The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Abstract

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognized in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition -glutamate and acetylcholine. Since this pathway -the kynurenine pathway of tryptophan metabolism -is induced by immunological activation and stress, it also stands in a unique position to mediate the effects of environmental factors on cognition and behaviour. Targeting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures. The neurochemistry of cognitionThe neural complexity of cognitive function makes it exceptionally difficult to identify specific neurochemical substrates, especially those that could provide pharmacologically relevant targets for the prevention or treatment of cognitive dysfunction (Millan et al., 2012). Most of the recognized neurotransmitters in the CNS have been linked with some aspect of cognition either as primary factors or as systems whose activity is modified as a secondary consequence of a neurochemically distinct previous event. Among the major candidates with a putatively primary role in cognition are the monoamines norepinephrine, dopamine and 5-hydroxytryptamine (5HT) (Dalley et al., 2004;Sarter et al., 2007;Robert and Benoit, 2008;Tadaiesky et al., 2008), although dopamine has received most attention because of its potential links to the cognitive dysfunction seen in schizophrenia and Parkinson's disease (Tadaiesky et al., 2008;Xu et al., 2012), with roles in executive functioning and perceptual response speed that are affected in both disorders (Backman et al., 2010). Several other neurotransmitter systems, such as those releasing histamine and neuropeptides have been implicated in cognitive performance or its modification by drugs (Minzenberg and Carter, 2008).The two systems which have received by far the greatest attention to date are those releasing glutamate or acetylcholine as their transmitters. Both these systems have wellestablished roles in various aspects of cognitive function, with the focus of interest being on glutamate receptors sensitive to the synthetic ligand NMDA (Castellano et al., 2001;Newcomer and Krystal, 2001;Neill et al., 2010). These systems are of particular relevance to this review since the primary compounds of interest -quinolinic acid and kynurenic acid -both have prominent actions on them. Conversely, little is known of the possible interactions between the kynurenine pathway and other systems contributing to cognitive function, so the focus of this review will be limited to glutamatergic and cholinergi...

Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis

“…We have to keep in mind that altered levels of kynurenate in both models may be due to genetic variation in SJL and B6 mice; therefore, this observation needs validation. Moreover, this pathway is altered in neurodegenerative diseases (58,59). Although some of the observed metabolite changes in RR and chronic models could easily be developed as biomarkers of the disease, the key to translating metabolomics into therapeutics requires figuring out the central altered metabolic pathway(s).…”

Kynurenine pathway metabolism and the microbiota-gut-brain axis

“…In the ENS and CNS, kynurenic acid is an antagonist of NMDA, and α7 nicotinic receptors, and in the ENS is an agonist of G-protein coupled GPR35 receptor (Turski et al, 2013). In the CNS, kynurenic acid has long been viewed as potentially neuroprotective whilst quinolinic acid is primarily considered an excitotoxic NMDA receptor agonist (Stone and Darlington, 2013). Less is understood regarding the functions of kynurenic acid and quinolinic acid in the GI tract; however, both appear to be involved in immunoregulation (Keszthelyi et al, 2009).…”

“…Over recent years, the influence of kynurenine pathway metabolites on brain function and behaviour has been the focus of increasing investigation Stone and Darlington, 2013). Despite methodological difficulties in definitively linking the gut microbiota, tryptophan metabolism and behaviour, it is clear there is significant overlap in behaviours under microbial influence and those modulated by neuroactives derived from tryptophan (Berger et al, 2009;O'Mahony et al, 2015a).…”

Envolvimento Da Flora Intestinal Na Modulação De Doenças Psiquiátricas

“…Por exemplo, a ingestão de carboidratos complexos, ricos em fibras, aumenta a concentração de espécies de Firmicutes e Bacteroidetes (32)(33)(34)(35). As bactérias intestinais também são particularmente importantes para a síntese de triptofano, um aminoácido essencial para a síntese proteica e do 5-hidroxitriptano (serotonina), melatonina e metabólitos como o ácido quinurênico, ácido quinolínico e nicotinamida (36)(37)(38)(39)(40). Estudos que investigam o impacto de alterações da flora intestinal sobre o organismo -como através do uso de animais livres de germes (germ-free), tratados com antibióticos e probióticos, com infecção do trato GI ou através do transplante de fezes -sugerem que a comunicação encéfalo-intestinal é fortemente influenciada pela flora intestinal, modulando desde o funcionamento neuronal até o comportamento do indivíduo (1,(41)(42)(43).…”