title: Antioxidant treatment strategies for hyperphenylalaninemia.
abstract: Hyperphenylalaninemia (HPA) leads to increased oxidative stress in patients with phenylketonuria (PKU) and in animal models of PKU. Early diagnosis and immediate adherence to a phenylalanine-restricted diet prevents HPA and, consequently, severe brain damage. However, treated adolescent and adult PKU patients have difficulties complying with the diet, leading to an oscillation of phenylalanine levels and associated oxidative stress. The brain is especially susceptible to reactive species, and oxidative stress might add to the impaired cognitive function found in these patients. The restricted PKU diet has a very limited nutrient content from natural foods and almost no animal protein, which reduces the intake of important compounds. These specific compounds can act as scavengers of reactive species and can be co-factors of antioxidant enzymes. Supplementation with nutrients, vitamins, and tetrahydropterin has given quite promising results in patients and animal models. Antioxidant supplementation has been studied in HPA, however there is no consensus about its always beneficial effects. In this way, regular exercise could be a beneficial addition on antioxidant status in PKU patients. A deeper understanding of PKU molecular biochemistry, and genetics, as well as the need for improved targeted treatment options, could lead to the development of new therapeutic strategies.
authors: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica. Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, CEP 90035-003, Porto Alegre, RS, Brazil, pku@priscilamazzola.com.
authors: Priscila Nicolao
authors: PN
authors: Mazzola
authors: George Albert
authors: GA
authors: Karikas
authors: Kleopatra H
authors: KH
authors: Schulpis
authors: Carlos Severo
authors: CS
authors: Dutra-Filho
mesh_terms: D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004032:Diet; D019587:Dietary Supplements; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects*; D010661:Phenylketonurias / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000975:Antioxidants
references: Acta Paediatr. 2000 Mar;89(3):366-7
references: 10772290
references: Mol Genet Metab. 2010;99 Suppl 1:S90-5
references: 20123478
references: J Mol Cell Cardiol. 2011 Oct;51(4):559-63
references: 21458460
references: PLoS One. 2012;7(8):e43021
references: 22912778
references: Brain. 1993 Aug;116 ( Pt 4):811-21
references: 8353710
references: Acta Paediatr. 2002;91(8):905-9
references: 12222713
references: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2339-44
references: 10051643
references: JIMD Rep. 2013;9:31-40
references: 23430545
references: Mol Genet Metab. 2011 Nov;104(3):231-4
references: 21676636
references: J Clin Endocrinol Metab. 2004 Aug;89(8):3983-7
references: 15292337
references: Top Clin Nutr. 2009 Oct 1;24(4):333-340
references: 20011454
references: Cell Mol Neurobiol. 2009 Mar;29(2):211-8
references: 18814025
references: Int J Mol Med. 2008 Oct;22(4):529-39
references: 18813861
references: Hum Mutat. 1992;1(3):216-20
references: 1301927
references: Lancet. 2002 Jul 6;360(9326):55-7
references: 12114043
references: Mol Neurobiol. 2010 Jun;41(2-3):73-86
references: 20195796
references: Neurobiol Aging. 2008 Sep;29(9):1404-11
references: 17416441
references: Neuroendocrinology. 2004;80(1):42-51
references: 15345906
references: Mol Genet Metab. 2012 Sep;107(1-2):31-6
references: 22841515
references: Life Sci. 2006 Jan 18;78(8):803-11
references: 16253281
references: Neurosci Lett. 2011 Jul 25;499(3):149-53
references: 21621586
references: J Inherit Metab Dis. 2009 Feb;32(1):3-9
references: 18668342
references: Biochemistry. 1992 Sep 8;31(35):8363-8
references: 1326329
references: Clin Nutr. 2005 Apr;24(2):172-83
references: 15784476
references: Clin Biochem Rev. 2008 Feb;29(1):31-41
references: 18566668
references: Mol Genet Metab. 2004 Jan;81(1):3-8
references: 14728985
references: N Engl J Med. 1993 Jul 29;329(5):363
references: 8321274
references: Metab Brain Dis. 2011 Dec;26(4):291-7
references: 21947687
references: Free Radic Biol Med. 2005 Sep 1;39(5):584-9
references: 16085177
references: Trends Pharmacol Sci. 2011 Mar;32(3):125-30
references: 21216018
references: J Hum Nutr Diet. 2009 Oct;22(5):422-7
references: 19743980
references: Clin Biochem. 2005 Mar;38(3):239-42
references: 15708545
references: Cell Mol Neurobiol. 2013 Mar;33(2):253-60
references: 23232760
references: J Pediatr Gastroenterol Nutr. 2009 Mar;48 Suppl 1:S2-7
references: 19214054
references: Eur J Clin Nutr. 2003 Feb;57(2):383-7
references: 12571675
references: Cell Mol Neurobiol. 2011 Apr;31(3):429-36
references: 21191647
references: J Pediatr. 2000 Apr;136(4):545-7
references: 10753257
references: J Inherit Metab Dis. 2012 Nov;35(6):975-81
references: 22388642
references: Int J Biochem Cell Biol. 2007;39(1):44-84
references: 16978905
references: J Neurol Phys Ther. 2009 Mar;33(1):14-26
references: 19265767
references: Mol Genet Metab. 2012 Jul;106(3):264-8
references: 22607939
references: Cell Mol Neurobiol. 2011 Jul;31(5):653-62
references: 21516352
references: Proc Natl Acad Sci U S A. 1985 Sep;82(18):6221-5
references: 3862128
references: Mol Genet Metab. 2010;99 Suppl 1:S86-9
references: 20123477
references: Indian J Med Res. 2005 Nov;122(5):400-3
references: 16456253
references: Biochim Biophys Acta. 2009 Nov;1790(11):1513-9
references: 19406206
references: Curr Neuropharmacol. 2011 Jun;9(2):301-12
references: 22131939
references: J Inherit Metab Dis. 2012 May;35(3):381-98
references: 22116469
references: Am J Med. 2004 Oct 15;117(8):590-5
references: 15465508
references: Mol Cell Biochem. 1995 Jun 7-21;147(1-2):77-81
references: 7494558
references: J Pediatr Nurs. 2012 Aug;27(4):319-27
references: 22703678
references: Mol Genet Metab. 2011 Nov;104(3):241-8
references: 21640623
references: Biochem J. 1993 Jun 1;292 ( Pt 2):419-24
references: 8389135
references: Br J Haematol. 2006 Jan;132(1):108-13
references: 16371026
references: J Neurosci. 2004 Feb 18;24(7):1531-40
references: 14973232
references: Physiol Rev. 2009 Apr;89(2):535-606
references: 19342614
references: J Neurosci Res. 2000 Sep 1;61(5):549-63
references: 10956425
references: Mol Genet Metab. 2012 Feb;105(2):193-7
references: 22112818
references: Nutr Hosp. 2010 Jan-Feb;25(1):60-6
references: 20204257
references: J Neurochem. 2006 Jun;97(6):1634-58
references: 16805774
references: Arch Biochem Biophys. 2013 Feb 15;530(2):73-82
references: 23296088
references: Neuropsychology. 2008 Jul;22(4):426-31
references: 18590354
references: Food Chem Toxicol. 2013 Jan;51:15-25
references: 23017782
references: Mol Genet Metab. 2011;104 Suppl:S97-9
references: 21813309
references: J Neurochem. 2007 Oct;103(1):1-16
references: 17561938
references: J Inherit Metab Dis. 1995;18(6):653-64
references: 8750601
references: Biochem J. 1995 Oct 15;311 ( Pt 2):353-66
references: 7487868
references: Mol Genet Metab. 2010 Feb;99(2):109-15
references: 19800826
references: Int J Dev Neurosci. 2009 May;27(3):243-7
references: 19429389
references: Acta Physiol (Oxf). 2010 Aug;199(4):509-18
references: 20353493
references: Eur J Appl Physiol. 2012 Nov;112(11):3905-11
references: 22415102
references: Neurobiol Dis. 2010 Nov;40(2):467-77
references: 20659557
references: Clin Chem Lab Med. 2006;44(5):623-7
references: 16681435
references: Mol Genet Metab. 2009 Apr;96(4):158-63
references: 19208488
references: Acta Paediatr. 2010 Oct;99(10):1565-70
references: 20491710
references: J Inherit Metab Dis. 2010 Dec;33(6):659-64
references: 20151202
references: J Neurol Sci. 2010 May 15;292(1-2):89-95
references: 20226470
references: Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2439-44
references: 16946131
references: Toxicol Lett. 2005 Jan 15;155(1):27-34
references: 15585356
references: Metab Brain Dis. 2006 Dec;21(4):287-96
references: 17146735
references: Cell Mol Neurobiol. 2010 Mar;30(2):317-26
references: 19774456
references: Mol Genet Metab. 2013 Jun;109(2):121-4
references: 23562298
references: J Pediatr. 1995 Aug;127(2):251-5
references: 7636650
references: Fundam Clin Pharmacol. 2013 Jun;27(3):252-61
references: 22145601
references: Acta Paediatr. 2011 Aug;100(8):1144-9
references: 21342250
references: J Inherit Metab Dis. 2013 Jan;36(1):7-13
references: 22526846
references: Clin Biochem. 2011 Jul;44(10-11):821-5
references: 21605553
references: Med Sci Sports Exerc. 2009 Sep;41(9):1752-60
references: 19657294
references: Neuropsychopharmacology. 2009 Mar;34(4):1011-26
references: 18843266
references: Heart. 2010 Dec;96(23):1872-7
references: 20837663
references: J Pediatr (Rio J). 2007 Sep-Oct;83(5):447-52
references: 17676249
references: J Nutr. 2007 Jun;137(6 Suppl 1):1568S-1572S; discussion 1573S-1575S
references: 17513427
references: J Int Soc Sports Nutr. 2012 Apr 05;9(1):13
references: 22480293
references: Eur J Clin Nutr. 2009 Feb;63(2):215-21
references: 17882129
references: Front Biosci (Landmark Ed). 2012 Jun 01;17:2433-41
references: 22652790
references: Ann Neurol. 2011 Sep;70(3):465-76
references: 21905080
references: Am J Clin Nutr. 2003 Jan;77(1):185-8
references: 12499340
references: Metab Brain Dis. 2012 Mar;27(1):79-89
references: 22101931
references: Clin Biochem. 2004 Mar;37(3):198-203
references: 14972641
references: Antioxid Redox Signal. 2012 Jan 15;16(2):179-82
references: 21895448
references: Eur J Pediatr. 2000 Oct;159 Suppl 2:S109-13
references: 11043156
references: J Med Genet. 1995 Dec;32(12):976-8
references: 8825928
references: Mol Genet Metab. 2011 Jul;103(3):220-5
references: 21514861
references: Antioxid Redox Signal. 2010 Apr 1;12(7):793-5
references: 19905883
references: Mol Genet Metab. 2011;104 Suppl:S80-5
references: 22014474
references: Neurochem Res. 2002 May;27(5):353-7
references: 12064349