Xanthurenic acid: A role in brain intercellular signaling

Xanthurenic acid (XA) raises a growing multidisciplinary interest based upon its oxidizing properties, its ability to complex certain metal ions, and its detoxifier capacity of 3-hydroxykynurenine (3-HK), its brain precursor. However, little is still known about the role and mechanisms of action of XA in the central nervous system (CNS). Therefore, many research groups have recently investigated XA and its central functions extensively. The present paper critically reviews and discusses all major data related to XA properties and neuronal activities to contribute to the improvement of the current knowledge on XA's central roles and mechanisms of action. In particular, our data showed the existence of a specific G-protein-coupled receptor (GPCR) for XA localized exclusively in brain neurons exhibiting Ca2+-dependent dendritic release and specific electrophysiological responses. XA properties and central activities suggest a role for this compound in brain intercellular signaling. Indeed, XA stimulates cerebral dopamine (DA) release contrary to its structural analog, kynurenic acid (KYNA). Thus, KYNA/XA ratio could be fundamental in the regulation of brain glutamate and DA release. Cerebral XA may also represent an homeostatic signal between the periphery and several brain regions where XA accumulates easily after peripheral administration. Therefore, XA status in certain psychoses or neurodegenerative diseases seems to be reinforced by its brain-specific properties in balance with its formation and peripheral inputs. The two compounds are structural analogues and the level of XA is regulated by the activity of KMO producing the precursor 3-hydroxykynurenine. XA accumulates in neurons, while KYNA is present in astrocytes. Unknown factors regulate the release of each of these compounds. XA stimulates glutamate metabotropic receptor and vesicular transport, but additionally, it presents agonistic effect on specific GPCR for which a specific synthetic antagonist has been described. KYNA is thought to be released from astrocyte and binds to NMDA and cholinergic receptors. TH neurons producing DA seem to be a target for both compounds: KYNA reduces DA release, while XA increases it. The balance between the two compounds participates in the control of DA release in several cerebral regions. This dopaminergic mechanism, controlled via the activity of some metabolites of the kynurenine pathway, could play a role in some diseases, particularly schizophrenia or neurodegenerative processes. DA, dopamine; GPCR, G-protein-coupled receptor; KAT, kynurenine aminotransferase; KMO, kynurenine monooxygenase; KYNA, kynurenine; TH, tyrosine hydroxylase; Tryp, tryptophane, XA, xanthurenic acid.image