New Antioxidant Drugs

  • Giuseppe Buonocore
  • Serafina Perrone
  • Maria Luisa Tataranno
Chapter
First Online:
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)

Abstract

Oxidative stress results from the combined effects of cellular energy failure, acidosis, hypoxia, hyperoxia, and inflammation that lead to increased free radicals (FR) generation. An excessive oxidized state and particularly OH production can impair cell function in the fetus and newborn, inducing apoptosis in rapidly growing structures. The increased oxidative stress (OS) of the fetus and newborn has been attributed to the deficiency of antioxidant factors. Antioxidant strategies have the potential to be used as add-on neuroprotective therapy after perinatal OS.

A long list of antioxidant drugs (vitamins, oxygen-free radical inhibitors, and scavengers) has been used in clinical and experimental approaches to reduce OS in free radical-related neonatal diseases, with still uncertain results. Of these antioxidant substances, only vitamin A supplementation, given to neonates within a few days of birth, was demonstrated to be beneficial in reducing death and oxygen requirement at 36 weeks’ postmenstrual age. Currently, some new drugs already tested in experimental studies, such as allopurinol and erythropoietin, are ready for large clinical trials.

Preliminary results show that the treatment with allopurinol attenuates hypoxia-induced vascular remodeling, without affecting normal growth and proliferation. Melatonin, another antioxidant molecule, is demonstrated to be protective against OS brain injury, in experimental hypoxic brain damage in rats. Iminobiotin, an inhibitor of inflammatory mediators, is protective after cerebral ischemia in neonatal rats. Neonatal treatment with lutein decreases plasma OS and increases antioxidant capacities in the first days of life in human newborns. Currently, antioxidant treatment still has several limitations: (a) prolonged interval to penetrate the blood-brain barrier, (b) narrow therapeutic dosage range, and (c) short window for protective intervention. Decreasing FR and restoring oxidative imbalance certainly appear to be beneficial in response to hypoxia, reperfusion, and inflammation, but to date studies have not adequately addressed the consequences of altering oxidative or immune balance. The administration of antioxidants when OS is suspected is not yet ready to enter clinical practice, for example, after resuscitation of asphyxiated newborns. Our challenge for the future is to better clarify the benefits and risks of antioxidant interventions and to verify their impact on infants’ health.

Keywords

Xanthine Oxidase Magnesium Sulfate Free Radical Oxygen Free Radical Oxidative Stress Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Halliwell B. Free radicals, antioxidants and human disease: curiosity, cause, or consequence? Lancet. 1994;344:721–4.PubMedGoogle Scholar
  2. 2.
    Thibeault D. The precarious antioxidant defenses of the preterm infant. Am J Perinatol. 2000;17:167–81.PubMedGoogle Scholar
  3. 3.
    Kowaltowski AJ, Vercesi AE. Mitochondrial damage induced by conditions of oxidative stress. Free Rad Biol Med. 1999;26:463–71.PubMedGoogle Scholar
  4. 4.
    McCord JM. Oxygen-derived free radicals in postischemic tissue injury. New Engl J Med. 1985;312:159–63.PubMedGoogle Scholar
  5. 5.
    Evans PJ, Evans R, Kovar IZ, Holton AF, Halliwell B. Bleomycin-detectable iron in the plasma of premature and full-term neonates. FEBS Lett. 1992;303:210–2.PubMedGoogle Scholar
  6. 6.
    Aruoma OI. Characterization of drugs as antioxidant prophylactic. Free Rad Biol Med. 1996;20:675–705.PubMedGoogle Scholar
  7. 7.
    Shadid M, Buonocore G, Groenendaal F, et al. Effect of deferoxamine and allopurinol on non protein bound iron concentrations in plasma and cortical brain tissue of newborn lambs following hypoxia ischemia. Neurosci Lett. 1998;22:5–8.Google Scholar
  8. 8.
    Shadid M, Moison R, Steendijk P, Hiltermann L, Berger HM, van Bel F. The effect of antioxidative combination therapy on post hypoxic-ischemic perfusion, metabolism, and electrical activity of the newborn brain. Pediatr Res. 1998;44(1):119–24.PubMedGoogle Scholar
  9. 9.
    Livrea MA, Tesoriere L, Bongiorno A, Pintaudi AM, Ciaccio M, Riccio A. Contribution of vitamin A to the oxidation resistance of human low density lipoproteins. Free Radic Biol Med. 1995;18(3):401–9.PubMedGoogle Scholar
  10. 10.
    Packer L, Weber SU, Rimbach G. Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr. 2001;131:369S–73.PubMedGoogle Scholar
  11. 11.
    Shin SM, Razdan B, Mishra OP, Johnson L, Delivoria-Papadopoulos M. Protective effect of alpha-tocopherol on brain cell membrane function during cerebral cortical hypoxia in newborn piglets. Brain Res. 1994;653(1–2):45–50.PubMedGoogle Scholar
  12. 12.
    Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S, Akaike A. Neuroprotective effects of alpha-tocopherol on oxidative stress in rat striatal cultures. Eur J Pharmacol. 2003;465:15–22.PubMedGoogle Scholar
  13. 13.
    Iwasa H, Aono T, Fukuzawa K. Protective effect of vitamin E on fetal distress induced by ischemia of the uteroplacental system in pregnant rats. Free Radic Biol Med. 1990;8(4):393–400.PubMedGoogle Scholar
  14. 14.
    Raju TN, Langenberg P, Bhutani V, Quinn GE. Vitamin E prophylaxis to reduce retinopathy of prematurity: a reappraisal of published trials. J Pediatr. 1997;131(6):844–50.PubMedGoogle Scholar
  15. 15.
    Shichiri M, Yoshida Y, Ishida N, Hagihara Y, Iwahashi H, Tamai H, Niki E. α-Tocopherol suppresses lipid peroxidation and behavioral and cognitive impairments in the Ts65Dn mouse model of Down syndrome. Free Radic Biol Med. 2011;50(12):1801–11.PubMedGoogle Scholar
  16. 16.
    van Tits LJ, Demacker PN, de Graaf J, Hak-Lemmers HL, Stalenhoef AF. alpha-tocopherol supplementation decreases production of superoxide and cytokines by leukocytes ex vivo in both normolipidemic and hypertriglyceridemic individuals. Am J Clin Nutr. 2000;71:458–64.PubMedGoogle Scholar
  17. 17.
    Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev. 2011;10:CD000501.PubMedGoogle Scholar
  18. 18.
    Kirkwood B, Humphrey J, Moulton L, Martines J. Neonatal vitamin A supplementation and infant survival. Lancet. 2010;376(9753):1643–4.PubMedGoogle Scholar
  19. 19.
    West Jr KP, Christian P, Labrique AB, Rashid M, Shamim AA, Klemm RD, et al. Effects of vitamin A or beta carotene supplementation on pregnancy-related mortality and infant mortality in rural Bangladesh: a cluster randomized trial. JAMA. 2011;305(19):1986–95.PubMedGoogle Scholar
  20. 20.
    Chen YC, Tain YL, Sheen JM, Huang LT. Melatonin utility in neonates and children. J Formos Med Assoc. 2012;111(2):57–66.PubMedGoogle Scholar
  21. 21.
    Beyer RE. The role of ascorbate in antioxidant protection of biomembranes: interaction with vitamin E and coenzyme Q. J Bioenerg Biomembr. 1994;26:349–58.PubMedGoogle Scholar
  22. 22.
    Nakai A, Shibazaki Y, Taniuchi Y, Oya A, Asakura H, Koshino T, Araki T. Vitamins ameliorate secondary mitochondrial failure in neonatal rat brain. Pediatr Neurol. 2002;27:30–5.PubMedGoogle Scholar
  23. 23.
    Bass WT, Malati N, Castle MC, White LE. Evidence for the safety of ascorbic acid administration to the premature infant. Am J Perinatol. 1998;15(2):133–40.PubMedGoogle Scholar
  24. 24.
    Tan S, Parks DA. Preserving brain function during neonatal asphyxia. Clin Perinatol. 1999;26(3):733–47.PubMedGoogle Scholar
  25. 25.
    Hisanaga K, Sagar SM, Sharp FR. Ascorbate neurotoxicity in cortical cell culture. Ann Neurol. 1992;31(5):562–5.PubMedGoogle Scholar
  26. 26.
    Then SM, Mazlan M, Mat Top G, Wan Ngah WZ. Is vitamin E toxic to neuron cells? Cell Mol Neurobiol. 2009;29:485–96.PubMedGoogle Scholar
  27. 27.
    Richter HG, Camm EJ, Modi BN, Naeem F, Cross CM, Cindrova-Davies T, et al. Ascorbate prevents placental oxidative stress and enhances birth weight in hypoxic pregnancy in rats. J Physiol. 2012;590:1377–87.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Chappell LC, Seed PT, Kelly FJ, Briley A, Hunt BJ, Charnock-Jones DS, et al. Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function. Am J Obstet Gynecol. 2002;187:777–84.PubMedGoogle Scholar
  29. 29.
    Roberts JM, Myatt L, Spong CY, et al. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med. 2010;362:1282–91.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Conde-Agudelo A, Romero R, Kusanovic JP, Hassan SS. Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol. 2011;204:503.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Solaroglu I, Solaroglu A, Kaptanoglu E, Dede S, Haberal A, Beskonakli E, Kilinc K. Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain. Childs Nerv Syst. 2003;19(1):19–22.PubMedGoogle Scholar
  32. 32.
    Kumral A, Baskin H, Gokmen N, Yilmaz O, Genc K, Genc S, et al. Selective inhibition of nitric oxide in hypoxic-ischemic brain model in newborn rats: is it an explanation for the protective role of erythropoietin? Biol Neonate. 2004;85(1):51–4.PubMedGoogle Scholar
  33. 33.
    Sun Y, Calvert JW, Zhang JH. Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration. Stroke. 2005;36(8):1672–8.PubMedGoogle Scholar
  34. 34.
    Bierer R, Peceny MC, Hartenberger CH, Ohls RK. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics. 2006;118(3):e635–40.PubMedGoogle Scholar
  35. 35.
    Maiese K, Li F, Chong ZZ. New avenues of explorations for erythropoietin. J Am Med Assoc. 2005;293:90–5.Google Scholar
  36. 36.
    Kellert BA, McPherson RJ, Juul SE. A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats. Pediatr Res. 2007;61:451–5.PubMedGoogle Scholar
  37. 37.
    Gonzalez FF, McQuillen P, Mu D, et al. Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Dev Neurosci. 2007;29:321–30.PubMedGoogle Scholar
  38. 38.
    van der Kooij MA, Groenendaal F, Kavelaars A, Heijnen CJ, van Bel F. Combination of deferoxamine and erythropoietin: therapy for hypoxia–ischemia-induced brain injury in the neonatal rat? Neurosci Lett. 2009;451:109–13.PubMedGoogle Scholar
  39. 39.
    Zhu C, Kang W, Xy F, et al. Erythropoietin improved neurological outcomes in newborns with hypoxic–ischemic encephalopathy. Pediatrics. 2009;124:e218–26.PubMedGoogle Scholar
  40. 40.
    Cariou A, Claessens Y-E, Pène F, et al. Early high dose erythropoietin therapy and hypothermia after out-of-hospital cardiac arrest: a matched control study. Resuscitation. 2008;76:397–404.PubMedGoogle Scholar
  41. 41.
    Ehrenreich H, Weissenborn K, Prange H, et al. For the EPO Stroke Trial Group. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40(12):e647–56.PubMedGoogle Scholar
  42. 42.
    Samdani AF, Dawson TM, Dawson VL. Nitric oxide synthase in models of focal ischemia. Stroke. 1997;28(6):1283–8.PubMedGoogle Scholar
  43. 43.
    Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996;271:C1424–37.PubMedGoogle Scholar
  44. 44.
    Sup SJ, Green BG, Grant SK. 2-Iminobiotin is an inhibitor of nitric oxide synthases. Biochem Biophys Res Commun. 1994;204(2):962–8.PubMedGoogle Scholar
  45. 45.
    Nijboer CH, Heijnen CJ, Groenendaal F, May MJ, van Bel F, Kavelaars A. Strong neuroprotection by inhibition of NF-kappaB after neonatal hypoxia-ischemia involves apoptotic mechanisms but is independent of cytokines. Stroke. 2008;39(7):2129–37.PubMedGoogle Scholar
  46. 46.
    Marro PJ, Mishra OP, Delivoria-Papadopoulos M. Effect of allopurinol on brain adenosine levels during hypoxia in newborn piglets. Brain Res. 2006;1073–1074:444–50.PubMedGoogle Scholar
  47. 47.
    Gunes T, Ozturk MA, Koklu E, Kose K, Gunes I. Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Pediatr Neurol. 2007;36(1):17–24.PubMedGoogle Scholar
  48. 48.
    Kaandorp JJ, van Bel F, Veen S, Derks JB, Groenendaal F, Rijken M, Roze E, Venema MM, Rademaker CM, Bos AF, Benders MJ. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed. 2012;97:162–6.Google Scholar
  49. 49.
    Torrance HL, Benders MJ, Derks JB, Rademaker CM, Bos AF, Van Den Berg P, Longini M, Buonocore G, et al. Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B. Pediatrics. 2009;124(1):350–7.PubMedGoogle Scholar
  50. 50.
    Kelen D, Robertson NJ. Experimental treatments for hypoxic ischaemic encephalopathy. Early Hum Dev. 2010;86(6):369–77.PubMedGoogle Scholar
  51. 51.
    Chaudhari T, McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy. Cochrane Database Syst Rev. 2012. doi: 10.1002/14651858.CD006817.PubMedGoogle Scholar
  52. 52.
    Marzocchi B, Perrone S, Paffetti P, Magi B, Bini L, Tani C, Longini M, Buonocore G. Nonprotein-bound iron and plasma protein oxidative stress at birth. Pediatr Res. 2005;58(6):1295–9.PubMedGoogle Scholar
  53. 53.
    Wayenberg JL, Ransy V, Vermeylen D, Damis E, Bottari SP. Nitrated plasma albumin as a marker of nitrative stress and neonatal encephalopathy in perinatal asphyxia. Free Radic Biol Med. 2009;47(7):975–82.PubMedGoogle Scholar
  54. 54.
    Liu Y, Belayev L, Zhao W, Busto R, Belayev A, Ginsberg MD. Neuroprotective effect of treatment with human albumin in permanent focal cerebral ischemia: histopathology and cortical perfusion studies. Eur J Pharmacol. 2001;428(2):193–201.PubMedGoogle Scholar
  55. 55.
    Ginsberg MD, Hill MD, Palesch YY, Ryckborst KJ, Tamariz D. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke-I: physiological responses and safety results. Stroke. 2006;37(8):2100–6.PubMedGoogle Scholar
  56. 56.
    Berman DR, Mozurkewich E, Liu Y, Barks J. Docosahexaenoic acid pretreatment confers neuroprotection in a rat model of perinatal cerebral hypoxia-ischemia. Am J Obstet Gynecol. 2009;200:305.e1-6.PubMedGoogle Scholar
  57. 57.
    Berman DR, Liu YQ, Barks J, Mozurkewich E. Docosahexaenoic acid confers neuroprotection in a rat model of perinatal hypoxia-ischemia potentiated by Escherichia coli lipopolysaccharide-induced systemic inflammation. Am J Obstet Gynecol. 2010;202(5):469.e1-6.PubMedGoogle Scholar
  58. 58.
    Peeters-Scholte C, Braun K, Koster J, Kops N, Blomgren K, Buonocore G, et al. Effects of allopurinol and deferoxamine on reperfusion brain injury in newborn piglets after neonatal hypoxia-ischemia. Pediatr Res. 2003;54(4):516–22.PubMedGoogle Scholar
  59. 59.
    deLemos RA, Roberts RJ, Coalson JJ, deLemos JA, Null Jr DM, Gerstmann DR. Toxic effects associated with the administration of deferoxamine in the premature baboon with hyaline membrane disease. Am J Dis Child. 1990;144:915–9.PubMedGoogle Scholar
  60. 60.
    Marret S, Doyle LW, Crowther CA, Middleton P. Antenatal magnesium sulphate neuroprotection in the preterm infant. Semin Fetal Neonatal Med. 2007;12(4):311–7.PubMedGoogle Scholar
  61. 61.
    Shogi T, Miyamoto A, Ishiguro S, Nishio A. Enhanced release of IL-1beta and TNF-alpha following endotoxin challenge from rat alveolar macrophages cultured in low-mg(2+) medium. Magnes Res. 2003;16(2):111–9.PubMedGoogle Scholar
  62. 62.
    Ovbiagele B, Kidwell CS, Starkman S, Saver JL. Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke. Curr Treat Options Cardiovasc Med. 2003;6:441–9.Google Scholar
  63. 63.
    Kim CR, Oh W, Stonestreet BS. Magnesium is a cerebrovasodilator in newborn piglets. Am J Physiol. 1997;272(1 Pt 2):H511–6.PubMedGoogle Scholar
  64. 64.
    Costantine MM, Weiner SJ, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis. Obstet Gynecol. 2009;114(2 Pt 1):354–64.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009;1:CD004661.PubMedGoogle Scholar
  66. 66.
    Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks’ gestation: a systematic review and metaanalysis. Am J Obstet Gynecol. 2009;200(6):595–609.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Zhu H, Meloni BP, Bojarski C, Knuckey MW, Knuckey NW. Post-ischemic modest hypothermia (35 degrees C) combined with intravenous magnesium is more effective at reducing CA1 neuronal death than either treatment used alone following global cerebral ischemia in rats. Exp Neurol. 2005;193(2):361–8.PubMedGoogle Scholar
  68. 68.
    Zhu H, Meloni BP, Moore SR, Majda BT, Knuckey NW. Intravenous administration of magnesium is only neuroprotective following transient global ischemia when present with post-ischemic mild hypothermia. Brain Res. 2004;1014(1–2):53–60.PubMedGoogle Scholar
  69. 69.
    Ramsey PS, Rouse DJ. Magnesium sulfate as a tocolytic agent. Semin Perinatol. 2001;25(4):236–47.PubMedGoogle Scholar
  70. 70.
    Azria E, Tsatsaris V, Goffinet F, Kayem G, Mignon A, Cabrol D. Magnesium sulfate in obstetrics: current data. J Gynecol Obstet Biol Reprod. 2004;33(6 Pt 1):510–7.Google Scholar
  71. 71.
    Khan M, Sekhon B, Jatana M, et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res. 2004;76:519–27.PubMedGoogle Scholar
  72. 72.
    Jatana M, Singh I, Singh AK, Jenkins D. Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic–ischemic brain injury in neonatal rats. Pediatr Res. 2006;59:684–9.PubMedGoogle Scholar
  73. 73.
    Cakir O, Erdem K, Oruc A, Kilinc N, Eren N. Neuroprotective effect of N-acetylcysteine and hypothermia on the spinal cord ischemia–reperfusion injury. Cardiovasc Surg. 2003;11:375–9.PubMedGoogle Scholar
  74. 74.
    Paintlia MK, Paintlia AS, Barbosa E, Singh I, Singh AK. N-Acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res. 2004;78:347–61.PubMedGoogle Scholar
  75. 75.
    Ahola T, Lapatto R, Raivio KO, et al. N-Acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial. J Pediatr. 2003;143:713–9.PubMedGoogle Scholar
  76. 76.
    Welin AK, 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(2):153–8.PubMedGoogle Scholar
  77. 77.
    Tütüncüler F, Eskiocak S, Başaran UN, Ekuklu G, Ayvaz S, Vatansever U. The protective role of melatonin in experimental hypoxic brain damage. Pediatr Int. 2005;47(4):434–9.PubMedGoogle Scholar
  78. 78.
    Vijayalaxmi Jr TCR, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol. 2002;20(10):2575–601.PubMedGoogle Scholar
  79. 79.
    Rousseau A, Petrén S, Plannthin J, Eklundh T, Nordin C. Serum and cerebrospinal fluid concentrations of melatonin: a pilot study in healthy male volunteers. J Neural Transm. 1999;106(9–10):883–8.PubMedGoogle Scholar
  80. 80.
    Vakkuri O, Leppäluoto J, Kauppila A. Oral administration and distribution of melatonin in human serum, saliva and urine. Life Sci. 1985;37(5):489–95.PubMedGoogle Scholar
  81. 81.
    Bornman MS, Schulenburg GW, Reif S, Oosthuizen JM, De Wet EH, Luus HG. Seminal plasma melatonin and semen parameters. S Afr Med J. 1992;81(9):485–6.PubMedGoogle Scholar
  82. 82.
    Kivelä A, Kauppila A, Leppäluoto J, Vakkuri O. Serum and amniotic fluid melatonin during human labor. J Clin Endocrinol Metab. 1989;69(5):1065–8.PubMedGoogle Scholar
  83. 83.
    Agez L, Laurent V, Guerrero HY, Pévet P, Masson-Pévet M, Gauer F. Endogenous melatonin provides an effective circadian message to both the suprachiasmatic nuclei and the pars tuberalis of the rat. J Pineal Res. 2009;46(1):95–105.PubMedGoogle Scholar
  84. 84.
    Shanahan TL, Czeisler CA. Physiological effects of light on the human circadian pacemaker. Semin Perinatol. 2000;24(4):299–320.PubMedGoogle Scholar
  85. 85.
    Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM. Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res. 2010;48(4):297–310.PubMedGoogle Scholar
  86. 86.
    Tan DX, Manchester LC, Terron MP, Flores LJ, Tamura H, Reiter RJ. Melatonin as a naturally occurring co-substrate of quinone reductase-2, the putative MT3 melatonin membrane receptor: hypothesis and significance. J Pineal Res. 2007;43(4):317–20.PubMedGoogle Scholar
  87. 87.
    Ceraulo L, Ferrugia M, Tesoriere L, Segreto S, Livrea MA, Turco Liveri V. Interactions of melatonin with membrane models: portioning of melatonin in AOT and lecithin reversed micelles. J Pineal Res. 1999;26(2):108–12.PubMedGoogle Scholar
  88. 88.
    Reiter RJ, Tan DX, Burkhardt S. Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech Ageing Dev. 2002;123(8):1007–19.PubMedGoogle Scholar
  89. 89.
    Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H, et al. Melatonin, mitochondria, and cellular bioenergetics. J Pineal Res. 2001;30:65–74.PubMedGoogle Scholar
  90. 90.
    Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, et al. Melatonin as a free radical scavenger in the ovarian follicle. Endocr J. 2013;60(1):1–13.PubMedGoogle Scholar
  91. 91.
    Reiter RJ, Tan DX, Manchester LC, Qi W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys. 2001;34(2):237–56.PubMedGoogle Scholar
  92. 92.
    Mishra OP, Delivoria-Papadopoulos M. Lipid peroxidation in developing fetal guinea pig brain during normoxia and hypoxia. Brain Res Dev Brain Res. 1989;45(1):129–35.PubMedGoogle Scholar
  93. 93.
    Esposito E, Cuzzocrea S. Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol. 2010;8(3):228–42.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Carrillo-Vico A, García-Mauriño S, Calvo JR, Guerrero JM. Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. FASEB J. 2003;17(6):755–77.PubMedGoogle Scholar
  95. 95.
    Briceño-Pérez C, Briceño-Sanabria L, Vigil-De Gracia P. Prediction and prevention of preeclampsia. Hypertens Pregnancy. 2009;28(2):138–55.PubMedGoogle Scholar
  96. 96.
    Gupta P, Narang M, Banerjee BD, Basu S. Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study. BMC Pediatr. 2004;4:14.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Longini M, Perrone S, Kenanidis A, Vezzosi P, Petraglia F, Buonocore G, et al. Isoprostanes in amniotic fluid: a predictive marker for fetal growth restriction in pregnancy. Free Radic Biol Med. 2005;38(11):1537–41.PubMedGoogle Scholar
  98. 98.
    Okatani Y, Wakatsuki A, Shinohara K, Kaneda C, Fukaya T. Melatonin stimulates glutathione peroxidase activity in human chorion. J Pineal Res. 2001;30(4):199–205.PubMedGoogle Scholar
  99. 99.
    Richter HG, Hansell JA, Raut S, Giussani DA. Melatonin improves placental efficiency and birth weight and increases the placental expression of antioxidant enzymes in undernourished pregnancy. J Pineal Res. 2009;46(4):357–64.PubMedGoogle Scholar
  100. 100.
    Gitto E, Reiter RJ. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res. 2004;36:250e5.Google Scholar
  101. 101.
    Gitto E, Reiter RJ, Cordaro SP, La Rosa M, Chiurazzi P, Trimarchi G, et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol. 2004;21:209e16.Google Scholar
  102. 102.
    Gitto E, Reiter RJ, Sabatino G, Buonocore G, Romeo C, Gitto P, et al. Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm newborns: improvement with melatonin treatment. J Pineal Res. 2005;39:287e93.Google Scholar
  103. 103.
    Carloni S, Perrone S, Buonocore G, Longini M, Proietti F, Balduini W. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res. 2008;44(2):157–64.PubMedGoogle Scholar
  104. 104.
    Buonocore G, Perrone S, Bracci R. Free radicals and brain damage in the newborn. Biol Neonate. 2001;79(3–4):180–6.PubMedGoogle Scholar
  105. 105.
    Kijlstra A, Tian Y, Kelly ER, Berendschot TT. Lutein: more than just a filter for blue light. Prog Retin Eye Res. 2012;31(4):303–15.PubMedGoogle Scholar
  106. 106.
    Vijayapadma V, Ramyaa P, Pavithra D, Krishnaswamy R. Protective effect of lutein against benzo(a)pyrene-induced oxidative stress in human erythrocytes. Toxicol Ind Health. 2014;30(3):284–93.PubMedGoogle Scholar
  107. 107.
    Li SY, Fung FK, Fu ZJ, Wong D, Chan HH, Lo AC. Anti-inflammatory effects of lutein in retinal ischemic/hypoxic injury: in vivo and in vitro studies. Invest Ophthalmol Vis Sci. 2012;53(10):5976–84.PubMedGoogle Scholar
  108. 108.
    Moukarzel AA, Bejjani RA, Fares FN. Xanthophylls and eye health of infants and adults. J Med Liban. 2009;57:261–7.PubMedGoogle Scholar
  109. 109.
    Perrone S, Longini M, Marzocchi B, Picardi A, Bellieni CV, Proietti F, et al. Effects of lutein on oxidative stress in the term newborn: a pilot study. Neonatology. 2010;97(1):36–40.PubMedGoogle Scholar
  110. 110.
    Bettler J, Zimmer JP, Neuringer M, DeRusso PA. Serum lutein concentrations in healthy term infants fed human milk or infant formula with lutein. Eur J Nutr. 2010;49(1):45–51.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Manzoni P, Guardione R, Bonetti P, Priolo C, Maestri A, Mansoldo C, et al. Lutein and zeaxanthin supplementation in preterm very low-birth-weight neonates in neonatal intensive care units: a multicenter randomized controlled trial. Am J Perinatol. 2013;30(1):25–32.PubMedGoogle Scholar
  112. 112.
    Rubin LP, Chan GM, Barrett-Reis BM, Fulton AB, Hansen RM, Ashmeade TL, et al. Effect of carotenoid supplementation on plasma carotenoids, inflammation and visual development in preterm infants. J Perinatol. 2012;32(6):418–24.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Giuseppe Buonocore
    • 1
  • Serafina Perrone
    • 1
  • Maria Luisa Tataranno
    • 1
  1. 1.Department of Molecular and Developmental MedicineUniversity of SienaSienaItaly

Personalised recommendations