Basic Neurosciences, Genetics and Immunology - Review article

Journal of Neural Transmission

, Volume 119, Issue 2, pp 225-234

First online:

The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications

  • Judit FüvesiAffiliated withDepartment of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged
  • , Cecilia RajdaAffiliated withDepartment of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged
  • , Krisztina BencsikAffiliated withDepartment of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged
  • , József ToldiAffiliated withDepartment of Physiology, Anatomy and Neuroscience, Faculty of Natural Sciences, University of SzegedNeuroscience Research Group of the Hungarian Academy of Sciences, University of Szeged
  • , László VécseiAffiliated withDepartment of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of SzegedNeuroscience Research Group of the Hungarian Academy of Sciences, University of Szeged Email author 

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Abstract

Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood–brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.

Keywords

Neurodegeneration Inflammation Kynurenic acid Multiple sclerosis Amyotrophic lateral sclerosis