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Changes in Extracellular Kynurenic Acid Concentrations in Rat Prefrontal Cortex After d-Kynurenine Infusion: An In vivo Microdialysis Study

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Abstract

Using a microdialysis technique, we continuously infused d-kynurenine (KYN) (0, 50, and 100 μM) into the prefrontal cortices (PFCs) of male Sprague–Dawley rats. We then used column-switching high-performance liquid chromatography to assess the alterations in the concentration of kynurenic acid (KYNA)—an antagonist of N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors—in the extracellular fluid in the PFC. Local infusion of d-KYN into the PFC remarkably increased the extracellular KYNA concentration, indicating that d-KYN is metabolized to KYNA in the PFC. The d-KYN-induced increase in KYNA levels was significantly attenuated by the co-administration of 3-methylpyrazole-5-carboxylic acid (AS057278)—a specific inhibitor of d-amino acid oxidase (DAAO). These results suggest that DAAO may be involved in the production of KYNA from d-KYN in the PFC in vivo.

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References

  1. Borchers R, Berg CP, Whitman NE (1942) Tryptophane metabolism. X. The effect of feeding l(−)-, dl-, and d(+)-tryptophane, d(−)- and dl-β-3-indolelactic acid, β-3-indolepyruvic acid, and l(−)-kynurenine upon the storage of liver glycogen and the urinary output of kynurenic acid, kynurenine, and total acetone bodies. J Biol Chem 145:657–666

    CAS  Google Scholar 

  2. Leklem JE (1971) Quantitative aspects of tryptophan metabolism in humans and other species: a review. Amer J Clin Nutr 24:659–672

    CAS  PubMed  Google Scholar 

  3. Mason M, Berg CP (1952) The metabolism of d- and l-tryptophan and d- and l-kynurenine by liver and kidney preparations. J Biol Chem 195:515–524

    CAS  PubMed  Google Scholar 

  4. Langner RR, Berg CP (1955) Metabolism of d-tryptophan in the normal human subject. J Biol Chem 214:699–707

    CAS  PubMed  Google Scholar 

  5. Higuchi K, Hayaishi O (1967) Enzymic formation of d-kynurenine from d-tryptophan. Arch Biochem Biophys 120:397–403

    Article  CAS  PubMed  Google Scholar 

  6. Loh HH, Berg CP (1971) Production of d-kynurenine and other metabolites from d-tryptophan by the intact rabbit and by rabbit tissue. J Nutr 101:465–475

    CAS  PubMed  Google Scholar 

  7. Moroni F (1999) Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol 375:87–100

    Article  CAS  PubMed  Google Scholar 

  8. Nemeth H, Toldi J, Vecsei L (2005) Role of kynurenines in the central and peripheral nervous systems. Curr Neurovascul Res 2:249–260

    Article  Google Scholar 

  9. Ruddick JP, Evans AK, Nutt DJ et al (2006) Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med 8:1–27

    Article  PubMed  Google Scholar 

  10. Hashimoto K, Koike K, Shimizu E et al (2005) α7 Nicotinic receptor agonists as potential therapeutic drugs for schizophrenia. Curr Med Chem Cent Nerv Syst Ag 5:171–184

    Article  CAS  Google Scholar 

  11. Swartz KJ, During MJ, Freese A et al (1990) Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors. J Neurosci 10:2965–2973

    CAS  PubMed  Google Scholar 

  12. Hilmas C, Pereira EFR, Alkondon M et al (2001) The brain metabolite kynurenic acid inhibits α7 nicotinic receptor activity and increases non-α7 nicotinic receptor expression: physiopathological implications. J Neurosci 21:7463–7473

    CAS  PubMed  Google Scholar 

  13. Schwarcz R, Rassoulpour A, Wu HQ et al (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatr 50:521–530

    Article  CAS  Google Scholar 

  14. Erhardt S, Blennow K, Nordin C et al (2001) Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 313:96–98

    Article  CAS  PubMed  Google Scholar 

  15. Nilsson LK, Linderholm KR, Engberg G et al (2005) Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 80:315–322

    Article  CAS  PubMed  Google Scholar 

  16. Erhardt S, Schwieler L, Nilsson L et al (2007) The kynurenic acid hypothesis of schizophrenia. Physiol Behav 92:203–209

    Article  CAS  PubMed  Google Scholar 

  17. Okuno E, Schmidt W, Parks DA et al (1991) Measurement of rat brain kynurenine aminotransferase at physiological kynurenine concentrations. J Neurochem 57:533–540

    Article  CAS  PubMed  Google Scholar 

  18. Guidetti P, Okuno E, Schwarcz R (1997) Characterization of rat brain kynurenine aminotransferases I and II. J Neurosci Res 50:457–465

    Article  CAS  PubMed  Google Scholar 

  19. Rossi F, Han Q, Li J et al (2004) Crystal structure of human kynurenine aminotransferase I. J Biol Chem 279:50214–50220

    Article  CAS  PubMed  Google Scholar 

  20. Han Q, Robinson H, Li J (2008) Crystal structure of human kynurenine aminotransferase II. J Biol Chem 283:3567–3573

    Article  CAS  PubMed  Google Scholar 

  21. Rossi F, Garavaglia S, Montalbano V et al (2007) Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia. J Biol Chem 283:3559–3566

    Article  PubMed  Google Scholar 

  22. Amori L, Guidetti P, Pellicciari R et al (2009) On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo. J Neurochem 109:316–325

    Article  CAS  PubMed  Google Scholar 

  23. Guidetti P, Amori L, Sapko MT et al (2007) Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem 102:103–111

    Article  CAS  PubMed  Google Scholar 

  24. Fukushima T, Sone Y, Mitsuhashi S et al (2009) Alteration of kynurenic acid concentration in rat plasma following optically pure kynurenine administration: a comparative study between enantiomers. Chirality 21:468–472

    Article  CAS  PubMed  Google Scholar 

  25. Pilone MS (2000) d-Amino acid oxidase: new findings. Cell Mol Life Sci 57:1732–1747

    Article  CAS  PubMed  Google Scholar 

  26. Corvin A, Donohoe G, McGhee K et al (2007) d-Amino acid oxidase (DAO) genotype and mood symptomatology in schizophrenia. Neurosci Lett 426:97–100

    Article  CAS  PubMed  Google Scholar 

  27. Ono K, Shishido Y, Park HK et al (2009) Potential pathophysiological role of d-amino acid oxidase in schizophrenia: immunohistochemical and in situ hybridization study of the expression in human and rat brain. J Neural Transm 116:1335–1347

    Article  CAS  PubMed  Google Scholar 

  28. Williams M (2009) Commentary: genome-based CNS drug discovery: d-amino acid oxidase (DAAO) as a novel target for antipsychotic medications: progress and challenges. Biochem Pharmacol 78:1360–1365

    Article  CAS  PubMed  Google Scholar 

  29. Adage T, Trillat AC, Quattropani A et al (2008) In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties. Eur Neuropsychopharmacol 18:200–214

    Article  CAS  PubMed  Google Scholar 

  30. Fukushima T, Kawai J, Imai K et al (2004) Simultaneous determination of d- and l-serine in rat brain microdialysis sample using a column-switching HPLC with fluorimetric detection. Biomed Chromatogr 18:813–819

    Article  CAS  PubMed  Google Scholar 

  31. Tomiya M, Fukushima T, Ogaya T et al (2009) Determination of kynurenic acid levels in rat brain microdialysis samples and changes in kynurenic acid levels induced by N-acetylaspartic acid. Biomed Chromatogr. doi: 10.1002/bmc.1336

  32. Mitsuhashi S, Fukushima T, Kawai J et al (2006) Improved method for the determination of kynurenic acid in rat plasma by column-switching HPLC with post-column fluorescence detection. Anal Chim Acta 562:36–43

    Article  CAS  Google Scholar 

  33. Fukushima T, Mitsuhashi S, Tomiya M et al (2007) Determination of kynurenic acid in human serum and its correlation with the concentration of certain amino acids. Clin Chim Acta 377:174–178

    Article  CAS  PubMed  Google Scholar 

  34. Fukushima T, Mitsuhashi S, Tomiya M et al (2007) Determination of rat brain kynurenic acid by column-switching HPLC with fluorescence detection. Biomed Chromatogr 21:514–519

    Article  CAS  PubMed  Google Scholar 

  35. Miller JM, MacGarvey U, Beal MF (1992) The effect of peripheral loading with kynurenine and probenecid on extracellular striatal kynurenic acid concentrations. Neurosci Lett 146:115–118

    Article  CAS  PubMed  Google Scholar 

  36. Wu HQ, Pereira EFR, Bruno JP et al (2009) The astrocyte-derived α7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex. J Mol Neurosci. doi: 10.1007/s12031-009-9235-2

  37. Mitsuhashi S, Fukushima T, Arai K et al (2007) Development of a column-switching high-performance liquid chromatography for kynurenine enantiomers and its application to a pharmacokinetic study in rat plasma. Anal Chim Acta 587:60–66

    Article  CAS  PubMed  Google Scholar 

  38. Tashiro M, Tsukada K, Kobayashi S et al (1961) A new pathway of d-tryptophan metabolism: enzymic formation of kynurenic acid via d-kynurenine. Biochem Biophys Res Commun 6:155–160

    Article  CAS  PubMed  Google Scholar 

  39. Schell MJ, Molliver ME, Snyder SH (1995) d-Serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci USA 92:3948–3952

    Article  CAS  PubMed  Google Scholar 

  40. Verrall L, Walker M, Rawlings N et al (2007) d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. Eur J Neurosci 26:1657–1669

    Article  PubMed  Google Scholar 

  41. Madeira C, Freitas ME, Vargas-Lopes C et al (2008) Increased brain d-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr Res 101:76–83

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. M. Sato, Toho University, for his helpful discussions on this study.

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Authors and Affiliations

  1. Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba, 274-8510, Japan

    Tadahiro Ogaya, Ziyu Song, Kana Ishii & Takeshi Fukushima

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  1. Tadahiro Ogaya
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  2. Ziyu Song
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  3. Kana Ishii
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  4. Takeshi Fukushima
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Correspondence to Takeshi Fukushima.

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Ogaya, T., Song, Z., Ishii, K. et al. Changes in Extracellular Kynurenic Acid Concentrations in Rat Prefrontal Cortex After d-Kynurenine Infusion: An In vivo Microdialysis Study. Neurochem Res 35, 559–563 (2010). https://doi.org/10.1007/s11064-009-0099-1

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