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Kynurenines in the mammalian brain: when physiology meets pathology

Key Points

  • The essential amino acid tryptophan is degraded to several neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. These metabolites, collectively termed 'kynurenines', directly target important neurotransmitter receptors and affect redox processes, and thus influence brain physiology.

  • In the mammalian brain, the catabolic cascade responsible for the neosynthesis of kynurenines — the kynurenine pathway — is physically segregated into two branches. One, leading to the neuroprotective agent kynurenic acid, is contained in astrocytes, whereas the other, leading to the neurotoxins 3-hydroxykynurenine and quinolinic acid, is present in microglial cells.

  • Brain kynurenines are not autonomous but are linked to, and affected by, the peripheral kynurenine pathway. As the pathway is stimulated by a host of cytokines and other intercellular signalling molecules, both peripheral and central functions of kynurenines are influenced by infections and other inflammatory conditions.

  • Dysregulations of the pathway, causing hyper- or hypofunction of active metabolites, are associated with neurodegenerative and other neurological disorders, as well as psychiatric diseases such as depression and schizophrenia.

  • Recently developed pharmacological agents make it increasingly possible to selectively influence the kynurenine pathway in the periphery and in the brain.

  • Targeted interventions with such specific 'kynurenergic' drugs can now be used to influence brain physiology. This approach is also envisaged to normalize pathophysiologically relevant imbalances in cerebral kynurenines and thus provide novel treatments for a host of brain diseases.

Abstract

The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper- or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

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Figure 1: The kynurenine pathway of tryptophan degradation in mammals.
Figure 2: Segregation of the two kynurenine pathway branches in the brain.
Figure 3: Communication between peripheral and central kynurenine pathways under normal and inflammatory conditions.
Figure 4: Effects of kynurenine pathway manipulation on cognition and neurodegeneration.
Figure 5: Targeting brain kynurenines pharmacologically: focus on KAT II and KMO.

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Acknowledgements

Studies in our laboratories have been supported by grants from the US National Institutes of Health (NIMH, NINDS and NICHD) (Maryland, USA), the National Alliance for Research in Schizophrenia and Affective Disorders, the Hereditary Disease Foundation/High Q and CHDI, Inc. We are grateful to the pre- and postdoctoral associates, who were instrumental in the design and completion of the work conducted in our laboratories. We feel special gratitude to our friend Paolo Guidetti, who passed away prematurely on 28 December 2007.

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Correspondence to Robert Schwarcz.

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R.S. and P.J.M. are listed as inventors on a patent claiming neuroprotective properties of JM6. R.S. received research support from Mitsubishi-Tanabe and Bristol-Myers Squibb.

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Schwarcz, R., Bruno, J., Muchowski, P. et al. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13, 465–477 (2012). https://doi.org/10.1038/nrn3257

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