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Amino Acids

, Volume 47, Issue 9, pp 1893–1908 | Cite as

Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free l-arginine in humans

  • Arslan Arinc Kayacelebi
  • Jennifer Langen
  • Katharina Weigt-Usinger
  • Kristine Chobanyan-Jürgens
  • François Mariotti
  • Jessica Y. Schneider
  • Sabine Rothmann
  • Jürgen C. Frölich
  • Dorothee Atzler
  • Chi-un Choe
  • Edzard Schwedhelm
  • Jean François Huneau
  • Thomas Lücke
  • Dimitrios TsikasEmail author
Original Article
Part of the following topical collections:
  1. Homoarginine, Arginine and Relatives

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis, whereas l-arginine (Arg) and l-homoarginine (hArg) serve as substrates for NO synthesis. ADMA and other methylated arginines are generally believed to exclusively derive from guanidine (N G)-methylated arginine residues in proteins by protein arginine methyltransferases (PRMTs) that use S-adenosylmethionine (SAM) as the methyl donor. l-Lysine is known for decades as a precursor for hArg, but only recent studies indicate that arginine:glycine amidinotransferase (AGAT) is responsible for the synthesis of hArg. AGAT catalyzes the formation of guanidinoacetate (GAA) that is methylated to creatine by guanidinoacetate methyltransferase (GAMT) which also uses SAM. The aim of the present study was to learn more about the mechanisms of ADMA and hArg formation in humans. Especially, we hypothesized that ADMA is produced by N G-methylation of free Arg in addition to the known PRMTs-involving mechanism. In knockout mouse models of AGAT- and GAMT-deficiency, we investigated the contribution of these enzymes to hArg synthesis. Arg infusion (0.5 g/kg, 30 min) in children (n = 11) and ingestion of high-fat protein meals by overweight men (n = 10) were used to study acute effects on ADMA and hArg synthesis. Daily Arg ingestion (10 g) or placebo for 3 or 6 months by patients suffering from peripheral arterial occlusive disease (PAOD, n = 20) or coronary artery disease (CAD, n = 30) was used to study chronic effects of Arg on ADMA synthesis. Mass spectrometric methods were used to measure all biochemical parameters in plasma and urine samples. In mice, AGAT but not GAMT was found to contribute to plasma hArg, while ADMA synthesis was independent of AGAT and GAMT. Arg infusion acutely increased plasma Arg, hArg and ADMA concentrations, but decreased the plasma hArg/ADMA ratio. High-fat protein meals acutely increased plasma Arg, hArg, ADMA concentrations, as well as the plasma hArg/ADMA ratio. In the PAOD and CAD studies, plasma Arg concentration increased in the verum compared to the placebo groups. Plasma ADMA concentration increased only in the PAOD patients who received Arg. Our study suggests that in humans a minor fraction of free Arg is rapidly metabolized to ADMA and hArg. In mice, GAMT and N G-methyltransferases contribute to ADMA and hArg synthesis from Arg, whereas AGAT is involved in the synthesis of hArg but not of ADMA. The underlying biochemical mechanisms remain still elusive.

Keywords

ADMA Arginine Homoarginine Knockout mouse NG-Methyltransferases SAM 

Abbreviations

ADMA

Asymmetric dimethylarginine (l-N G,N G-dimethylarginine)

AGAT

Arginine:glycine amidinotransferase

CAD

Coronary artery disease

Cr

Creatine

DDAH

Dimethylarginine dimethylaminohydrolase

DMA

Dimethylamine

GAA

Guanidinoacetate

GAMT

Guanidinoacetate methyltransferase

GC–MS

Gas chromatography–mass spectrometry

GC–MS/MS

Gas chromatography–tandem mass spectrometry

GHD

Growth hormone deficiency

hArg

Homoarginine

KO

Knockout

Me

Methyl

MMA

l-N G-Monomethylarginine

NO

Nitric oxide

NOS

Nitric oxide synthase

PAOD

Peripheral arterial occlusive disease

PRMT

Protein arginine methyltransferase

SAM

S-Adenosylmethionine

SDMA

Symmetric dimethylarginine (l-N G, G-dimethylarginine)

WT

Wild type

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

All studies reported here were approved by the local Ethics Committees for animals and humans. All adult participants and the parents of the children gave their written informed consent prior to enrolment.

References

  1. Atzler D, Rosenberg M, Andersso M, Choe CU, Lutz M, Zugck C et al (2013) Homoarginine—an independent marker of mortality in heart failure. Int J Cardiol 168:4907–4909CrossRefPubMedGoogle Scholar
  2. Atzler D, Gore MO, Ayers CR, Choe CU, Böger RH, de Lemos JA, McGuire DK, Schwedhelm E (2014) Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study. Arterioscler Thromb Vasc Biol 34:2501–2507CrossRefPubMedGoogle Scholar
  3. Bode-Böger SM (2006) Effect of arginine supplementation on NO production in man. Eur J Clin Pharmacol 62:91–99CrossRefGoogle Scholar
  4. Bode-Böger SM, Böger RH, Galland A, Tsikas D, Frölich JC (1998) Arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol 46:489–497PubMedCentralCrossRefPubMedGoogle Scholar
  5. Bode-Böger SM, Böger RH, Löffler M, Tsikas D, Brabant G, Frölich JC (1999) l-Arginine stimulates NO-dependent vasodilation in healthy humans—effect of somatostatin pretreatment. J Investig Med 47:43–50PubMedGoogle Scholar
  6. Böger RH, Maas R, Schulze F, Schwedhelm E (2009) Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality-an update on patient populations with a wide range of cardiovascular risk. Pharmacol Res 60:481–487CrossRefPubMedGoogle Scholar
  7. Bretscher LE, Li H, Poulos TL, Griffith OW (2003) Structural characterization and kinetics of nitric-oxide synthase inhibition by novel N5-(iminoalkyl)- and N5-(iminoalkenyl)-ornithines. J Biol Chem 278:46789–46797CrossRefPubMedGoogle Scholar
  8. Brosnan ME, Brosnan JT (2004) Renal arginine metabolism. J Nutr 134:2791S–2895SPubMedGoogle Scholar
  9. Burnett GH, Cohen PP (1957) Study of carbamyl phosphate-ornithine transcarbamylase. J Biol Chem 229:337–344PubMedGoogle Scholar
  10. Cathelineau L, Saudubray JM, Charpentier C, Polonovski C (1974) Letter: the presence of the homoanalogues of substrates of the urea cycle in the presence of argininosuccinate synthetase deficiency. Pediatr Res 8:857CrossRefPubMedGoogle Scholar
  11. Choe CU, Atzler D, Wild PS, Carter AM, Boger RH, Ojeda F et al (2013a) Homoarginine levels are regulated by arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. Circulation 128:1451–1461CrossRefPubMedGoogle Scholar
  12. Choe CU, Nabuurs C, Stockebrand MC, Neu A, Nunes P, Morellini F et al (2013b) Arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. Hum Mol Genet 22:110–123CrossRefPubMedGoogle Scholar
  13. Cullen ME, Yuen AH, Felkin LE, Smolenski RT, Hall JL, Grindle S et al (2006) Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation 114:I16–I20CrossRefPubMedGoogle Scholar
  14. da Silva RP, Clow K, Brosnan JT, Brosnan ME (2014) Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas. Br J Nutr 111:571–577CrossRefPubMedGoogle Scholar
  15. Davids M, Ndika JD, Salomons GS, Blom HJ, Teerlink T (2012a) Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine. FEBS Lett 586:3653–3657CrossRefPubMedGoogle Scholar
  16. Davids M, Swieringa E, Palm F, Smith DE, Smulders YM, Scheffer PG et al (2012b) Simultaneous determination of asymmetric and symmetric dimethylarginine, l-monomethylarginine, arginine, and l-homoarginine in biological samples using stable isotope dilution liquid chromatography tandem mass spectrometry. J Chromatogr B 900:38–47CrossRefGoogle Scholar
  17. Drechsler C, Meinitzer A, Pilz S, Krane V, Tomaschitz A, Ritz E et al (2011) Homoarginine, heart failure, and sudden cardiac death in haemodialysis patients. Eur J Heart Fail 13:852–859PubMedCentralCrossRefPubMedGoogle Scholar
  18. Hecker M, Walsh DT, Vane JR (1991) On the substrate specificity of nitric oxide synthase. FEBS Lett 294:221–224CrossRefPubMedGoogle Scholar
  19. Horner WH, Mackenzie CG (1950) The biological formation of sarcosine. J Biol Chem 187:15–22PubMedGoogle Scholar
  20. Humm A, Fritsche E, Steinbacher S, Huber R (1997) Crystal structure and mechanism of human l-arginine:glycine amidinotransferase: a mitochondrial enzyme involved in creatine biosynthesis. EMBO J 16:3373–3385PubMedCentralCrossRefPubMedGoogle Scholar
  21. Jaźwińska-Kozuba A, Martens-Lobenhoffer J, Kruszelnicka O, Rycaj J, Chyrchel B, Surdacki A, Bode-Böger SM (2013) Opposite associations of plasma homoarginine and ornithine with arginine in healthy children and adolescents. Int J Mol Sci 14:21819–21832CrossRefPubMedGoogle Scholar
  22. Kato T, Sano M, Mizutani N, Hayakawa C (1988) Homocitrullinuria and homoargininuria in hyperargininaemia. J Inherit Metab Dis 11:261–265CrossRefPubMedGoogle Scholar
  23. Katz JE, Dlakić M, Clarke S (2003) Automated identification of putative methyltransferases from genomic open reading frames. Mol Cell Proteomics 2:525–540PubMedGoogle Scholar
  24. Kayacelebi AA, Nguyen TH, Neil C, Horowitz JD, Jordan J, Tsikas D (2014a) Homoarginine and 3-nitrotyrosine in patients with takotsubo cardiomyopathy. Int J Cardiol 173:546–547CrossRefPubMedGoogle Scholar
  25. Kayacelebi AA, Beckmann B, Gutzki FM, Jordan J, Tsikas D (2014b) GC–MS and GC–MS/MS measurement of the cardiovascular risk factor homoarginine in biological samples. Amino Acids 46:2205–2217CrossRefPubMedGoogle Scholar
  26. Kayacelebi AA, Knöfel AK, Beckmann B, Hanff E, Warnecke G, Tsikas D (2015a) Measurement of unlabeled and stable isotope-labeled homoarginine, arginine and their metabolites in biological samples by GC–MS and GC–MS/MS. Amino Acids. doi: 10.1007/s00726-015-1984-3 Google Scholar
  27. Kayacelebi AA, Willers J, Pham VV, Hahn A, Schneider JY, Rothmann S, Frölich JC, Tsikas D (2015b) Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease. Amino Acids. doi: 10.1007/s00726-015-1915-3 Google Scholar
  28. Khalil AA, Tsikas D, Akolekar R, Jordan J, Nicolaides KH (2013) Asymmetric dimethylarginine, arginine and homoarginine at 11–13 weeks’ gestation and preeclampsia: a case-control study. J Hum Hypertens 27:38–43CrossRefPubMedGoogle Scholar
  29. Kielstein A, Tsikas D, Galloway GP, Mendelson JE (2007) Asymmetric dimethylarginine (ADMA)—a modulator of nociception in opiate tolerance and addiction? Nitric Oxide 17:55–59PubMedCentralCrossRefPubMedGoogle Scholar
  30. Leiper J, Vallance P (1999) Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 43:542–548CrossRefPubMedGoogle Scholar
  31. Levin B, Oberholzer VG, Palmer T (1974) Letter: the high levels of lysine, homocitrulline, and homoarginine found in argininosuccinate synthetase deficiency. Pediatr Res 8:857–858CrossRefPubMedGoogle Scholar
  32. Lücke T, Tsikas D, Kanzelmeyer N, Vaske B, Das AM (2006) Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine in citrullinemia. Metabolism 55:1599–1603CrossRefPubMedGoogle Scholar
  33. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H et al (1996) Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 119:1533–1540PubMedCentralCrossRefPubMedGoogle Scholar
  34. Mariotti F, Petzke KJ, Bonnet D, Szezepanski I, Bos C, Huneau JF et al (2013) Kinetics of the utilization of dietary arginine for nitric oxide and urea synthesis: insight into the arginine-nitric oxide metabolic system in humans. Am J Clin Nutr 97:972–979CrossRefPubMedGoogle Scholar
  35. Martens-Lobenhoffer J, Bode-Böger SM (2012) Quantification of l-arginine, asymmetric dimethylarginine and symmetric dimethylarginine in human plasma: a step improvement in precision by stable isotope dilution mass spectrometry. J Chromatogr B 904:140–143CrossRefGoogle Scholar
  36. März W, Meinitzer A, Drechsler C, Pilz S, Krane V, Kleber ME et al (2010) Homoarginine, cardiovascular risk, and mortality. Circulation 122:967–975CrossRefPubMedGoogle Scholar
  37. McGuire DM, Tormanen CD, Segal IS, Van Pilsum JF (1980) The effect of growth hormone and thyroxine on the amount of l-arginine:glycine amidinotransferase in kidneys of hypophysectomized rats. Purification and some properties of rat kidney transamidinase. J Biol Chem 255:1152–1159PubMedGoogle Scholar
  38. Miller LL, Bale WF, Yuile CL, Masters RE, Tishkoff GH, Whipple GH (1949) The use of radioactive lysine in studies on protein metabolism. Synthesis and utilization of plasma proteins. J Exp Med 90:297–313PubMedCentralCrossRefPubMedGoogle Scholar
  39. Moali C, Boucher JL, Sari MA, Stuehr DJ, Mansuy D (1998) Substrate specificity of NO synthases: detailed comparison of arginine, homo-arginine, their N omega-hydroxy derivatives, and N omega-hydroxynor-arginine. Biochemistry 37:10453–10460CrossRefPubMedGoogle Scholar
  40. Moncada S, Higgs A (1993) The arginine-nitric oxide pathway. New Engl J Med 329:2002–2012CrossRefPubMedGoogle Scholar
  41. Ogawa H, Ishiguro Y, Fujioka M (1983) Guanidoacetate methyltransferase from rat liver: purification, properties, and evidence for the involvement of sulfhydryl groups for activity. Arch Biochem Biophys 226:265–275CrossRefPubMedGoogle Scholar
  42. Pilz S, Tomaschitz A, Meinitzer A, Drechsler C, Ritz E, Krane V, Wanner C, Böhm BO, März W (2011a) Low serum homoarginine is a novel risk factor for fatal strokes in patients undergoing coronary angiography. Stroke 42:1132–1134CrossRefPubMedGoogle Scholar
  43. Pilz S, Meinitzer A, Tomaschitz A, Drechsler C, Ritz E, Krane V et al (2011b) Low homoarginine concentration is a novel risk factor for heart disease. Heart 97:1127–1222CrossRefGoogle Scholar
  44. Pilz S, Teerlink T, Scheffer PG, Meinitzer A, Rutters F, Tomaschitz A, Drechsler C, Kienreich K, Nijpels G, Stehouwer CD, März W, Dekker JM (2014) Homoarginine and mortality in an older population: the Hoorn study. Eur J Clin Invest 44:200–208CrossRefPubMedGoogle Scholar
  45. Pilz S, Meinitzer A, Gaksch M, Grübler M, Verheyen N, Drechsler C, Hartaigh BÓ, Lang F, Alesutan I, Voelkl J, März W, Tomaschitz A (2015a) Homoarginine in the renal and cardiovascular systems. Amino Acids. doi: 10.1007/s00726-015-1993-2 Google Scholar
  46. Pilz S, Putz-Bankuti C, Meinitzer A, März W, Kienreich K, Stojakovic T, Pieber TR, Stauber RE (2015b) Association of homoarginine and methylarginines with liver dysfunction and mortality in chronic liver disease. Amino Acids. doi: 10.1007/s00726-015-2000-7 Google Scholar
  47. Roberts JJ, Walker JB (1985) Higher homolo and N-ethyl analog of creatine as synthetic phosphagen precursors in brain, heart, and muscle, repressors of liver amidinotransferase, and substrates for creatine catabolic enzymes. J Biol Chem 260:13502–13508PubMedGoogle Scholar
  48. Ryan WL, Wells IC (1964) Homocitrulline and homoarginine synthesis from lysine. Science 144:1122–1127CrossRefPubMedGoogle Scholar
  49. Ryan WL, Barak AJ, Johnson RJ (1968) Lysine, homocitrulline, and homoarginine metabolism by the isolated perfused rat liver. Arch Biochem Biophys 123:294–297CrossRefPubMedGoogle Scholar
  50. Ryan WL, Johnson RJ, Dimari S (1969) Homoarginine synthesis by rat kidney. Arch Biochem Biophys 131:521–526CrossRefPubMedGoogle Scholar
  51. Schmidt A, Marescau B, Boehm EA, Renema WK, Peco R, Das A et al (2004) Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum Mol Genet 13:905–921CrossRefPubMedGoogle Scholar
  52. Siroen MP, Teerlink T, Nijveldt RJ, Prins HA, Richir MC, van Leeuwen PA (2006) The clinical significance of asymmetric dimethylarginine. Annu Rev Nutr 26:203–228CrossRefPubMedGoogle Scholar
  53. Takata Y, Date T, Fujioka M (1991) Rat liver guanidinoacetate methyltransferase. Proximity of cysteine residues at positions 15, 90 and 219 as revealed by site-directed mutagenesis and chemical modification. Biochem J 277(Pt 2):399–406PubMedCentralCrossRefPubMedGoogle Scholar
  54. Teerlink T, Luo Z, Palm F, Wilcox CS (2009) Cellular ADMA: regulation and action. Pharmacol Res 60:448–460PubMedCentralCrossRefPubMedGoogle Scholar
  55. Tomaschitz A, Meinitzer A, Pilz S, Rus-Machan J, Genser B, Drechsler C et al (2014) Homoarginine, kidney function and cardiovascular mortality risk. Nephrol Dial Transplant 29:663–671CrossRefPubMedGoogle Scholar
  56. Tsikas D (2009) De novo synthesis of trideuteromethyl esters of amino acids for use in GC- MS and GC-tandem MS exemplified for ADMA in human plasma and urine: standardization, validation, comparison and proof of evidence for their aptitude as internal standards. J Chromatogr B 877:2308–2320CrossRefGoogle Scholar
  57. Tsikas D, Kayacelebi AA (2014) Do homoarginine and asymmetric dimethylarginine act antagonistically in the cardiovascular system? Circ J 78:2092–2093CrossRefGoogle Scholar
  58. Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frölich JC (2000) Endogenous nitric oxide synthase inhibitors are responsible for the Arginine paradox. FEBS Lett 478:1–3CrossRefPubMedGoogle Scholar
  59. Tsikas D, Schubert B, Gutzki FM, Sandmann J, Frölich JC (2003) Quantitative determination of circulating and urinary asymmetric dimethylarginine (ADMA) in humans by gas chromatography-tandem mass spectrometry as methyl ester tri(N-pentafluoropropionyl) derivative. J Chromatogr B 798:87–99CrossRefGoogle Scholar
  60. Tsikas D, Wolf A, Mitschke A, Gutzki FM, Will W, Bader M (2010) GC–MS determination of creatinine in human biological fluids as pentafluorobenzyl derivative in clinical studies and biomonitoring: inter-laboratory comparison in urine with Jaffé, HPLC and enzymatic assays. J Chromatogr B 878:2582–2592CrossRefGoogle Scholar
  61. Tsikas D, Beckmann B, Gutzki FM, Jordan J (2011) Simultaneous gas chromatography-tandem mass spectrometry quantification of symmetric and asymmetric dimethylarginine in human urine. Anal Biochem 413:60–62CrossRefPubMedGoogle Scholar
  62. Valtonen P, Laitinen T, Lyyra-Laitinen T, Raitakari OT, Juonala M, Viikari JS et al (2008) Serum l-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72:1879–1884CrossRefPubMedGoogle Scholar
  63. van der Zwan LP, Davids M, Scheffer PG, Dekker JM, Stehouver CDA, Teerlink T (2013) l-Homoarginine and arginine are antagonistically related to blood pressure in an elderly population: the Hoorn study. J Hypertens 31:1114–1123CrossRefPubMedGoogle Scholar
  64. Walker JB, Hannan JK (1976) Creatine biosynthesis during embryonic development. False feedback suppression of liver amidinotransferase by N-acetimidoylsarcosine and 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine). Biochemistry 15:2519–2522CrossRefPubMedGoogle Scholar
  65. Wu G, Bazer FW, Cudd TA, Jobgen WS, Kim SW, Lassala A, Li P, Matis JH, Meininger CJ, Spencer TE (2007) Pharmacokinetics and safety of arginine supplementation in animals. J Nutr 137(6 Suppl 2):1673S–1680SPubMedGoogle Scholar
  66. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J et al (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168PubMedCentralCrossRefPubMedGoogle Scholar
  67. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213PubMedGoogle Scholar
  68. Yang Y, Wu Z, Jia S, Dahanayaka S, Feng S, Meininger CJ, McNeal CJ, Wu G (2015) Safety of long-term dietary supplementation with l-arginine in rats. Amino Acids. doi: 10.1007/s00726-015-1992-3 Google Scholar
  69. Yin J, Ren W, Hou Y, Wu M, Xiao H, Duan J, Zhao Y, Li T, Yin Y, Wu G, Nyachoti CM (2015) Use of homoarginine for measuring true ileal digestibility of amino acids in food protein. Amino Acids. doi: 10.1007/s00726-015-1958-5 Google Scholar
  70. Yuile CL, Lampson BG, Miller LL, Whipple GH (1951) Conversion of plasma protein to tissue protein without evidence of protein breakdown; results of giving plasma protein labeled with carbon 14 parenterally to dogs. J Exp Med 93:539–557PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Arslan Arinc Kayacelebi
    • 1
  • Jennifer Langen
    • 2
  • Katharina Weigt-Usinger
    • 2
  • Kristine Chobanyan-Jürgens
    • 1
  • François Mariotti
    • 3
    • 4
  • Jessica Y. Schneider
    • 1
  • Sabine Rothmann
    • 1
  • Jürgen C. Frölich
    • 1
  • Dorothee Atzler
    • 5
    • 6
  • Chi-un Choe
    • 7
    • 8
  • Edzard Schwedhelm
    • 5
    • 6
  • Jean François Huneau
    • 3
    • 4
  • Thomas Lücke
    • 2
  • Dimitrios Tsikas
    • 1
    Email author
  1. 1.Centre of Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
  2. 2.Department of Neuropaediatrics, University Children’s HospitalRuhr UniversityBochumGermany
  3. 3.INRACRNH-IdF, UMR914 Nutrition Physiology and Ingestive BehaviorParisFrance
  4. 4.AgroParisTechCRNH-IdF, UMR914 Nutrition Physiology and Ingestive BehaviorParisFrance
  5. 5.Department of Clinical Pharmacology and ToxicologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.DZHK (German Centre for Cardiovascular Research)HamburgGermany
  7. 7.Department of NeurologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  8. 8.Experimental NeuropediatricsUniversity Medical Center Hamburg-EppendorfHamburgGermany

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