Role of the Kynurenine Pathway in Epilepsy

Abstract

A role for the kynurenine pathway (KP) of tryptophan (TRP) metabolism in epilepsy was first discovered when injections of the KP metabolite quinolinic acid (QA) in brain produced seizures in mice (Lapin IP. J Neural Transm. 42(1):37–43;1978). Subsequent studies have reported altered KP metabolites in animal models of epilepsy and in human epilepsy. Epilepsy is a complex group of disorders involving abnormal firing of neurons linked to an imbalance of excitatory and inhibitory mechanisms in the brain. KP metabolites act at several neurotransmitter receptors and can produce both excitatory and inhibitory effects. Thus, the role of the KP mechanisms in epilepsy, a condition characterized by an imbalance in excitation and inhibition, is important to consider. Furthermore, the KP is induced by inflammatory cytokines and is part of the inflammatory response increasingly recognized to play a role in epilepsy and epileptogenesis (Vezzani A. Epilepsy Curr. 14(1 Suppl):3–7;2014). In this chapter, we discuss evidence for the role of the KP in the balance of excitation and inhibition and the inflammatory process in animal models, as well as evidence for a role of kynurenines in human epilepsy. Finally, therapeutic targets for epilepsy in the KP are discussed.

Keywords

Epilepsy Kynurenine Tryptophan Inflammation α-[11C]methyl-l-tryptophan 

List of Abbreviations

3-HK

3-Hydroxykynurenine

ACMSD

α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase

AMPA

α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid

AMT

α-[11C]methyl-l-tryptophan

CSF

Cerebrospinal fluid

IDO

Indoleamine 2,3-dioxygenase (IDO)

KATs

Kynurenine aminotransferases

KMO

Kynurenine monoxygenase

KP

Kynurenine pathway

KYNA

Kynurenic acid

NMDA

N-methyl-d-aspartate

NORSE

New-onset refractory status epilepticus

PET

Positron emission tomography

PTZ

Pentylenetetrazole

QA

Quinolinic acid

TRP

Tryptophan

TSC

Tuberous sclerosis complex

References

  1. 1.
    Lapin IP. Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J Neural Transm. 1978;42(1):37–43.CrossRefPubMedGoogle Scholar
  2. 2.
    Stone TW, Perkins MN. Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol. 1981;72(4):411–2.CrossRefPubMedGoogle Scholar
  3. 3.
    Rios C, Santamaria A. Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res. 1991;16(10):1139–43.CrossRefPubMedGoogle Scholar
  4. 4.
    Santamaria A, Jimenez-Capdeville ME, Camacho A, Rodriguez-Martinez E, Flores A, Galvan-Arzate S. In vivo hydroxyl radical formation after quinolinic acid infusion into rat corpus striatum. Neuroreport. 2001;12(12):2693–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Rodriguez-Martinez E, Camacho A, Maldonado PD, Pedraza-Chaverri J, Santamaria D, Galvan-Arzate S, et al. Effect of quinolinic acid on endogenous antioxidants in rat corpus striatum. Brain Res. 2000;858(2):436–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Vezzani A, Stasi MA, Wu HQ, Castiglioni M, Weckermann B, Samanin R. Studies on the potential neurotoxic and convulsant effects of increased blood levels of quinolinic acid in rats with altered blood-brain barrier permeability. Exp Neurol. 1989;106(1):90–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Nakano K, Takahashi S, Mizobuchi M, Kuroda T, Masuda K, Kitoh J. High levels of quinolinic acid in brain of epilepsy-prone E1 mice. Brain Res. 1993;619(1-2):195–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Eastman CL, Urbanska E, Love A, Kristensson K, Schwarcz R. Increased brain quinolinic acid production in mice infected with a hamster neurotropic measles virus. Exp Neurol. 1994;125(1):119–24.CrossRefPubMedGoogle Scholar
  9. 9.
    Lehrmann E, Guidetti P, Love A, Williamson J, Bertram EH, Schwarcz R. Glial activation precedes seizures and hippocampal neurodegeneration in measles virus-infected mice. Epilepsia. 2008;49 Suppl 2:13–23.CrossRefPubMedGoogle Scholar
  10. 10.
    Perkins MN, Stone TW. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 1982;247(1):184–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Kessler M, Terramani T, Lynch G, Baudry M. A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists. J Neurochem. 1989;52(4):1319–28.CrossRefPubMedGoogle Scholar
  12. 12.
    Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci. 2001;21(19):7463–73.PubMedGoogle Scholar
  13. 13.
    Beggiato S, Antonelli T, Tomasini MC, Tanganelli S, Fuxe K, Schwarcz R, et al. Kynurenic acid, by targeting alpha7 nicotinic acetylcholine receptors, modulates extracellular GABA levels in the rat striatum in vivo. Eur J Neurosci. 2013;37(9):1470–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Wu HQ, Pereira EF, Bruno JP, Pellicciari R, Albuquerque EX, Schwarcz R. The astrocyte-derived alpha7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex. J Mol Neurosci. 2010;40(1–2):204–10.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem. 2006;281(31):22021–8.CrossRefPubMedGoogle Scholar
  16. 16.
    DiNatale BC, Murray IA, Schroeder JC, Flaveny CA, Lahoti TS, Laurenzana EM, et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol Sci. 2010;115(1):89–97.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197–203.CrossRefPubMedGoogle Scholar
  18. 18.
    Guo J, Williams DJ, Puhl 3rd HL, Ikeda SR. Inhibition of N-type calcium channels by activation of GPR35, an orphan receptor, heterologously expressed in rat sympathetic neurons. J Pharmacol Exp Therap. 2008;324(1):342–51.CrossRefGoogle Scholar
  19. 19.
    Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA. 2010;107(46):19961–6.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Thompson JL, Holmes GL, Taylor GW, Feldman DR. Effects of kynurenic acid on amygdaloid kindling in the rat. Epilepsy Res. 1988;2(5):302–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Szyndler J, Maciejak P, Turzynska D, Sobolewska A, Walkowiak J, Plaznik A. The effects of electrical hippocampal kindling of seizures on amino acids and kynurenic acid concentrations in brain structures. J Neural Transm. 2012;119(2):141–9.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Wu HQ, Monno A, Schwarcz R, Vezzani A. Electrical kindling is associated with a lasting increase in the extracellular levels of kynurenic acid in the rat hippocampus. Neurosci Lett. 1995;198(2):91–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Loscher W, Ebert U, Lehmann H. Kindling induces a lasting, regionally selective increase of kynurenic acid in the nucleus accumbens. Brain Res. 1996;725(2):252–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Nemeth H, Robotka H, Kis Z, Rozsa E, Janaky T, Somlai C, et al. Kynurenine administered together with probenecid markedly inhibits pentylenetetrazol-induced seizures. An electrophysiological and behavioural study. Neuropharmacology. 2004;47(6):916–25.CrossRefPubMedGoogle Scholar
  25. 25.
    Wu HQ, Schwarcz R. Seizure activity causes elevation of endogenous extracellular kynurenic acid in the rat brain. Brain Res Bull. 1996;39(3):155–62.CrossRefPubMedGoogle Scholar
  26. 26.
    Maciejak P, Szyndler J, Turzynska D, Sobolewska A, Taracha E, Skorzewska A, et al. Time course of changes in the concentration of kynurenic acid in the brain of pentylenetetrazol-kindled rats. Brain Res Bull. 2009;78(6):299–305.CrossRefPubMedGoogle Scholar
  27. 27.
    Scharfman HE, Hodgkins PS, Lee SC, Schwarcz R. Quantitative differences in the effects of de novo produced and exogenous kynurenic acid in rat brain slices. Neurosci Lett. 1999;274(2):111–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Rozsa E, Robotka H, Nagy D, Farkas T, Sas K, Vecsei L, et al. The pentylenetetrazole-induced activity in the hippocampus can be inhibited by the conversion of L-kynurenine to kynurenic acid: an in vitro study. Brain Res Bull. 2008;76(5):474–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Carpenedo R, Chiarugi A, Russi P, Lombardi G, Carla V, Pellicciari R, et al. Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. Neuroscience. 1994;61(2):237–43.CrossRefPubMedGoogle Scholar
  30. 30.
    Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 2013;36(3):174–84.CrossRefPubMedGoogle Scholar
  31. 31.
    Guillemin GJ, Smith DG, Kerr SJ, Smythe GA, Kapoor V, Armati PJ, et al. Characterisation of kynurenine pathway metabolism in human astrocytes and implications in neuropathogenesis. Redox Rep. 2000;5(2-3):108–11.CrossRefPubMedGoogle Scholar
  32. 32.
    Guillemin GJ, Kerr SJ, Pemberton LA, Smith DG, Smythe GA, Armati PJ, et al. IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment. J Interferon Cytokine Res. 2001;21(12):1097–101.CrossRefPubMedGoogle Scholar
  33. 33.
    Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia. 2005;46(11):1724–43.CrossRefPubMedGoogle Scholar
  34. 34.
    Vezzani A. Epilepsy and inflammation in the brain: overview and pathophysiology. Epilepsy Curr. 2014;14(1 Suppl):3–7.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Mandi Y, Vecsei L. The kynurenine system and immunoregulation. J Neural Transm. 2012;119(2):197–209.CrossRefPubMedGoogle Scholar
  36. 36.
    Young SN, Joseph MH, Gauthier S. Studies on kynurenine in human cerebrospinal fluid: lowered levels in epilepsy. J Neural Transm. 1983;58(3-4):193–204.CrossRefPubMedGoogle Scholar
  37. 37.
    Feldblum S, Rougier A, Loiseau H, Loiseau P, Cohadon F, Morselli PL, et al. Quinolinic-phosphoribosyl transferase activity is decreased in epileptic human brain tissue. Epilepsia. 1988;29(5):523–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Heyes MP, Wyler AR, Devinsky O, Yergey JA, Markey SP, Nadi NS. Quinolinic acid concentrations in brain and cerebrospinal fluid of patients with intractable complex partial seizures. Epilepsia. 1990;31(2):172–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Marti-Masso JF, Bergareche A, Makarov V, Ruiz-Martinez J, Gorostidi A, Lopez de Munain A, et al. The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism. J Mol Med. 2013;91(12):1399–406.CrossRefPubMedGoogle Scholar
  40. 40.
    Chugani DC, Chugani HT, Muzik O, Shah JR, Shah AK, Canady A, et al. Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann Neurol. 1998;44(6):858–66.CrossRefPubMedGoogle Scholar
  41. 41.
    Batista C, Chugani, D. C., Luat, A. et al. Differential expression of the kynurenine pathway enzymes in epileptogenic tubers in tuberous sclerosis complex (TSC). Presented at 64th Annual Meeting of the American Epilepsy Society; 3–7 December 2010; San Antonio, TX, USA.Google Scholar
  42. 42.
    Rubi S, Costes N, Heckemann RA, Bouvard S, Hammers A, Marti Fuster B, et al. Positron emission tomography with alpha-[11C]methyl-L-tryptophan in tuberous sclerosis complex-related epilepsy. Epilepsia. 2013;54(12):2143–50.CrossRefPubMedGoogle Scholar
  43. 43.
    Fedi M, Reutens DC, Andermann F, Okazawa H, Boling W, White C, et al. alpha-[11C]-Methyl-L-tryptophan PET identifies the epileptogenic tuber and correlates with interictal spike frequency. Epilepsy Res. 2003;52(3):203–13.CrossRefPubMedGoogle Scholar
  44. 44.
    Juhasz C, Chugani DC, Muzik O, Shah A, Asano E, Mangner TJ, et al. Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology. 2003;60(6):960–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Chugani DC. Alpha-methyl-L-tryptophan: mechanisms for tracer localization of epileptogenic brain regions. Biomark Med. 2011;5(5):567–75.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Fedi M, Reutens D, Okazawa H, Andermann F, Boling W, Dubeau F, et al. Localizing value of alpha-methyl-L-tryptophan PET in intractable epilepsy of neocortical origin. Neurology. 2001;57(9):1629–36.CrossRefPubMedGoogle Scholar
  47. 47.
    Natsume J, Kumakura Y, Bernasconi N, Soucy JP, Nakai A, Rosa P, et al. Alpha-[11C] methyl-L-tryptophan and glucose metabolism in patients with temporal lobe epilepsy. Neurology. 2003;60(5):756–61.CrossRefPubMedGoogle Scholar
  48. 48.
    Juhasz C, Chugani DC, Muzik O, Wu D, Sloan AE, Barger G, et al. In vivo uptake and metabolism of alpha-[11C]methyl-L-tryptophan in human brain tumors. J Cereb Blood Flow Metab. 2006;26(3):345–57.CrossRefPubMedGoogle Scholar
  49. 49.
    Natsume J, Bernasconi N, Aghakhani Y, Kumakura Y, Nishikawa M, Fedi M, et al. Alpha-[11C]methyl-L-tryptophan uptake in patients with periventricular nodular heterotopia and epilepsy. Epilepsia. 2008;49(5):826–31.CrossRefPubMedGoogle Scholar
  50. 50.
    Alkonyi B, Mittal S, Zitron I, Chugani DC, Kupsky WJ, Muzik O, et al. Increased tryptophan transport in epileptogenic dysembryoplastic neuroepithelial tumors. J Neuro-Oncol. 2012;107(2):365–72.CrossRefGoogle Scholar
  51. 51.
    Juhasz C, Buth A, Chugani DC, Kupsky WJ, Chugani HT, Shah AK, et al. Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus. Neurosurg Focus. 2013;34(6), E5.CrossRefPubMedGoogle Scholar
  52. 52.
    Chiarugi A, Carpenedo R, Molina MT, Mattoli L, Pellicciari R, Moroni F. Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J Neurochem. 1995;65(3):1176–83.CrossRefPubMedGoogle Scholar
  53. 53.
    Wu HQ, Lee SC, Scharfman HE, Schwarcz R. L-4-chlorokynurenine attenuates kainate-induced seizures and lesions in the rat. Exp Neurol. 2002;177(1):222–32.CrossRefPubMedGoogle Scholar
  54. 54.
    Zhang DX, Williamson JM, Wu HQ, Schwarcz R, Bertram EH. In situ-produced 7-chlorokynurenate has different effects on evoked responses in rats with limbic epilepsy in comparison to naive controls. Epilepsia. 2005;46(11):1708–15.CrossRefPubMedGoogle Scholar
  55. 55.
    Wu HQ, Rassoulpour A, Goodman JH, Scharfman HE, Bertram EH, Schwarcz R. Kynurenate and 7-chlorokynurenate formation in chronically epileptic rats. Epilepsia. 2005;46(7):1010–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Monika Sharma
    • 1
  • Chaitali Anand
    • 2
  • Diane C. Chugani
    • 1
    • 3
  1. 1.Carman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan, Detroit Medical CenterWayne State University School of MedicineDetroitUSA
  2. 2.Translational Neuroscience Program, Children’s Hospital of Michigan, Detroit Medical CenterWayne State University School of MedicineDetroitUSA
  3. 3.Division of Clinical Pharmacology and Toxicology, Children’s Hospital of MichiganWayne State University School of MedicineDetroitUSA

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