Pharmacological Neuroprotection of the Preterm Brain: Current Evidence and Perspectives

Abstract

Despite improvements in viability, the long-term neurodevelopmental outcomes of preterm babies remain serious concern as a significant percentage of these infants develop neurological and/or intellectual impairment, and they are also at increased risk of psychiatric illnesses later in life. The current challenge is to develop neuroprotective approaches to improve adverse outcomes in preterm survivors. The purpose of this review was to provide an overview of the current evidence on pharmacological agents targeting the neuroprotection of the preterm brain. Among them, magnesium sulfate, given antenatally to pregnant women with imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine administered to preterm infants after birth, exhibited neuroprotective effects for human preterm brain. Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions. Further studies are also required to assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be implemented as neuroprotectants in clinical practice. Furthermore, other pharmacological agents showing promising signs of neuroprotective efficacy in preclinical studies (growth factors, hyaluronidase inhibitors or treatment, antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as well as stem cell- or exosomal-based therapies and nanomedicine, may prove useful in the future as potential neuroprotective approaches for human preterm brain.

Key Points

• Magnesium and caffeine have neuroprotective effects for the preterm brain.

• Follow-up of infants treated with erythropoietin is needed.

• Neuroprotective efficacy of several drugs in animals needs to be shown in humans.

Keywords

brain - prematurity - neonates - drugs - neuroprotective agents - medications

Note

This article does not contain any studies with human participants or animals performed by the authors.

Publication History

Received: 05 May 2020

Accepted: 07 August 2020

Article published online:
22 September 2020

• References

• 1 Johnson S, Marlow N. Early and long-term outcome of infants born extremely preterm. Arch Dis Child 2017; 102 (01) 97-102
• 2 Pascal A, Govaert P, Oostra A, Naulaers G, Ortibus E, Van den Broeck C. Neurodevelopmental outcome in very preterm and very-low-birthweight infants born over the past decade: a meta-analytic review. Dev Med Child Neurol 2018; 60 (04) 342-355
• 3 Pierrat V, Marchand-Martin L, Arnaud C. et al. EPIPAGE-2 writing group. Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks' gestation in France in 2011: EPIPAGE-2 cohort study. BMJ 2017; 358: j3448
• 4 Johnson S, Marlow N. Preterm birth and childhood psychiatric disorders. Pediatr Res 2011; 69 (5 Pt 2): 11R-18R
• 5 Kapellou O, Counsell SJ, Kennea N. et al. Abnormal cortical development after premature birth shown by altered allometric scaling of brain growth. PLoS Med 2006; 3 (08) e265
• 6 Malik S, Vinukonda G, Vose LR. et al. Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth. J Neurosci 2013; 33 (02) 411-423
• 7 Volpe JJ. Dysmaturation of premature brain: importance, cellular mechanisms, and potential interventions. Pediatr Neurol 2019; 95: 42-66
• 8 Parikh P, Juul SE. Neuroprotection strategies in preterm encephalopathy. Semin Pediatr Neurol 2019; 32: 100772
• 9 Truttmann AC, Ginet V, Puyal J. Current evidence on cell death in preterm brain injury in human and preclinical models. Front Cell Dev Biol 2020; 8: 27
• 10 Back SA, Volpe JJ. Encephalopathy of prematurity: pathophysiology. In: Volpe JJ, Inder TE, Darras BT. et al., eds. Volpe's Neurology of the Newborn. 6th ed. Chapter 15. Philadelphia, PA: Elsevier; 2018: 405e424
• 11 Fleiss B, Gressens P. Neuroprotection of the preterm brain. Handb Clin Neurol 2019; 162: 315-328
• 12 Grimes DA, Nanda K. Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 2006; 108 (04) 986-989
• 13 Du L, Wenning LA, Carvalho B. et al. Alternative magnesium sulfate dosing regimens for women with preeclampsia: a population pharmacokinetic exposure-response modeling and simulation study. J Clin Pharmacol 2019; 59 (11) 1519-1526
• 14 Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?. Pediatrics 1995; 95 (02) 263-269
• 15 Doyle LW, Crowther CA, Middleton P, Marret S. Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol 2009; 113 (06) 1327-1333
• 16 Doyle LW. Antenatal magnesium sulfate and neuroprotection. Curr Opin Pediatr 2012; 24 (02) 154-159
• 17 Crowther CA, Middleton PF, Voysey M. et al; AMICABLE Group. Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: an individual participant data meta-analysis. PLoS Med 2017; 14 (10) e1002398
• 18 Stark MJ, Hodyl NA, Andersen CC. Effects of antenatal magnesium sulfate treatment for neonatal neuro-protection on cerebral oxygen kinetics. Pediatr Res 2015; 78 (03) 310-314
• 19 Koning G, Leverin AL, Nair S. et al. Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection. J Cereb Blood Flow Metab 2019; 39 (06) 1038-1055
• 20 American College of Obstetricians and Gynecologists Committee on Obstetric Practice Society for Maternal-Fetal Medicine. Committee Opinion No 652: Magnesium Sulfate Use in Obstetrics. Obstet Gynecol 2016; 127 (01) e52-e53
• 21 Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel, Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant, and child national clinical practice guidelines. Adelaide, Australia: The University of Adelaide. 2010 . Accessed July 20, 2020 at: https://www.clinicalguidelines.gov.au/register/antenatal-magnesium-sulphate-prior-preterm-birth-neuroprotection-fetus-infant-and-child
• 22 Sentilhes L, Sénat MV, Ancel PY. et al. Prevention of spontaneous preterm birth: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol 2017; 210: 217-224
• 23 National Institute for Health and Care Excellence. Preterm labour and birth. Full guideline. NICE Guideline 25. Methods, evidence and recommendations. November 2015. Accessed July 20, 2020 at: https://www.nice.org.uk/guidance/ng25/chapter/Recommendations#magnesium-sulfate-for-neuroprotection
• 24 Royal College of Obstetricians and Gynaecologists. Magnesium sulphate to prevent cerebral palsy following preterm birth. Scientific impact paper no 29. 2011 :1–7. Accessed July 20, 2020 at: https://www.rcog.org.uk/globalassets/documents/guidelines/scientific-impact-papers/sip_29.pdf
• 25 Magee LA, De Silva DA, Sawchuck D, Synnes A, von Dadelszen P. No. 376-magnesium sulphate for fetal neuroprotection. J Obstet Gynaecol Can 2019; 41 (04) 505-522
• 26 WHO Reproductive Health Library. WHO recommendation on the use of magnesium sulfate for fetal protection from neurological complications (November 2015). The WHO Reproductive Health Library; Geneva: World Health Organization. Accessed July 20, 2020 at: https://extranet.who.int/rhl/topics/newborn-health/who-recommendation-use-magnesium-sulfate-fetal-protection-neurological-complications
• 27 Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017; 3: CD004454
• 28 Jobe AH. Antenatal corticosteroids: a concern for lifelong outcomes. J Pediatr 2020; 217: 184-188
• 29 van der Merwe JL, Sacco A, Toelen J, Deprest J. Long-term neuropathological and/or neurobehavioral effects of antenatal corticosteroid therapy in animal models: a systematic review. Pediatr Res 2020; 87 (07) 1157-1170
• 30 Wolford E, Lahti-Pulkkinen M, Girchenko P. et al. Associations of antenatal glucocorticoid exposure with mental health in children. Psychol Med 2020; 50 (02) 247-257
• 31 Savoy C, Ferro MA, Schmidt LA, Saigal S, Van Lieshout RJ. Prenatal betamethasone exposure and psychopathology risk in extremely low birth weight survivors in the third and fourth decades of life. Psychoneuroendocrinology 2016; 74: 278-285
• 32 Carlo WA, McDonald SA, Fanaroff AA. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks' gestation. JAMA 2011; 306 (21) 2348-2358
• 33 Gentle SJ, Carlo WA, Tan S. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network. Association of antenatal corticosteroids and magnesium sulfate therapy with neurodevelopmental outcome in extremely preterm children. Obstet Gynecol 2020; 135 (06) 1377-1386
• 34 Sotiriadis A, Tsiami A, Papatheodorou S, Baschat AA, Sarafidis K, Makrydimas G. Neurodevelopmental outcome after a single course of antenatal steroids in children born preterm: a systematic review and meta-analysis. Obstet Gynecol 2015; 125 (06) 1385-1396
• 35 Crowther CA, McKinlay CJ, Middleton P, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev 2015; 2015 (07) CD003935
• 36 González-Orozco JC, Camacho-Arroyo I. Progesterone actions during central nervous system development. Front Neurosci 2019; 13: 503
• 37 Shaw JC, Berry MJ, Dyson RM, Crombie GK, Hirst JJ, Palliser HK. Reduced neurosteroid exposure following preterm birth and its' contribution to neurological impairment: a novel avenue for preventative therapies. Front Physiol 2019; 10: 599
• 38 Novak CM, Ozen M, McLane M. et al. Progesterone improves perinatal neuromotor outcomes in a mouse model of intrauterine inflammation via immunomodulation of the placenta. Am J Reprod Immunol 2018; 79 (05) e12842
• 39 Shaw JC, Dyson RM, Palliser HK, Gray C, Berry MJ, Hirst JJ. Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs. Pediatr Res 2019; 85 (01) 86-96
• 40 Palliser HK, Kelleher MA, Tolcos M, Walker DW, Hirst JJ. Effect of postnatal progesterone therapy following preterm birth on neurosteroid concentrations and cerebellar myelination in guinea pigs. J Dev Orig Health Dis 2015; 6 (04) 350-361
• 41 Romero R, Conde-Agudelo A, Da Fonseca E. et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol 2018; 218 (02) 161-180
• 42 Norman JE, Marlow N, Messow CM. et al; OPPTIMUM study group. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet 2016; 387 (10033): 2106-2116
• 43 Jing X, Huang YW, Jarzembowski J, Shi Y, Konduri GG, Teng RJ. Caffeine ameliorates hyperoxia-induced lung injury by protecting GCH1 function in neonatal rat pups. Pediatr Res 2017; 82 (03) 483-489
• 44 Mandell EW, Kratimenos P, Abman SH, Steinhorn RH. Drugs for the prevention and treatment of bronchopulmonary dysplasia. Clin Perinatol 2019; 46 (02) 291-310
• 45 Di Martino E, Bocchetta E, Tsuji S. et al. Defining a time window for neuroprotection and glia modulation by caffeine after neonatal hypoxia-ischaemia. Mol Neurobiol 2020; 57 (05) 2194-2205
• 46 Back SA, Craig A, Luo NL. et al. Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol 2006; 60 (06) 696-705
• 47 Lopes JP, Pliássova A, Cunha RA. The physiological effects of caffeine on synaptic transmission and plasticity in the mouse hippocampus selectively depend on adenosine A₁ and A_2A receptors. Biochem Pharmacol 2019; 166: 313-321
• 48 Schmidt B, Roberts RS, Davis P. et al; Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 2007; 357 (19) 1893-1902
• 49 Schmidt B, Roberts RS, Anderson PJ. et al; Caffeine for Apnea of Prematurity (CAP) Trial Group. Academic performance, motor function, and behavior 11 years after neonatal caffeine citrate therapy for apnea of prematurity: an 11-year follow-up of the CAP randomized clinical trial. JAMA Pediatr 2017; 171 (06) 564-572
• 50 Lodha A, Entz R, Synnes A. et al; investigators of the Canadian Neonatal Network (CNN) and the Canadian Neonatal Follow-up Network (CNFUN). Early caffeine administration and neurodevelopmental outcomes in preterm infants. Pediatrics 2019; 143 (01) e20181348
• 51 Vliegenthart R, Miedema M, Hutten GJ, van Kaam AH, Onland W. High versus standard dose caffeine for apnoea: a systematic review. Arch Dis Child Fetal Neonatal Ed 2018; 103 (06) F523-F529
• 52 Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2020; 2: CD004865
• 53 Juul SE, Pet GC. Erythropoietin and neonatal neuroprotection. Clin Perinatol 2015; 42 (03) 469-481
• 54 Statler PA, McPherson RJ, Bauer LA, Kellert BA, Juul SE. Pharmacokinetics of high-dose recombinant erythropoietin in plasma and brain of neonatal rats. Pediatr Res 2007; 61 (06) 671-675
• 55 Fauchère JC, Koller BM, Tschopp A, Dame C, Ruegger C, Bucher HU. Swiss Erythropoietin Neuroprotection Trial Group. Safety of early high-dose recombinant erythropoietin for neuroprotection in very preterm infants. J Pediatr 2015; 167 (01) 52-7.e1-3
• 56 Song J, Sun H, Xu F. et al. Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Ann Neurol 2016; 80 (01) 24-34
• 57 Juul SE, Comstock BA, Wadhawan R. et al; PENUT Trial Consortium. A randomized trial of erythropoietin for neuroprotection in preterm infants. N Engl J Med 2020; 382 (03) 233-243
• 58 Volpe JJ. Commentary: do the negative results of the PENUT trial close the book on erythropoietin for premature infant brain?. J Neonatal Perinatal Med 2020; 13 (02) 149-152
• 59 Ohls RK, Kamath-Rayne BD, Christensen RD. et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics 2014; 133 (06) 1023-1030
• 60 Jakab A, Ruegger C, Bucher HU. et al; Swiss EPO Neuroprotection Trial Group. Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very preterm infants. Neuroimage Clin 2019; 22: 101806
• 61 Natalucci G, Latal B, Koller B. et al; Swiss EPO Neuroprotection Trial Group. Effect of early prophylactic high-dose recombinant human erythropoietin in very preterm infants on neurodevelopmental outcome at 2 years: a randomized clinical trial. JAMA 2016; 315 (19) 2079-2085
• 62 Wehrle FM, Held U, O'Gorman RT. et al. Long-term neuroprotective effect of erythropoietin on executive functions in very preterm children (EpoKids): protocol of a prospective follow-up study. BMJ Open 2018; 8 (04) e022157
• 63 Cardinali DP. An assessment of melatonin's therapeutic value in the hypoxic-ischemic encephalopathy of the newborn. Front Synaptic Neurosci 2019; 11: 34
• 64 Colella M, Biran V, Baud O. Melatonin and the newborn brain. Early Hum Dev 2016; 102: 1-3
• 65 Biran V, Decobert F, Bednarek N. et al. Melatonin levels in preterm and term infants and their mothers. Int J Mol Sci 2019; 20 (09) 2077
• 66 Merchant NM, Azzopardi DV, Hawwa AF. et al. Pharmacokinetics of melatonin in preterm infants. Br J Clin Pharmacol 2013; 76 (05) 725-733
• 67 Palmer KR, Mockler JC, Davies-Tuck ML. et al. Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction. BMJ Open 2019; 9 (06) e028243
• 68 Merchant N, Azzopardi D, Counsell S. et al. Melatonin as a novel neuroprotectant in preterm infants: a double blinded randomised controlled trial (mint study). Arch Dis Child 2014; 99 (Suppl. 02) A43
• 69 Angelis D, Savani R, Chalak L. Nitric oxide and the brain. Part 1: mechanisms of regulation, transport and effects on the developing brain. Pediatr Res 2021; 89 (04) 738-745
• 70 Olivier P, Loron G, Fontaine RH. et al. Nitric oxide plays a key role in myelination in the developing brain. J Neuropathol Exp Neurol 2010; 69 (08) 828-837
• 71 Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev 2017; 1: CD000509
• 72 Angelis D, Savani R, Chalak L. Nitric oxide and the brain. Part 2: effects following neonatal brain injury-friend or foe?. Pediatr Res 2020; DOI: 10.1038/s41390-020-1021-4.
• 73 Pham H, Vottier G, Pansiot J. et al. Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats. Exp Neurol 2014; 252: 114-123
• 74 Pham H, Duy AP, Pansiot J. et al. Impact of inhaled nitric oxide on white matter damage in growth-restricted neonatal rats. Pediatr Res 2015; 77 (04) 563-569
• 75 Charriaut-Marlangue C, Bonnin P, Gharib A. et al. Inhaled nitric oxide reduces brain damage by collateral recruitment in a neonatal stroke model. Stroke 2012; 43 (11) 3078-3084
• 76 Donohue PK, Gilmore MM, Cristofalo E. et al. Inhaled nitric oxide in preterm infants: a systematic review. Pediatrics 2011; 127 (02) e414-e422
• 77 Rodríguez-Fanjul J, Durán Fernández-Feijóo C, Lopez-Abad M. et al. Neuroprotection with hypothermia and allopurinol in an animal model of hypoxic-ischemic injury: is it a gender question?. PLoS One 2017; 12 (09) e0184643
• 78 Chaudhari T, McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy. Cochrane Database Syst Rev 2012; 7 (07) CD006817
• 79 Kaandorp JJ, van Bel F, Veen S. et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed 2012; 97 (03) F162-F166
• 80 Kaandorp JJ, Benders MJ, Schuit E. et al. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 2015; 100 (03) F216-F223
• 81 Maiwald CA, Annink KV, Rüdiger M. et al; ALBINO Study Group. Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III). BMC Pediatr 2019; 19 (01) 210
• 82 Kaandorp JJ, van den Broek MP, Benders MJ. et al; ALLO-trial Study Group. Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour. Arch Dis Child Fetal Neonatal Ed 2014; 99 (02) F144-F148
• 83 Hortensius LM, van Elburg RM, Nijboer CH, Benders MJNL, de Theije CGM. Postnatal nutrition to improve brain development in the preterm infant: a systematic review from bench to bedside. Front Physiol 2019; 10: 961
• 84 Shaw OEF, Yager JY. Preventing childhood and lifelong disability: maternal dietary supplementation for perinatal brain injury. Pharmacol Res 2019; 139: 228-242
• 85 McNamara RK, Vannest JJ, Valentine CJ. Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation: mechanisms and implications for psychopathology. World J Psychiatry 2015; 5 (01) 15-34
• 86 Clandinin MT, Chappell JE, Leong S, Heim T, Swyer PR, Chance GW. Intrauterine fatty acid accretion rates in human brain: implications for fatty acid requirements. Early Hum Dev 1980; 4 (02) 121-129
• 87 Carbone BE, Abouleish M, Watters KE. et al. Synaptic connectivity and cortical maturation are promoted by the ω-3 fatty acid docosahexaenoic acid. Cereb Cortex 2020; 30 (01) 226-240
• 88 Zhang W, Zhang H, Mu H. et al. Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury. Neurobiol Dis 2016; 91: 37-46
• 89 Tuzun F, Kumral A, Dilek M. et al. Maternal omega-3 fatty acid supplementation protects against lipopolysaccharide-induced white matter injury in the neonatal rat brain. J Matern Fetal Neonatal Med 2012; 25 (06) 849-854
• 90 Moon K, Rao SC, Schulzke SM, Patole SK, Simmer K. Long chain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev 2016; 12: CD000375
• 91 Hewawasam E, Collins CT, Muhlhausler BS. et al. Docosahexaenoic acid supplementation in infants born preterm and the effect on attention at 18 months' corrected age: follow-up of a subset of the N3RO randomised controlled trial. Br J Nutr 2020; 1-26 ; [Epub ahead of print]
• 92 Wang Q, Cui Q, Yan C. The effect of supplementation of long-chain polyunsaturated fatty acids during lactation on neurodevelopmental outcomes of preterm infant from infancy to school age: a systematic review and meta-analysis. Pediatr Neurol 2016; 59: 54-61.e1
• 93 Keim SA, Boone KM, Klebanoff MA. et al. Effect of docosahexaenoic acid supplementation vs placebo on developmental outcomes of toddlers born preterm: a randomized clinical trial. JAMA Pediatr 2018; 172 (12) 1126-1134
• 94 Middleton P, Gomersall JC, Gould JF, Shepherd E, Olsen SF, Makrides M. Omega-3 fatty acid addition during pregnancy. Cochrane Database Syst Rev 2018; 11: CD003402
• 95 Zeisel SH, Klatt KC, Caudill MA. Choline. Adv Nutr 2018; 9 (01) 58-60
• 96 Bekdash RA. Neuroprotective effects of choline and other methyl donors. Nutrients 2019; 11 (12) 2995
• 97 Moreno HC, de Brugada I, Carias D, Gallo M. Long-lasting effects of prenatal dietary choline availability on object recognition memory ability in adult rats. Nutr Neurosci 2013; 16 (06) 269-274
• 98 Boeke CE, Gillman MW, Hughes MD, Rifas-Shiman SL, Villamor E, Oken E. Choline intake during pregnancy and child cognition at age 7 years. Am J Epidemiol 2013; 177 (12) 1338-1347
• 99 Cheatham CL, Goldman BD, Fischer LM, da Costa KA, Reznick JS, Zeisel SH. Phosphatidylcholine supplementation in pregnant women consuming moderate-choline diets does not enhance infant cognitive function: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2012; 96 (06) 1465-1472
• 100 Chen H, Tang Y, Wang H, Chen W, Jiang H. Curcumin alleviates lipopolysaccharide-induced neuroinflammation in fetal mouse brain. Restor Neurol Neurosci 2018; 36 (05) 583-592
• 101 Rocha-Ferreira E, Sisa C, Bright S. et al. Curcumin: novel treatment in neonatal hypoxic-ischemic brain injury. Front Physiol 2019; 10: 1351
• 102 Cui X, Song H, Su J. Curcumin attenuates hypoxic-ischemic brain injury in neonatal rats through induction of nuclear factor erythroid-2-related factor 2 and heme oxygenase-1. Exp Ther Med 2017; 14 (02) 1512-1518
• 103 Liu ZJ, Liu HQ, Xiao C. et al. Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-γ function. J Neurosci Res 2014; 92 (11) 1549-1559
• 104 Zhou J, Wu N, Lin L. Curcumin suppresses apoptosis and inflammation in hypoxia/reperfusion-exposed neurons via Wnt signaling pathway. Med Sci Monit 2020; 26: e920445
• 105 He LF, Chen HJ, Qian LH, Chen GY, Buzby JS. Curcumin protects pre-oligodendrocytes from activated microglia in vitro and in vivo. Brain Res 2010; 1339: 60-69
• 106 Panaro MA, Corrado A, Benameur T, Paolo CF, Cici D, Porro C. The emerging role of curcumin in the modulation of TLR-4 signaling pathway: focus on neuroprotective and anti-rheumatic properties. Int J Mol Sci 2020; 21 (07) 2299
• 107 Turner MA. Clinical trials of medicines in neonates: the influence of ethical and practical issues on design and conduct. Br J Clin Pharmacol 2015; 79 (03) 370-378
• 108 Guardia Clausi M, Paez PM, Pasquini LA, Pasquini JM. Inhalation of growth factors and apo-transferrin to protect and repair the hypoxic-ischemic brain. Pharmacol Res 2016; 109: 81-85
• 109 Lin S, Fan LW, Rhodes PG, Cai Z. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Exp Neurol 2009; 217 (02) 361-370
• 110 Cai Z, Fan LW, Lin S, Pang Y, Rhodes PG. Intranasal administration of insulin-like growth factor-1 protects against lipopolysaccharide-induced injury in the developing rat brain. Neuroscience 2011; 194: 195-207
• 111 Tien LT, Lee YJ, Pang Y. et al. Neuroprotective effects of intranasal IGF-1 against neonatal lipopolysaccharide-induced neurobehavioral deficits and neuronal inflammation in the substantia nigra and locus coeruleus of juvenile rats. Dev Neurosci 2017; 39 (06) 443-459
• 112 Lekic T, Flores J, Klebe D. et al. Intranasal IGF-1 reduced rat pup germinal matrix hemorrhage. Acta Neurochir Suppl (Wien) 2016; 121: 209-212
• 113 Scafidi J, Hammond TR, Scafidi S. et al. Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 2014; 506 (7487): 230-234
• 114 El Ghazi F, Desfeux A, Brasse-Lagnel C. et al. NO-dependent protective effect of VEGF against excitotoxicity on layer VI of the developing cerebral cortex. Neurobiol Dis 2012; 45 (03) 871-886
• 115 Hansen-Pupp I, Hellström A, Hamdani M. et al. Continuous longitudinal infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants: Evaluation of feasibility in a phase II study. Growth Horm IGF Res 2017; 36: 44-51
• 116 Preston M, Gong X, Su W. et al. Digestion products of the PH20 hyaluronidase inhibit remyelination. Ann Neurol 2013; 73 (02) 266-280
• 117 Vinukonda G, Dohare P, Arshad A. et al. Hyaluronidase and hyaluronan oligosaccharides promote neurological recovery after intraventricular hemorrhage. J Neurosci 2016; 36 (03) 872-889
• 118 Poupon-Bejuit L, Rocha-Ferreira E, Thornton C, Hagberg H, Rahim AA. Neuroprotective effects of diabetes drugs for the treatment of neonatal hypoxia-ischemia encephalopathy. Front Cell Neurosci 2020; 14: 112
• 119 Qi B, Hu L, Zhu L. et al. Metformin attenuates cognitive impairments in hypoxia-ischemia neonatal rats via improving remyelination. Cell Mol Neurobiol 2017; 37 (07) 1269-1278
• 120 Fang M, Jiang H, Ye L. et al. Metformin treatment after the hypoxia-ischemia attenuates brain injury in newborn rats. Oncotarget 2017; 8 (43) 75308-75325
• 121 Tosun C, Koltz MT, Kurland DB. et al. The protective effect of glibenclamide in a model of hemorrhagic encephalopathy of prematurity. Brain Sci 2013; 3 (01) 215-238
• 122 Lu M, Qi Y, Han Y. et al. Design and development of novel thiazolidin-4-one-1,3,5-triazine derivatives as neuro-protective agent against cerebral ischemia-reperfusion injury in mice via attenuation of NF-κB. Chem Biol Drug Des 2020; 96 (05) 1315-1327
• 123 Barata-Antunes S, Cristóvão AC, Pires J, Rocha SM, Bernardino L. Dual role of histamine on microglia-induced neurodegeneration. Biochim Biophys Acta Mol Basis Dis 2017; 1863 (03) 764-769
• 124 Chen Y, Zhen W, Guo T. et al. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination. PLoS One 2017; 12 (12) e0189380
• 125 Rangon CM, Schang AL, Van Steenwinckel J. et al. Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury. Brain Behav Immun 2018; 74: 265-276
• 126 Fiani B, Sarhadi KJ, Soula M, Zafar A, Quadri SA. Current application of cannabidiol (CBD) in the management and treatment of neurological disorders. Neurol Sci 2020; DOI: 10.1007/s10072-020-04514-2.
• 127 Abrantes De Lacerda Almeida T, Santos MV, Da Silva Lopes L. et al. Intraperitoneal cannabidiol attenuates neonatal germinal matrix hemorrhage-induced neuroinflamation and perilesional apoptosis. Neurol Res 2019; 41 (11) 980-990
• 128 Ceprián M, Vargas C, García-Toscano L. et al. Cannabidiol administration prevents hypoxia-ischemia-induced hypomyelination in newborn rats. Front Pharmacol 2019; 10: 1131
• 129 Wagenaar N, Nijboer CH, van Bel F. Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev Med Child Neurol 2017; 59 (10) 997-1003
• 130 Thompson M, Mei SHJ, Wolfe D. et al. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: an updated systematic review and meta-analysis. EClinicalMedicine 2020; 19: 100249
• 131 Mukai T, Mori Y, Shimazu T. et al. Intravenous injection of umbilical cord-derived mesenchymal stromal cells attenuates reactive gliosis and hypomyelination in a neonatal intraventricular hemorrhage model. Neuroscience 2017; 355: 175-187
• 132 Thomi G, Joerger-Messerli M, Haesler V, Muri L, Surbek D, Schoeberlein A. Intranasally administered exosomes from umbilical cord stem cells have preventive neuroprotective effects and contribute to functional recovery after perinatal brain injury. Cells 2019; 8 (08) 855
• 133 Vinukonda G, Liao Y, Hu F. et al. Human cord blood-derived unrestricted somatic stem cell infusion improves neurobehavioral outcome in a rabbit model of intraventricular hemorrhage. Stem Cells Transl Med 2019; 8 (11) 1157-1169
• 134 Ahn SY, Chang YS, Sung SI, Park WS. Mesenchymal stem cells for severe intraventricular hemorrhage in preterm infants: phase I dose-escalation clinical trial. Stem Cells Transl Med 2018; 7 (12) 847-856
• 135 Romantsik O, Bruschettini M, Moreira A, Thébaud B, Ley D. Stem cell-based interventions for the prevention and treatment of germinal matrix-intraventricular haemorrhage in preterm infants. Cochrane Database Syst Rev 2019; 9: CD013201
• 136 Sandoval-Yañez C, Castro Rodriguez C. Dendrimers: amazing platforms for bioactive molecule delivery systems. Materials (Basel) 2020; 13 (03) 570
• 137 Niño DF, Zhou Q, Yamaguchi Y. et al. Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain. Sci Transl Med 2018; 10 (471) 237
• 138 Bersani I, Pluchinotta F, Dotta A. et al. Early predictors of perinatal brain damage: the role of neurobiomarkers. Clin Chem Lab Med 2020; 58 (04) 471-486
• 139 Douglas-Escobar M, Weiss MD. Biomarkers of brain injury in the premature infant. Front Neurol 2013; 3: 185
• 140 Rajatileka S, Odd D, Robinson MT. et al. Variants of the EAAT2 glutamate transporter gene promoter are associated with cerebral palsy in preterm infants. Mol Neurobiol 2018; 55 (03) 2013-2024
• 141 Van Steenwinckel J, Schang AL, Krishnan ML. et al. Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain. Brain 2019; 142 (12) 3806-3833
• 142 Tataranno ML, Perrone S, Longini M. et al. Predictive role of urinary metabolic profile for abnormal MRI score in preterm neonates. Dis Markers 2018; 2018: 4938194
• 143 Cho KHT, Xu B, Blenkiron C, Fraser M. Emerging roles of miRNAs in brain development and perinatal brain injury. Front Physiol 2019; 10: 227
• 144 Janjic T, Pereverzyev Jr S, Hammerl M. et al. Feed-forward neural networks using cerebral MR spectroscopy and DTI might predict neurodevelopmental outcome in preterm neonates. Eur Radiol 2020; 30 (12) 6441-6451
• 145 American College of Obstetricians and Gynecologists. Delayed umbilical cord clamping after birth. Committee Opinion No 684. Obstet Gynecol 2017; 129 (01) e5-e10
• 146 Feldman R, Rosenthal Z, Eidelman AI. Maternal-preterm skin-to-skin contact enhances child physiologic organization and cognitive control across the first 10 years of life. Biol Psychiatry 2014; 75 (01) 56-64
• 147 Blesa M, Sullivan G, Anblagan D. et al. Early breast milk exposure modifies brain connectivity in preterm infants. Neuroimage 2019; 184: 431-439
• 148 Bennet L, Dhillon S, Lear CA. et al. Chronic inflammation and impaired development of the preterm brain. J Reprod Immunol 2018; 125: 45-55
• 149 Panfoli I, Candiano G, Malova M. et al. Oxidative stress as a primary risk factor for brain damage in preterm newborns. Front Pediatr 2018; 6: 369
• 150 Duerden EG, Grunau RE, Guo T. et al. Early procedural pain is associated with regionally-specific alterations in thalamic development in preterm neonates. J Neurosci 2018; 38 (04) 878-886
• 151 Soleimani F, Azari N, Ghiasvand H, Shahrokhi A, Rahmani N, Fatollahierad S. Do NICU developmental care improve cognitive and motor outcomes for preterm infants? A systematic review and meta-analysis. BMC Pediatr 2020; 20 (01) 67
• 152 Spittle A, Orton J, Anderson PJ, Boyd R, Doyle LW. Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants. Cochrane Database Syst Rev 2015; 11 (11) CD005495