Kynurenine Pathway of Tryptophan Metabolism in Neuropsychiatric Disorders: Pathophysiologic and Therapeutic Considerations

Abstract

Under physiological conditions 95% of the ingested essential amino acid tryptophan is metabolized by the kynurenine pathway (KP) to yield the ubiquitous co-enzyme nicotinamide adenine dinucleotide, fulfilling cellular energy requirements. Importantly, the intermediaries of KP exert crucial effects throughout the body, including the central nervous system. Besides, KP metabolites are implicated in diverse disease processes such as inflammation/immune disorders, endocrine/metabolic conditions, cancers and neuropsychiatric diseases. A burgeoning body of research indicates that the KP plays a pathogenic role in major psychiatric diseases like mood disorders and schizophrenia. Triggered by inflammatory processes, the balance between neurotoxic and neuroprotective branches of the KP is disturbed. In preclinical models these discrepancies result in behaviors reminiscent of depression and psychosis. In clinical samples, recent studies are discovering key kynurenine pathway abnormalities which incriminate it in the pathogenesis of the main psychiatric disorders. Harnessing this knowledge has the potential to find disease biomarkers helpful in identifying and prognosticating neuropsychiatric disorders. Concurrently, earnest research efforts directed towards manipulating the KP hold the promise of discovering novel pharmacological agents that have therapeutic value. In this manuscript, an in-depth appraisal of the extant literature is done to understand the working of KP as this applies to neuropsychiatric disorders. It is concluded that this pathway plays an overarching role in the development of major psychiatric disorders, the KP metabolites have the potential to serve as disease markers and new medications based on KP modulation can bring lasting cures for patients suffering from these intractable conditions.

Keywords: Inflammation; Kynurenic acid; Kynurenine pathway; Mood Disorders; Quinolinic acid; Schizophrenia..

Fig. 1

Tryptophan metabolism along the kynurenine pathway. Tryptophan is an essential amino acid wholly derived from the diet. It is metabolized into active molecules, namely the neurotransmitter serotonin and the hormone melatonin. However, greater than 95% of tryptophan is metabolized along the kynurenine pathway to neuroactive metabolites like quinolinic acid and kynurenic acid. Here key metabolites and enzymes of the kynurenine pathway are illustrated. Refer to the text for a full description of the role of kynurenine pathway in neuropsychiatric disorders. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan dioxygenase; KAT, kynurenine aminotransferase; ACMSD, amino-β-carboxymuconate-semialdehyde-decarboxylase; QPRT, quinolinate phosphoribosyltransferase; NAD⁺, nicotinamide adenine dinucleotide; KMO, kynurenine 3-monooxygenase; 3-HAO, 3-hydroxyanthranilic acid oxidase.

Fig. 2

Kynurenine pathway abnormalities in depression and schizophrenia. An illustration of main biochemical abnormalities in two major psychiatric disorders, i.e., depression and schizophrenia. In the brain, proinflammatory cytokines and other inflammatory mediators cause induction of indoleamine 2,3-dioxygenase and triggering of microglia with increased production of quinolinic acid which is an agonist at the N-methyl-D-aspartate receptor and also acts as an excitotoxin. This mechanism is thought to underlie the expression of the depressive phenotype during inflammatory processes. On the contrary in schizophrenia, kynurenine amino transferase, another key kynurenine pathway enzyme is expressed which increases the formation of kynurenic acid. The latter is the only known endogenous NMDAR antagonist and acting through intermediary mechanisms, indirectly increases dopaminergic neurotransmission in the mesolimbic pathway, which is the chief abnormality in schizophrenia. See also text for a full description of KP abnormalities in neuropsychiatric disorders. NMDAR, NMDA receptor; KP, kynurenine pathway; IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase.