Cinnabarinic acid and xanthurenic acid: Two kynurenine metabolites that interact with metabotropic glutamate receptors

Abstract

Cinnabarinic and xanthurenic acids are kynurenine metabolites generated by oxidative dimerization of 3-hydroxyanthranilic acid and transamination of 3-hydroxykynurenine, respectively. Recent evidence suggests that both compounds can affect brain function and neurotransmission and interact with metabotropic glutamate (mGlu) receptors. Cinnabarinic acid behaves as an orthosteric agonist of mGlu4 receptors, whereas some of the in vitro and in vivo effects produced by xanthurenic acid appear to be mediated by the activation of mGlu2 and mGlu3 receptors. Cinnabarinic acid could play an important role in mechanisms of neuroinflammation acting as a linking bridge between the immune system and the CNS. Xanthurenic acid has potential implications in the pathophysiology of schizophrenia and is a promising candidate as a peripheral biomarker of the disorder. The action of cinnabarinic acid and xanthurenic acid may extend beyond the regulation of mGlu receptors and may involve several diverse molecular targets, such as the aryl hydrocarbon receptor for cinnabarinic acid and vesicular glutamate transporters for xanthurenic acid. The growing interest on these two metabolites of the kynurenine pathway may unravel new aspects in the complex interaction between tryptophan metabolism and brain function, and lead to the discovery of new potential targets for the treatment of neurological and psychiatric disorders. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

Xanthurenic Acid Formation from 3-Hydroxykynurenine in the Mammalian Brain: Neurochemical Characterization and Physiological Effects

“…The present results, as well as a series of studies demonstrating the ability of XA to influence glutamatergic neurotransmission by inhibiting vesicular glutamate transport (Neale et al, 2013, Neale et al, 2014) and possibly by modulating Group II metabotropic glutamate receptors (Copeland et al, 2013, Fazio et al, 2015, Fazio et al, 2017b), provide support for the idea that endogenous XA, synthesized from 3-HK, plays a role in brain physiology. In addition to the reduction in 3-HK- or XA-induced synaptic transmission and gamma oscillations in the hippocampus shown here, previous studies in rodents had demonstrated that local perfusion of XA reduces glutamate release in the substantia nigra (Fukuyama et al, 2014), affects sensory transmission in the thalamus (Copeland et al, 2013), and decreases the amplitude of field excitatory postsynaptic potentials in the hippocampus and cerebral cortex (Neale et al, 2014).…”

Mitochondria, Oxidative Stress and the Kynurenine System, with a Focus on Ageing and Neuroprotection

“…Cinnabarinic acid is thought to play a major role in neuroinflammation and acts as a link between the immune system and the central nervous system. XA has potential implications in the pathophysiology of schizophrenia [ 86 ].…”

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

“…There are attempts to use KYNA analogues to treat neurodegenerative disorders [72,76,176,177,178,179,180]. The structural KYNA analogue quinoline carboxamide (laquinimod) slowed the progression of MS and the annual relapse rate in a phase 3 study [71].…”