Diuresis by intravenous administration of xanthurenic acid in rats, and inhibition by probenecid.

The conjugates with sulfate and glucoside of xanthurenic acid, a tryptophan metabolite, were reported to show natriuresis. Sulfotransferase for xanthurenic acid works in the renal proximal tubule to produce the sulfate of xanthurenic acid as well as the liver, and we recently found that xanthurenic acid is a substrate of renal organic anion transporter OAT1. The purpose of this study was to examine relationship between the transport by OAT1 and diuresis related with xanthurenic acid. Drug transport experiment using Xenopus laevis oocytes represented that probenecid inhibited xanthurenic acid uptake by rat OAT1 (rOAT1). Although no diuresis was recognized by the intravenous injection of xanthurenic acid as a bolus in rats, the addition of its infusion exhibited natriuresis. Simultaneous administration of probenecid significantly decreased the urine volume and excreted amounts of sodium into urine. These findings showed the diuresis by the xanthurenic acid administration, and it was probenecid-sensitive. The rOAT1-mediated transport of xanthurenic acid might, at least in part, contribute to its diuretic effect.

Actions of Xanthurenic acid, a putative endogenous Group II metabotropic glutamate receptor agonist, on sensory transmission in the thalamus.

Xanthurenic acid (XA), a molecule arising from tryptophan metabolism by transamination of 3-hydroxykynurenine, has recently been identified as an endogenous Group II (mGlu2 and mGlu3) metabotropic glutamate (mGlu) receptor ligand in vitro. Impairments in Group II mGlu receptor expression and function have been implicated in the pathophysiology of schizophrenia, as have multiple steps in the kynurenine metabolism pathway. Therefore, we examined XA in vivo to further investigate its potential as a Group II mGlu receptor ligand using a preparation that has been previously demonstrated to efficiently reveal the action of other Group II mGlu receptor ligands in vivo. Extracellular single-neurone recordings were made in the rat ventrobasal thalamus (VB) in conjunction with iontophoresis of agonists, an antagonist and a positive allosteric modulator and/or intravenous (i.v.) injection of XA. We found the XA effect on sensory inhibition, when applied iontophoretically and i.v., was similar to that of other Group II mGlu receptor agonists in reducing inhibition evoked in the VB from the thalamic reticular nucleus upon physiological sensory stimulation. Furthermore, we postulate that XA may be the first potential endogenous allosteric agonist (termed 'endocoid') for the mGlu receptors. As the Group II receptors and kynurenine metabolism pathway have both been heavily implicated in the pathophysiology of schizophrenia, XA could play a pivotal role in antipsychotic research as this potential endocoid represents both a convergence within these two biological parameters and a novel class of Group II mGlu receptor ligand. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

[Enhancement of the convulsant action of strychnine following administration of kynurenines into the cerebral ventricles of frogs]. / Usilenie sudorozhnogo deistviia strikhnina pri vvedenii kinureninov v zheludochki mozga liagushki.

In frogs (Rana temporaria) injection of L-kynurenine, quinolinic, nicotinic and picolinic acids (10 microgram) into brain ventricles potentiated the stimulant ad convulsant effects of a subthreshold dose of strychnine. Xanthurenic and anthranilic acids were ineffective. At a dose of 100 micrograms picolinic acid produced seizures in 25% of animals, quinolinic acid and L-kynurenine motor excitement in all animals, and the action of nicotinic acid was shown by severe muscle hypotonus. The doses lower than 100 g proved inactive.

[Toxicity and tolerance of tryptophan and its metabolites]. / Sulla tossicità e tollerabilità del triptofano e di suoi metaboliti.

For the therapeutic use of tryptophan it is necessary to know its toxicity and pharmacological effects; but very few data are reported in literature on these aspects. On the other hand there are many researches on tryptophan metabolism after a load test and related side effects. From these data it appears that a tryptophan dose of 100 mg/Kg body weight per os is usually well tolerated with exception of some short and slight gastric troubles (vomit, etc.). The lack of references to repeated and long lasting administrations (chronic toxicity) and of a therapeutic index must be filled. Side effects due to a single dose of 5.OH-tryptophan, e.g. head twitches, resemble those due to serotonine. With regard to the most important metabolites of the kynurenine pathway, the available data have been obtained with kynurenine and especially with xanthurenic acid. These compounds have a low toxicity and do not appear to have important pharmacological properties. However, systematic researches are necessary before using these compounds either in load tests or for therapy in man.

Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice.

Each of six kynurenines tested (DL-kynurenine, quinolinic, 3-hydroxy-anthranilic, xanthurenic, picolinic, and nicotinic acids) injected into brain ventricles in mice in doses of 25--60 mcg produced motor excitement and/or clonic convulsions. Anthranilic acid did not produce these effects. The strongest metabolite was quinolinic acid, which was active in a dose of 1 mcg. It was also the only compound which produced motor excitement and convulsions after intraperitoneal injection (in doses of 400--600 mg/kg, i.e. 10,000--15,000 mcg per mouse). The hypothermic effect of intraventricularly-injected kynurenines was roughly similar to that of intraperitoneally-injected material at 100--1000 times higher doses. These data suggest poor penetration of kynurenines formed in the liver into the brain, and the possible involvement of these metabolites of tryptophan (particularly if they are formed inside the brain) in the mechanism of seizures.