google Scholar Melatonin actions are mediated through specific receptors,31Boutin J.A. Audinot V. Ferry G. Delagrange P. Molecular tools to study melatonin pathways and actions.Trends Pharmacol Sci. 2005; 26: 412-419Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar but it can also function as an antioxidant32Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance.Endocrine. 2005; 27: 119-130Crossref PubMed Scopus (287) Google Scholar and has anti-apoptotic effects.33Luchetti F. Canonico B. Betti M. Arcangeletti M. Pilolli F. Piroddi M. et al.Melatonin signaling and cell protection function.FASAB J. 2010; 24: 3603-3624Crossref PubMed Scopus (63) Google Scholar Because of its lipophilic properties, melatonin easily crosses most biological cell membranes, including the placenta34Okatani Y. Okamoto K. Hayashi K. Wakatsuki A. Tamura S. Sagara Y. Maternal-fetal transfer of melatonin in pregnant women near term.J Pineal Res. 1998; 25: 129-134Crossref PubMed Scopus (87) Google Scholar, 35Reppert S. Chez R. Anderson A. Klein D. Maternal-fetal transfer of melatonin in the non-human primate.Pediatr Res. 1979; 13: 788-791Crossref PubMed Google Scholar, 36Sadowsky D. Yellon S. Mitchell M. Nathanielsz P. Lack of effect of melatonin on myometrial electromyographic activity in the pregnant sheep at 138-142 days gestation (term = 147 days gestation).Endocronology. 1991; 128: 1812-1818Crossref PubMed Google Scholar and the blood-brain barrier.37Vitte P. Harthe C. Lestage P. Claustrat B. Bobillier P. Plasma, cerebrospinal fluid, and brain distribution of 14C-melatonin in rat: a biochemical and autoradiographic study.J Pineal Res. 1988; 5: 437-453Crossref PubMed Google Scholar Melatonin can be administered intravenously, although it needs to be dissolved in an excipient, such as alcohol or propylene glycol. Oral doses show good uptake in tissues, even in patients who are critically ill.38Mistraletti G. Sabbatini G. Taverna M. Figini M.A. Umbrello M. Magni P. et al.Pharmacokinetics of orally administered melatonin in critically ill patients.J Pineal Res. 2010; 48: 142-147Crossref PubMed Scopus (19) Google Scholar A neonatal intravenous formulation needs to be developed; it is unclear how much melatonin is absorbed after oral or rectal doses in infants who have been cooled and asphyxiated. A wide range of melatonin doses were used in various species to treat brain injury. An intraperitoneal melatonin dose of 0.005 mg/kg is neuroprotective in newborn mice,39Husson I. Mesplès B. Bac P. Vamecq J. Evrard P. Gressens P. Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge.Ann Neurol. 2002; 51: 82-92Crossref PubMed Scopus (106) Google Scholar and doses as high as 200 mg/kg have been administered to pregnant rats throughout most of pregnancy without adverse effects to either the mother or the offspring.40Jahnke G. Marr M. Myers C. Wilson R. Travlos G. Price C. Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats.Toxicol Sci. 1999; 50: 271-279Crossref PubMed Scopus (125) Google Scholar The optimal neuroprotective dose still needs to be determined, although a 5-mg/kg infusion for 6 hours started 10 minutes after resuscitation and repeated at 24 hours augmented hypothermic neuroprotection in the newborn piglet.41Robertson N. Powell E. Faulkner S. Bainbridge A. Chandrasekaran M. Hristova M. et al.Improved neuroprotection with melatonin-augmented hypothermia vs hypothermia alone in a perinatal asphysia model.EPAS. 2012; Google Scholar Continuous infusion of a relatively high dose of melatonin (20 mg/kg/h for 6 hours) to fetal sheep after intrauterine asphyxia resulted in slower recovery of fetal blood pressure after umbilical cord occlusion, without changes in fetal heart rate, acid base status, or mortality rate.42Welin A.K. Svedin P. Lapatto R. Sultan B. Hagberg H. Gressens P. et al.Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion.Pediatr Res. 2007; 61: 153-158Crossref PubMed Scopus (66) Google Scholar Melatonin has been used safely in children with sleep abnormalities related to neurological disease43Jan J. O’Donnell M. Use of melatonin in the treatment of paediatric sleep disorders.J Pineal Res. 1996; 21: 193-199Crossref PubMed Google Scholar and in septic newborns without serious adverse effects.44Gitto E. Karbownik M. Reiter R. Tan D. Cuzzocrea S. Chiurazzi P. et al.Effects of melatonin treatment in septic newborns.Pediatr Res. 2001; 50: 756-760Crossref PubMed Google Scholar There are no clinical safety studies of antenatal melatonin administration; however, animal studies indicate that even doses as high as 200 mg/kg for several days during pregnancy in rats do not have toxic effects on either mother or fetus.40Jahnke G. Marr M. Myers C. Wilson R. Travlos G. Price C. Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats.Toxicol Sci. 1999; 50: 271-279Crossref PubMed Scopus (125) Google Scholar Melatonin has very low toxicity in clinical studies.45Reiter R. Tan D. Mayo J. Sainz R. Leon J. Czarnocki Z. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans.Acta Biochim Pol. 2003; 50: 1129-1146PubMed Google Scholar Several animal studies have shown neuroprotective benefits from melatonin treatment, both when given before and after birth. When administered directly to the sheep fetus after umbilical cord occlusion, melatonin attenuated the production of 8-isoprostanes and reduced the number of activated microglia cells and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the brain.42Welin A.K. Svedin P. Lapatto R. Sultan B. Hagberg H. Gressens P. et al.Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion.Pediatr Res. 2007; 61: 153-158Crossref PubMed Scopus (66) Google Scholar Maternal administration (1 mg bolus, then 1 mg/h for 2 hours) also prevented subsequent increase in free radical production in fetal sheep exposed to intrauterine asphyxia.46Miller S.L. Yan E.B. Castillo-Meléndez M. Jenkin G. Walker D.W. Melatonin provides neuroprotection in the late-gestation fetal sheep brain in response to umbilical cord occlusion.Dev Neurosci. 2005; 27: 200-210Crossref PubMed Scopus (45) Google Scholar Low-dose melatonin (0.1 mg/kg/day) administered to the mother for 7 days at the end of pregnancy reduced signs of cerebral inflammation and apoptosis after birth asphyxia in the spiny mouse.47Hutton L.C. Abbass M. Dickinson H. Ireland Z. Walker D.W. Neuroprotective properties of melatonin in a model of birth asphyxia in the spiny mouse (Acomys cahirinus).Dev Neurosci. 2009; 31: 437-451Crossref PubMed Scopus (18) Google Scholar Evidence from both clinical and experimental studies supports the safety of melatonin antenatally, with no teratological or other toxic effects. Clinically, melatonin appears to have beneficial effects when given to children who were both asphyxiated48Fulia F. Gitto E. Cuzzocrea S. Reiter R. Dugo L. Gitto P. et al.Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin.J Pineal Res. 2005; 31: 343-349Crossref Scopus (113) Google Scholar and septic.44Gitto E. Karbownik M. Reiter R. Tan D. Cuzzocrea S. Chiurazzi P. et al.Effects of melatonin treatment in septic newborns.Pediatr Res. 2001; 50: 756-760Crossref PubMed Google Scholar After birth, melatonin can protect against excitotoxic lesions induced by ibotenate in newborn mice. Given in low doses (0.005-5 mg/kg i.p.), melatonin reduced brain lesions in the white matter >80%, and melatonin was still (but less) effective when given 4 hours after the insult39Husson I. Mesplès B. Bac P. Vamecq J. Evrard P. Gressens P. Melatoninergic neuroprotection of the murine periventricular white matter against neonatal excitotoxic challenge.Ann Neurol. 2002; 51: 82-92Crossref PubMed Scopus (106) Google Scholar and reduced learning deficits.49Bouslama M. Renaud J. Olivier P. Fontaine R.H. Matrot B. Gressens P. et al.Melatonin prevents learning disorders in brain-lesioned newborn mice.Neuroscience. 2007; 150: 712-719Crossref PubMed Scopus (21) Google Scholar Protection of the cerebral white matter has also been shown after 2 hours of hypoxic insults in newborn rats,50Kaur C. Sivakumar V. Ling E. Melatonin protects periventricular white matter from damage due to hypoxia.J Pineal Res. 2010; 48: 185-193Crossref PubMed Scopus (26) Google Scholar and melatonin decreased microglial activation and astroglial reaction and promoted oligodendrocyte maturation in growth restricted rat pups.51Olivier P. Fontaine R.H. Loron G. Van Steenwinckel J. Biran V. Massonneau V. et al.Melatonin promotes oligodendroglial maturation of injured white matter in neonatal rats.PLoS One. 2009; 22: e7128Crossref Scopus (30) Google Scholar Furthermore, in a model of lipopolysacchride-induced hypoxic-ischemic injury in neonatal rats, melatonin reduced injury by 45% when given repeatedly at 5 mg/kg, and a higher dose (20 mg/kg) did not significantly protect the brain.52Wang X. Svedin" @default.
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• W2149763277 title "Which Neuroprotective Agents are Ready for Bench to Bedside Translation in the Newborn Infant?" @default.
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