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Role of the Kynurenine Pathway in Epilepsy

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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

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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

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Acknowledgements

This work was supported by the U.S. National Institutes of Health (NINDS 5R01NS064989-03).

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Correspondence to Diane C. Chugani Ph.D. .

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Sharma, M., Anand, C., Chugani, D.C. (2015). Role of the Kynurenine Pathway in Epilepsy. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_16

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