Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats
详细信息 查看全文
- 作者：Gerald A. Dienel ; Nancy F. Cruz
- 关键词：Amino acids ; Behavior ; Brain development ; Glucose utilization ; Hyperphenylalaninemia ; Hyperglycinemia ; Phenylketonuria
- 刊名：Neurochemical Research
- 出版年：2016
- 出版时间：February 2016
- 年：2016
- 卷：41
- 期：1-2
- 页码：16-32
- 全文大小：602 KB
- 参考文献：1.Mitchell JJ, Trakadis YJ, Scriver CR (2011) Phenylalanine hydroxylase deficiency. Genet Med 13:697–707CrossRef PubMed
2.Scriver CR, Eisensmith RC, Woo SL, Kaufman S (1994) The hyperphenylalaninemias of man and mouse. Annu Rev Genet 28:141–165CrossRef PubMed
3.Knox WE (1972) Phenylketonuria. In: Stanbury JB, Wyngaarden JB, Fredrickson DS (eds) The metabolic basis of inherited disease, 3rd edn. McGraw-Hill, New York, pp 266–295
4.Tourian A, Sidbury JB (1983) Phenylketonuria and hyperphenylalanemia. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS (eds) The metabolic basis of inherited disease, 5th edn. McGraw-Hill, New York, pp 270–286
5.Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, Brown CS, Burlina AB, Burton BK, Chang CS, Coates PM, Cunningham AC, Dobrowolski SF, Ferguson JH, Franklin TD, Frazier DM, Grange DK, Greene CL, Groft SC, Harding CO, Howell RR, Huntington KL, Hyatt-Knorr HD, Jevaji IP, Levy HL, Lichter-Konecki U, Lindegren ML, Lloyd-Puryear MA, Matalon K, MacDonald A, McPheeters ML, Mitchell JJ, Mofidi S, Moseley KD, Mueller CM, Mulberg AE, Nerurkar LS, Ogata BN, Pariser AR, Prasad S, Pridjian G, Rasmussen SA, Reddy UM, Rohr FJ, Singh RH, Sirrs SM, Stremer SE, Tagle DA, Thompson SM, Urv TK, Utz JR, van Spronsen F, Vockley J, Waisbren SE, Weglicki LS, White DA, Whitley CB, Wilfond BS, Yannicelli S, Young JM (2014) Phenylketonuria scientific review conference: state of the science and future research needs. Mol Genet Metab 112:87–122CrossRef PubMed
6.Blau K (1979) Phenylalanine hydroxylase deficiency: biochemical, physiological, and clinical aspects of phenylketonuria and related phenylalaninemias. In: Youdim MBH (ed) Aromatic amino acid hydroxylases and mental disease. John Wiley & Sons, Chichester, pp 77–139
7.Kaufman S (1977) Phenylketonuria: biochemical mechanisms. In: Agranoff BW, Aprison MH (eds) Advances in neurochemistry. Plenum Press, New York, pp 1–132CrossRef
8.Kaufman S (1989) An evaluation of the possible neurotoxicity of metabolites of phenylalanine. J Pediatr 114:895–900CrossRef PubMed
9.Loo YH, Potempska A, Wisniewski HM (1985) A biochemical explanation of phenyl acetate neurotoxicity in experimental phenylketonuria. J Neurochem 45:1596–1600CrossRef PubMed
10.Wen GY, Wisniewski HM, Shek JW, Loo YH, Fulton TR (1980) Neuropathology of phenylacetate poisoning in rats: an experimental model of phenylketonuria. Ann Neurol 7:557–566CrossRef PubMed
11.Clarke JT, Lowden JA (1969) Hyperphenylalaninemia: effect on the developing rat brain. Can J Biochem 47:291–295CrossRef PubMed
12.Delvalle JA, Dienel G, Greengard O (1978) Comparison of alpha-methylphenylalanine and p-chlorophenylalanine as inducers of chronic hyperphenylalaninaemia in developing rats. Biochem J 170:449–459CrossRef PubMed PubMedCentral
13.Shedlovsky A, McDonald JD, Symula D, Dove WF (1993) Mouse models of human phenylketonuria. Genetics 134:1205–1210PubMed PubMedCentral
14.Lane JD, Schone B, Langenbeck U, Neuhoff V (1980) Characterization of experimental phenylketonuria. Augmentation of hyperphenylalaninemia with alpha-methylphenylalanine and p-chlorophenylalanine. Biochim Biophys Acta 627:144–156CrossRef PubMed
15.McGeer EG, McGeer PL (1973) Amino acid hydroxylase inhibitors. In: Hochster RM, Kates M, Quastel JH (eds) Metabolic inhibitors A comprehensive treatise. Academic Press, New York, pp 45–105CrossRef
16.Udenfriend S, Zaltzman-Nirenberg P, Nagatsu T (1965) Inhibitors of purified beef adrenal tyrosine hydroxylase. Biochem Pharmacol 14:837–845CrossRef PubMed
17.McDonald JD, Andriolo M, Cali F, Mirisola M, Puglisi-Allegra S, Romano V, Sarkissian CN, Smith CB (2002) The phenylketonuria mouse model: a meeting review. Mol Genet Metab 76:256–261CrossRef PubMed
18.Dienel GA (1977) Brain development in normal and chronic hyperphenylalanemic rats. PhD thesis, Department of Biological Chemistry, Harvard University
19.Dienel GA (1981) Chronic hyperphenylalaninemia produces cerebral hyperglycinemia in immature rats. J Neurochem 36:34–43CrossRef PubMed
20.Benson JV Jr, Patterson JA (1965) Accelerated chromatographic analysis of amino acids commonly found in physiological fluids on a spherical resin of specific design. Anal Biochem 13:265–280CrossRef PubMed
21.Krebs HA (1950) Manometric determination of l -aspartic acid and l -asparagine. Biochem J 47:605–614CrossRef PubMed PubMedCentral
22.Minard FN, Mushahwar IK (1966) Synthesis of gamma-aminobutyric acid from a pool of glutamic acid in brain after decapitation. Life Sci 5:1409–1413CrossRef PubMed
23.Yoshino Y, Elliott KA (1970) Incorporation of carbon atoms from glucose into free amino acids in brain under normal and altered conditions. Can J Biochem 48:228–235CrossRef PubMed
24.Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916CrossRef PubMed
25.Cruz NF, Duffy TE (1983) Local cerebral glucose metabolism in rats with chronic portacaval shunts. J Cereb Blood Flow Metab 3:311–320CrossRef PubMed
26.Miquel J, Blasco M (1978) A simple technique for evaluation of vitality loss in aging mice, by testing their muscular coordination and vigor. Exp Gerontol 13:389–396CrossRef PubMed
27.Barclay LL, Gibson GE, Blass JP (1981) The string test: an early behavioral change in thiamine deficiency. Pharmacol Biochem Behav 14:153–157CrossRef PubMed
28.Udenfriend S (1962) Fluorescence assays in biology and medicine. Academic Press, New York
29.Wong PW, O’Flynn ME, Inouye T (1964) Micromethods for measuring phenylalanine and tyrosine in serum. Clin Chem 10:1098–1104PubMed
30.Daniel PM, Moorhouse SR, Pratt OE (1976) Amino acid precursors of monoamine neurotransmitters and some factors influencing their supply to the brain. Psychol Med 6:277–286CrossRef PubMed
31.Pardridge WM (1977) Kinetics of competitive inhibition of neutral amino acid transport across the blood–brain barrier. J Neurochem 28:103–108CrossRef PubMed
32.Kreis R, Pietz J, Penzien J, Herschkowitz N, Boesch C (1995) Identification and quantitation of phenylalanine in the brain of patients with phenylketonuria by means of localized in vivo 1H magnetic-resonance spectroscopy. J Magn Reson B 107:242–251CrossRef PubMed
33.Novotny EJ Jr, Avison MJ, Herschkowitz N, Petroff OA, Prichard JW, Seashore MR, Rothman DL (1995) In vivo measurement of phenylalanine in human brain by proton nuclear magnetic resonance spectroscopy. Pediatr Res 37:244–249CrossRef PubMed
34.Leuzzi V, Bianchi MC, Tosetti M, Carducci CL, Carducci CA, Antonozzi I (2000) Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria. J Inherit Metab Dis 23:563–570CrossRef PubMed
35.Moats RA, Moseley KD, Koch R, Nelson M Jr (2003) Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics 112:1575–1579PubMed
36.Moller HE, Ullrich K, Weglage J (2000) In vivo proton magnetic resonance spectroscopy in phenylketonuria. Eur J Pediatr 159(Suppl 2):S121–S125CrossRef PubMed
37.Rupp A, Kreis R, Zschocke J, Slotboom J, Boesch C, Rating D, Pietz J (2001) Variability of blood–brain ratios of phenylalanine in typical patients with phenylketonuria. J Cereb Blood Flow Metab 21:276–284CrossRef PubMed
38.Pietz J, Rupp A, Ebinger F, Rating D, Mayatepek E, Boesch C, Kreis R (2003) Cerebral energy metabolism in phenylketonuria: findings by quantitative in vivo 31P MR spectroscopy. Pediatr Res 53:654–662CrossRef PubMed
39.Koch R, Moseley KD, Yano S, Nelson M Jr, Moats RA (2003) Large neutral amino acid therapy and phenylketonuria: a promising approach to treatment. Mol Genet Metab 79:110–113CrossRef PubMed
40.Pietz J, Kreis R, Rupp A, Mayatepek E, Rating D, Boesch C, Bremer HJ (1999) Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest 103:1169–1178CrossRef PubMed PubMedCentral
41.Adriaenssens K, Allen RJ, Lowenthal A, Mardens Y, Tourtellotte WW (1969) Brain and cerebrospinal fluid free amino acids in phenylketonuria. J Genet Hum 17:223–230PubMed
42.McKean CM, Peterson NA (1970) Glutamine in the phenylketonuric central nervous system. N Engl J Med 283:1364–1367CrossRef PubMed
43.Miller AL, Hawkins RA, Veech RL (1973) Phenylketonuria: phenylalanine inhibits brain pyruvate kinase in vivo. Science 179:904–906CrossRef PubMed
44.Patel MS (1972) The effect of phenylpyruvate on pyruvate metabolism in rat brain. Biochem J 128:677–684CrossRef PubMed PubMedCentral
45.Land JM, Mowbray J, Clark JB (1976) Control of pyruvate and beta-hydroxybutyrate utilization in rat brain mitochondria and its relevance to phenylketonuria and maple syrup urine disease. J Neurochem 26:823–830CrossRef PubMed
46.Castells S, Zischka R, Addo N (1971) Alternation in composition of deoxyribonucleic acid, ribonucleic acid, proteins, and amino acids in brain of rats fed high and low phenylalanine diets. Pediatr Res 5:329–334CrossRef
47.O’Brien D, Ibbot FA (1966) Effect of prolonged phenylalanine loading on the free amino-acid and lipid content of the infant monkey brain. Dev Med Child Neurol 8:724–728CrossRef PubMed
48.Vogel KR, Arning E, Wasek BL, Bottiglieri T, Gibson KM (2013) Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood–brain phenylalanine transport in Pah enu2 mice: preliminary findings. Mol Genet Metab 110(Suppl):S71–S78CrossRef PubMed PubMedCentral
49.Arning E, Bottiglieri T, Sun Q, Jansen EEW, Jakobs C, Lin B, Stetson L, Harding CO, Gibson KM (2009) Metabolic profiling in phenylalanine hydroxylase deficient (PAH −/−) mouse brain reveals decreased amino acid neurotransmitters and preferential alterations of the serotonergic system. Mol Genet Metab 98:21
50.Perry TL, Urquhart N, MacLean J, Evans ME, Hansen S, Davidson GF, Applegarth DA, MacLeod PJ, Lock JE (1975) Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain. N Engl J Med 292:1269–1273CrossRef PubMed
51.Applegarth DA, Toone JR (2004) Glycine encephalopathy (nonketotic hyperglycinaemia): review and update. J Inherit Metab Dis 27:417–422CrossRef PubMed
52.Kikuchi G, Motokawa Y, Yoshida T, Hiraga K (2008) Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc Jpn Acad Ser B Phys Biol Sci 84:246–263CrossRef PubMed PubMedCentral
53.Banerjee A, Ganji S, Hulsey K, Dimitrov I, Maher E, Ghose S, Tamminga C, Choi C (2012) Measurement of glycine in gray and white matter in the human brain in vivo by 1H MRS at 7.0 T. Magn Reson Med 68:325–331CrossRef PubMed PubMedCentral
54.Schindeler S, Ghosh-Jerath S, Thompson S, Rocca A, Joy P, Kemp A, Rae C, Green K, Wilcken B, Christodoulou J (2007) The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab 91:48–54CrossRef PubMed
55.Kochi H, Hayasaka K, Hiraga K, Kikuchi G (1979) Reduction of the level of the glycine cleavage system in the rat liver resulting from administration of dipropylacetic acid: an experimental approach to hyperglycinemia. Arch Biochem Biophys 198:589–597CrossRef PubMed
56.Mortensen PB, Kolvraa S, Christensen E (1980) Inhibition of the glycine cleavage system: hyperglycinemia and hyperglycinuria caused by valproic acid. Epilepsia 21:563–569CrossRef PubMed
57.Martin-Gallardo A, Rodriguez P, Lopez M, Benavides J, Ugarte M (1985) Effects of dipropylacetate on the glycine cleavage enzyme system and glycine levels. A possible experimental approach to non-ketotic hyperglycinemia. Biochem Pharmacol 34:2877–2882CrossRef PubMed
58.Simila S, von Wendt L, Linna SL, Saukkonen AL, Huhtaniemi I (1979) Dipropylacetate and hyperglycinemia. Neuropadiatrie 10:158–160CrossRef PubMed
59.Dhamija R, Gavrilova RH, Wirrell EC (2011) Valproate-induced worsening of seizures: clue to underlying diagnosis. J Child Neurol 26:1319–1321CrossRef PubMed
60.Subramanian V, Kadiyala P, Hariharan P, Neeraj E (2015) A rare case of glycine encephalopathy unveiled by valproate therapy. J Pediatr Neurosci 10:143–145CrossRef PubMed PubMedCentral
61.Kochi H, Seino H, Ono K (1986) Inhibition of glycine oxidation by pyruvate, alpha-ketoglutarate, and branched-chain alpha-keto acids in rat liver mitochondria: presence of interaction between the glycine cleavage system and alpha-keto acid dehydrogenase complexes. Arch Biochem Biophys 249:263–272CrossRef PubMed
62.Smith CB, Kang J (2000) Cerebral protein synthesis in a genetic mouse model of phenylketonuria. Proc Natl Acad Sci USA 97:11014–11019CrossRef PubMed PubMedCentral
63.Qin M, Smith CB (2007) Regionally selective decreases in cerebral glucose metabolism in a mouse model of phenylketonuria. J Inherit Metab Dis 30:318–325CrossRef PubMed
64.Burri R, Matthieu JM, Vandevelde M, Lazeyras F, Posse S, Herschkowitz N (1990) Brain damage and recovery in hyperphenylalaninemic rats. Dev Neurosci 12:116–125CrossRef PubMed
65.Lutz Mda G, Feksa LR, Wyse AT, Dutra-Filho CS, Wajner M, Wannmacher CM (2003) Alanine prevents the in vitro inhibition of glycolysis caused by phenylalanine in brain cortex of rats. Metab Brain Dis 18:87–94CrossRef PubMed
66.Martynyuk AE, Ucar DA, Yang DD, Norman WM, Carney PR, Dennis DM, Laipis PJ (2007) Epilepsy in phenylketonuria: a complex dependence on serum phenylalanine levels. Epilepsia 48:1143–1150CrossRef PubMed
67.Hasselbalch S, Knudsen GM, Toft PB, Hogh P, Tedeschi E, Holm S, Videbaek C, Henriksen O, Lou HC, Paulson OB (1996) Cerebral glucose metabolism is decreased in white matter changes in patients with phenylketonuria. Pediatr Res 40:21–24CrossRef PubMed
68.Yanai K, Iinuma K, Matsuzawa T, Ito M, Miyabayashi S, Narisawa K, Ido T, Yamada K, Tada K (1987) Cerebral glucose utilization in pediatric neurological disorders determined by positron emission tomography. Eur J Nucl Med 13:292–296CrossRef PubMed
69.Ficicioglu C, Dubroff JG, Thomas N, Gallagher PR, Burfield J, Hussa C, Randall R, Zhuang H (2013) A pilot study of fluorodeoxyglucose positron emission tomography findings in patients with phenylketonuria before and during sapropterin supplementation. J Clin Neurol 9:151–156CrossRef PubMed PubMedCentral
70.Lane JD, Neuhoff V (1980) Phenylketonuria: clinical and experimental considerations revealed by the use of animal models. Naturwissenschaften 67:227–233CrossRef PubMed
71.Binek PA, Johnson TC, Kelly CJ (1981) Effect of alpha-methylphenylalanine and phenylalanine on brain polyribosomes and protein synthesis. J Neurochem 36:1476–1484CrossRef PubMed
72.Figlewicz DA, Druse MJ (1980) Experimental hyperphenylalaninemia: effect on central nervous system myelin subfractions. Exp Neurol 67:315–329CrossRef PubMed
73.Johnson RC, Shah SN (1980) Effects of alpha-methylphenylalanine plus phenylalanine treatment during development on myelin in rat brain. Neurochem Res 5:709–718CrossRef PubMed
74.Luttges MW, Gerren RA (1979) Postnatal alpha-methylphenylalanine treatment effects on adult mouse locomotor activity and avoidance learning. Pharmacol Biochem Behav 11:493–498CrossRef PubMed
75.Nigam MP, Labar DR (1979) The effect of hyperphenylalaninemia on size and density of synapses in rat neocortex. Brain Res 179:195–198CrossRef PubMed
76.Diamond A, Ciaramitaro V, Donner E, Djali S, Robinson MB (1994) An animal model of early-treated PKU. J Neurosci 14:3072–3082PubMed
77.Sourkes TL, Murphy GF, Chavez B, Zielinska M (1961) The action of some alpha-methyl and other amino acids on cerebral catecholamines. J Neurochem 8:109–115CrossRef PubMed
78.Torchiana ML, Porter CC, Stone CA, Hanson HM (1970) Some biochemical and pharmacological actions of-methylphenylalanine. Biochem Pharmacol 19:1601–1614CrossRef PubMed
79.Dos Reis EA, Rieger E, de Souza SS, Rasia-Filho AA, Wannmacher CM (2013) Effects of a co-treatment with pyruvate and creatine on dendritic spines in rat hippocampus and posterodorsal medial amygdala in a phenylketonuria animal model. Metab Brain Dis 28:509–517CrossRef PubMed
80.Iacobas DA, Iacobas S, Urban-Maldonado M, Scemes E, Spray DC (2008) Similar transcriptomic alterations in Cx43 knockdown and knockout astrocytes. Cell Commun Adhes 15:195–206CrossRef PubMed PubMedCentral
81.Iacobas DA, Iacobas S, Urban-Maldonado M, Spray DC (2005) Sensitivity of the brain transcriptome to connexin ablation. Biochim Biophys Acta 1711:183–196CrossRef PubMed
82.Surtees R, Blau N (2000) The neurochemistry of phenylketonuria. Eur J Pediatr 159(Suppl 2):S109–S113CrossRef PubMed
83.Ribas GS, Sitta A, Wajner M, Vargas CR (2011) Oxidative stress in phenylketonuria: What is the evidence? Cell Mol Neurobiol 31:653–662CrossRef PubMed
84.de Groot MJ, Hoeksma M, Blau N, Reijngoud DJ, van Spronsen FJ (2010) Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. Mol Genet Metab 99(Suppl 1):S86–S89CrossRef PubMed
85.Martynyuk AE, van Spronsen FJ, Van der Zee EA (2010) Animal models of brain dysfunction in phenylketonuria. Mol Genet Metab 99(Suppl 1):S100–S105CrossRef PubMed
86.Sarkissian CN, Gamez A, Scriver CR (2009) What we know that could influence future treatment of phenylketonuria. J Inherit Metab Dis 32:3–9CrossRef PubMed
87.van Spronsen FJ, Hoeksma M, Reijngoud DJ (2009) Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause? J Inherit Metab Dis 32:46–51CrossRef PubMed
88.Moura AP, Grings M, Marcowich GF, Bumbel AP, Parmeggiani B, de Moura Alvorcem L, Wajner M, Leipnitz G (2014) Evidence that glycine induces lipid peroxidation and decreases glutathione concentrations in rat cerebellum. Mol Cell Biochem 395:125–134CrossRef PubMed
89.Moura AP, Grings M, Dos Santos Parmeggiani B, Marcowich GF, Tonin AM, Viegas CM, Zanatta A, Ribeiro CA, Wajner M, Leipnitz G (2013) Glycine intracerebroventricular administration disrupts mitochondrial energy homeostasis in cerebral cortex and striatum of young rats. Neurotox Res 24:502–511CrossRef PubMed
90.Seminotti B, Knebel LA, Fernandes CG, Amaral AU, da Rosa MS, Eichler P, Leipnitz G, Wajner M (2011) Glycine intrastriatal administration induces lipid and protein oxidative damage and alters the enzymatic antioxidant defenses in rat brain. Life Sci 89:276–281CrossRef PubMed
91.Busanello ENB, Moura AP, Viegas CM, Zanatta Â, da Costa Ferreira G, Schuck PF, Wajner M (2010) Neurochemical evidence that glycine induces bioenergetical dysfunction. Neurochem Int 56:948–954CrossRef PubMed
92.Waniewski RA, Martin DL (1998) Preferential utilization of acetate by astrocytes is attributable to transport. J Neurosci 18:5225–5233PubMed
93.Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329:364–367CrossRef PubMed
94.Yu AC, Drejer J, Hertz L, Schousboe A (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 41:1484–1487CrossRef PubMed
95.Sarkissian CN, Scriver CR, Mamer OA (2000) Measurement of phenyllactate, phenylacetate, and phenylpyruvate by negative ion chemical ionization–gas chromatography/mass spectrometry in brain of mouse genetic models of phenylketonuria and non-phenylketonuria hyperphenylalaninemia. Anal Biochem 280:242–249CrossRef PubMed
96.Martynyuk AE, Glushakov AV, Sumners C, Laipis PJ, Dennis DM, Seubert CN (2005) Impaired glutamatergic synaptic transmission in the PKU brain. Mol Genet Metab 86(Suppl 1):S34–S42CrossRef PubMed
97.Glushakov AV, Dennis DM, Sumners C, Seubert CN, Martynyuk AE (2003) L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses. J Neurosci Res 72:116–124CrossRef PubMed
98.Glushakov AV, Glushakova O, Varshney M, Bajpai LK, Sumners C, Laipis PJ, Embury JE, Baker SP, Otero DH, Dennis DM, Seubert CN, Martynyuk AE (2005) Long-term changes in glutamatergic synaptic transmission in phenylketonuria. Brain 128:300–307CrossRef PubMed
99.Imperlini E, Orru S, Corbo C, Daniele A, Salvatore F (2014) Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model. J Neurochem 129:1002–1012CrossRef PubMed PubMedCentral
100.Schulz JB, Wree A, Schleicher A, Zilles K (1992) Plasticity in the rat hippocampal formation following ibotenic acid lesion of the septal region: a quantitative [14C]deoxyglucose and acetylcholinesterase study. J Cereb Blood Flow Metab 12:1007–1021CrossRef PubMed
101.Wree A, Schleicher A, Zilles K, Beck T (1988) Local cerebral glucose utilization in the Ammon’s horn and dentate gyrus of the rat brain. Histochemistry 88:415–426PubMed - 作者单位：Gerald A. Dienel (1)
Nancy F. Cruz (1)
1. Department of Neurology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Mail Slot 500, Little Rock, AR, 72205, USA - 刊物类别：Biomedical and Life Sciences
- 刊物主题：Biomedicine
Neurosciences
Biochemistry
Neurology - 出版者：Springer Netherlands
- ISSN：1573-6903
文摘
Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16 h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25–27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least 3 weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired.