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.
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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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.
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.
- Reactive oxygen species
(ROS). Natural byproducts of oxidative phosphorylation in the mitochondria. They include free radicals, peroxides and oxygen ions. Under pathological conditions, ROS levels can increase significantly, resulting in cellular damage.
- Pre-pulse inhibition
(PPI). A reduction in the magnitude of the startle reflex that occurs when an organism is presented with a non-startling stimulus (a pre-pulse) before being presented with the startling stimulus. Deficits in PPI have been observed in patients with schizophrenia.
A pathological process by which neurons are damaged and killed by the overactivation of glutamate receptors.
- Pro-inflammatory cytokines
Soluble mediators of local and systemic inflammatory responses. They are produced at the site of infection by activated immune cells and include interleukin-1α and interleukin-1β, tumour necrosis factor-α and interleukin-6.
- Prodromal events
Early symptoms that might indicate the start of a disease before specific symptoms occur.
- Single-nucleotide polymorphism
(SNP). A DNA sequence variation in which a single nucleotide in the genome is altered. SNPs can occur in coding as well as non-coding regions of DNA.
- Cerebral malaria
Encephalopathy that develops when red blood cells infected with the malaria parasite adhere to the cerebral microvasculature.
- Apoptotic cell death
Innate, programmed cell death that is energy-dependent and leads to nuclear and cytoplasmic compaction with characteristic blebbing of the nucleus. It occurs during development but also in disease states.
The process whereby an open or closed system regulates its internal environment to maintain its states within bounds.
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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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