Kynurenic Acid Abstracts 1

© 2011

Elevations of endogenous kynurenic acid produce spatial working memory deficits

            (Chess, Simoni et al. 2007) Download

Kynurenic acid (KYNA) is a tryptophan metabolite that is synthesized and released by astrocytes and acts as a competitive antagonist of the glycine site of N-methyl-D-aspartate receptors at high concentrations and as a noncompetitive antagonist of the alpha7-nicotinic acetylcholine receptor at low concentrations. The discovery of increased cortical KYNA levels in schizophrenia prompted the hypothesis that elevated KYNA concentration may underlie the working memory dysfunction observed in this population that has been attributed to altered glutamatergic and/or cholinergic transmission. The present study investigated the effect of elevated endogenous KYNA on spatial working memory function in rats. Increased KYNA levels were achieved with intraperitoneal administration of kynurenine (100 mg/kg), the precursor of KYNA synthesis. Rats were treated with either kynurenine or a vehicle solution prior to testing in a radial arm maze task at various delays. Elevations of endogenous KYNA resulted in increased errors in the radial arm maze. In separate experiments, assessment of locomotor activity in an open field and latency to retrieve food reward from one of the maze arms ruled out the possibility that deficits in the maze were attributable to altered locomotor activity or motivation to consume food. These results provide evidence that increased KYNA levels produce spatial working memory deficits and are among the first to demonstrate the influence of glia-derived molecules on cognitive function. The implications for psychopathological conditions such as schizophrenia are discussed.

The kynurenic acid hypothesis of schizophrenia

            (Erhardt, Schwieler et al. 2007) Download

In recent years progress in the field of schizophrenia research has led to the suggestion that dopamine only plays an intermediary role in the pathophysiology of the disease and that the main abnormalities lie elsewhere. In particular, deficits in brain glutamatergic systems are suggested to play a prominent role in the pathophysiology of the disease. Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl-D-aspartate-receptor. Mounting evidence indicates that the compound is significantly involved in basal neurophysiological processes in the brain. Thus, pharmacologically elevated levels of kynurenic acid, in similarity to systemic administration of phencyclidine or ketamine, were associated with increased firing rate and burst firing activity of midbrain dopamine neurons, indicating per se that elevated levels of brain kynurenic acid is associated with psychotomimetic effects. Indeed, cerebrospinal fluid level of kynurenic acid was elevated in schizophrenic patients as compared to healthy controls. The present paper also describes a prostaglandin-mediated regulation of kynurenic acid formation as well as a relationship between brain kynurenic acid concentration and the excitatory responses of ventral tegmental area dopamine neurons by clozapine and nicotine. Our results suggest that kynurenic acid contributes to the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency in glutamatergic function in this disease.

Targeting the kynurenine pathway as a potential strategy to prevent and treat Alzheimer's disease

            (Gong, Li et al. 2011) Download

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly accounting for the vast majority of dementia. Recently, many studies have implicated the role of inflammatory response, especially neuroinflammatory response in the development and progression of AD. However, the underlying mechanism of how inflammatory response induces AD is unknown. Kynurenine pathway is a major route of the amino acid tryptophan catabolism, resulting in the production of nicotine adenine dinucleotide and other neuroactive intermediates: quinolinic acid (QA) and kynurenic acid (KA). QA exerts different toxic effects, including over-activation of N-methyl-d-aspartate (NMDA) receptor and excitotoxicity, synaptic dysfunction and neuronal death. On the other hand, KA is identified as the only endogenous NMDA receptor antagonist and could modulate neurotoxic effects of QA. We hypothesize that an activated kynurenine pathway induced by inflammatory cytokines would generate more neurotoxic metabolites, which could be closely related to the pathogenesis of AD in elderly patients. Moreover, some measures, which facilitate KA synthesis and reduce the formation of QA, may emerge as a new therapeutic strategy against AD.

Cysteine and keto acids modulate mosquito kynurenine aminotransferase catalyzed kynurenic acid production

            (Han and Li 2004) Download

Kynurenine aminotransferase (KAT) catalyzes the formation of kynurenic acid (KYNA), the natural antagonist of ionotropic glutamate receptors. This study tests potential substrates and assesses the effects of amino acids and keto acids on the activity of mosquito KAT. Various keto acids, when simultaneously present in the same reaction mixture, display a combined effect on KAT catalyzed KYNA production. Moreover, methionine and glutamine show inhibitory effects on KAT activity, while cysteine functions as either an antagonist or an inhibitor depending on the concentration. Therefore, the overall level of keto acids and cysteine might modulate the KYNA synthesis. Results from this study will be useful in the study of KAT regulation in other animals.

L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II

            (Kocki, Luchowski et al. 2003) Download

In the present study the effect of endogenous sulphur-containing amino acids, L-cysteine sulphinate, L-cysteate, L-homocysteine sulphinate and L-homocysteate, on the production of glutamate receptor antagonist, kynurenic acid (KYNA), was evaluated. The experiments comprised the measurements of (a). KYNA synthesis in rat cortical slices and (b). the activity of KYNA biosynthetic enzymes, kynurenine aminotransferases (KATs). All studied compounds reduced KYNA production and inhibited the activity of KAT I and/or KAT II, thus acting most probably intracellularly. L-Cysteine sulphinate in very low, micromolar concentrations selectively affected the activity of KAT II, the enzyme catalyzing approximately 75% of KYNA synthesis in the brain. L-Cysteine sulphinate potency was higher than other studied sulphur-containing amino acids, than L-aspartate, L-glutamate, or any other known KAT II inhibitor. Thus, L-cysteine sulphinate might act as a modulator of KYNA formation in the brain.

Urinary excretory ratio of anthranilic acid/kynurenic acid as an index of the tolerable amount of tryptophan

            (Okuno, Fukuwatari et al. 2008) Download

Some people may take excessive tryptophan as a supplement in the expectation that the tryptophan metabolite, melatonine, will help to induce sufficient sleep. We investigated the basis for a useful index to assess the risk of a tryptophan excess. Young rats were fed on a 20% casein diet with 0, 0.5, 1.0, 2.0 or 5.0% added tryptophan for 30 d the apparent toxicity and growth retardation was observed in the 5.0% tryptophan-added group. Metabolites of the Tryptophan-nicotinamide pathway and such intermediates as kynurenic acid (KA), anthranilic acid (AnA), xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid in 24-h urine increased in a dose-dependent manner. Of those metabolites and intermediates, the urinary excretion of KA progressively increased, and that of AnA dramatically increased in the 2.0 and 5.0% tryptophan-added groups. The urinary excretory ratio of AnA/KA was a high value for both the groups. These results suggest that the urinary ratio of AnA/KA could be a useful index to monitoran excessive tryptophan intake.

Targeting the kynurenine pathway-related alterations in Alzheimer's disease: a future therapeutic strategy

            (Plangar, Zadori et al. 2011) Download

Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as a main feature. Despite decades of thorough research in the field of AD, the pathomechanism is still not fully understood. The development of novel experimental models can help us in the discovery of both genetic and non-genetic components of disease pathogenesis. As currently available therapies in AD can provide merely moderate or only temporary symptomatic relief, there is a great demand for the development of new drugs with higher therapeutic potential. Some of the candidates would be those targeting the kynurenine pathway, the neuroactive metabolites of which are surely involved in both neurodegeneration and neuroprotection, mainly in relation with glutamate excitotoxicity and oxidative stress. Both analogs of the neuroprotective kynurenic acid and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. However, there is a great need for new strategies to improve efficacy, transport across the blood-brain barrier and bioavailability, naturally with simultaneous minimization of the adverse side-effects.

Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior

            (Potter, Elmer et al. 2010) Download

At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the alpha 7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (-71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro. These functional changes were accompanied by reduced extracellular KYNA (-66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo. Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.

Curiosity to kill the KAT (kynurenine aminotransferase): structural insights into brain kynurenic acid synthesis

            (Rossi, Schwarcz et al. 2008) Download

Kynurenine aminotransferases are pyridoxal-5'-phosphate-dependent enzymes, which catalyze the synthesis of kynurenic acid, a highly neuroactive metabolite whose impairment is associated with a number of severe brain disorders. Crystallographic studies of these enzymes from different organisms, including humans, have revealed distinctive structural traits of type I and type II kynurenine aminotransferases. A striking difference concerns domain swapping of the N-terminal regions, which play equivalent key functional roles in both an unswapped and swapped structure in type I and type II isozymes. Different conformational changes during catalysis create divergent active sites in the two isozymes and affect substrate specificity. Structural investigations indicate intriguing evolutionary relationships and pave the way for the design of isozyme-specific inhibitors, which are of interest for the treatment of catastrophic brain diseases such as Alzheimer's disease and schizophrenia.

Effects of vitamin B6 deficiency on the conversion ratio of tryptophan to niacin

            (Shibata, Mushiage et al. 1995) Download

To investigate how vitamin B6 (B6) deficiency affects the whole metabolism of tryptophan-niacin, rats were fed for 19 days with each of the following four kinds of diets; a complete 20% casein diet (control diet), the control diet without B6, the control diet without nicotinic acid, and the control diet without nicotinic acid and B6, and the urinary excretion of such tryptophan metabolites as kynurenic acid, xanthurenic acid, nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide each and the enzyme activities involved in tryptophan-niacin pathway were measured. The urinary excretion of kynurenic acid decreased while that of xanthurenic acid increased drastically in the two B6-deficient groups, when compared with the B6-containing groups. These results indicate that the rats fed with the B6-free diets were in the vitamin-deficient state. The conversion ratio was calculated from the ratio of the urinary excretion of sum of nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, to the Trp intake. The ratio was statistically lower in the B6-free diet than in the B6-containing diet under the niacin-free conditions.

Serum kynurenic acid positively correlates with cardiovascular disease risk factor, homocysteine: a study in stroke patients

            (Urbanska, Luchowski et al. 2006) Download

KYNA, an antagonist of ionotropic glutamate receptors and alpha7 nicotinic receptors, has been found as well in the brain as in the periphery. The altered metabolism of KYNA, especially its deficiency, can lead to the enhanced glutamate-mediated excitotoxicity, and was suggested to be a factor contributing to the development of neurodegeneration and seizures. Elevated serum concentration of homocysteine is considered to be an independent risk factor of atherosclerosis and is an emerging risk factor of cognitive dysfunction and stroke. In the present study, serum level of KYNA, homocysteine and other biochemical parameters were assessed in patients at early (up to 24 h after infarct) stage of stroke. Serum KYNA and homocysteine levels were similar in control (N = 26) and stroke (N = 24) groups. KYNA level correlated positively with the level of homocysteine in control and in stroke group, with p = 0.018; r = 0.462 and p = 0.027; r = 0.451, respectively. In control group, KYNA correlated positively also with age (p = 0.007; r = 0.514) and with creatinine level (p = 0.002; r = 0.581). In stroke group, serum KYNA correlated positively with creatinine (p = 0.001; r = 0.644) and with urea level (p < 0.001; r = 0.716). Homocysteine level correlated inversely with folate level in control (p = 0.01; r = -0.499) but not in stroke group (p = 0.13; r = -0.317). Serum homocysteine in stroke group correlated positively also with age (p = 0.001; r = 0.6401), and with urea level (p = 0.017; r = 0.4813). Clinical significance of the association between serum KYNA and homocysteine levels requires further investigation.

Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in Schizophrenia

            (Wonodi and Schwarcz 2010) Download

The brain concentration of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist at both the glycine coagonist site of the N-methyl-D-aspartic acid receptor (NMDAR) and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), is elevated in the prefrontal cortex (PFC) of individuals with schizophrenia. This increase may be clinically relevant because hypofunction of both the NMDAR and the alpha7nAChR are implicated in the pathophysiology, and especially in the cognitive deficits associated with the disease. In rat PFC, fluctuations in endogenous KYNA levels bidirectionally modulate extracellular levels of 3 neurotransmitters closely related to cognitive function (glutamate, dopamine, and acetylcholine). Moreover, behavioral studies in rats have demonstrated a causal link between increased cortical KYNA levels and neurocognitive deficits, including impairment in spatial working memory, contextual learning, sensory gating, and prepulse inhibition of the startle reflex. In recent human postmortem studies, impairments in gene expression and activity of kynurenine pathway enzymes were found in cortical areas of individuals with schizophrenia. Additional studies have revealed an interesting association between a sequence variant in the gene of one of these enzymes, kynurenine 3-monooxygenase, and neurocognitive deficits seen in patients. The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical kynurenine pathway metabolism for cognition enhancement in schizophrenia and beyond.

Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration

            (Zwilling, Huang et al. 2011) Download

Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.


References

Chess, A. C., M. K. Simoni, et al. (2007). "Elevations of endogenous kynurenic acid produce spatial working memory deficits." Schizophr Bull 33(3): 797-804.

Erhardt, S., L. Schwieler, et al. (2007). "The kynurenic acid hypothesis of schizophrenia." Physiol Behav 92(1-2): 203-9.

Gong, C. Y., Z. Li, et al. (2011). "Targeting the kynurenine pathway as a potential strategy to prevent and treat Alzheimer's disease." Med Hypotheses.

Han, Q. and J. Li (2004). "Cysteine and keto acids modulate mosquito kynurenine aminotransferase catalyzed kynurenic acid production." FEBS Lett 577(3): 381-5.

Kocki, T., P. Luchowski, et al. (2003). "L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II." Neurosci Lett 346(1-2): 97-100.

Okuno, A., T. Fukuwatari, et al. (2008). "Urinary excretory ratio of anthranilic acid/kynurenic acid as an index of the tolerable amount of tryptophan." Biosci Biotechnol Biochem 72(7): 1667-72.

Plangar, I., D. Zadori, et al. (2011). "Targeting the kynurenine pathway-related alterations in Alzheimer's disease: a future therapeutic strategy." J Alzheimers Dis 24 Suppl 2: 199-209.

Potter, M. C., G. I. Elmer, et al. (2010). "Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior." Neuropsychopharmacology 35(8): 1734-42.

Rossi, F., R. Schwarcz, et al. (2008). "Curiosity to kill the KAT (kynurenine aminotransferase): structural insights into brain kynurenic acid synthesis." Curr Opin Struct Biol 18(6): 748-55.

Shibata, K., M. Mushiage, et al. (1995). "Effects of vitamin B6 deficiency on the conversion ratio of tryptophan to niacin." Biosci Biotechnol Biochem 59(11): 2060-3.

Urbanska, E. M., P. Luchowski, et al. (2006). "Serum kynurenic acid positively correlates with cardiovascular disease risk factor, homocysteine: a study in stroke patients." Pharmacol Rep 58(4): 507-11.

Wonodi, I. and R. Schwarcz (2010). "Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in Schizophrenia." Schizophr Bull 36(2): 211-8.

Zwilling, D., S. Y. Huang, et al. (2011). "Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration." Cell 145(6): 863-74.