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Kynurenic Acid (kynurenic + acid)
Selected AbstractsAstrocyte-derived kynurenic acid modulates basal and evoked cortical acetylcholine releaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2009A. Zmarowski Abstract We tested the hypothesis that fluctuations in the levels of kynurenic acid (KYNA), an endogenous antagonist of the ,7 nicotinic acetylcholine (ACh) receptor, modulate extracellular ACh levels in the medial prefrontal cortex in rats. Decreases in cortical KYNA levels were achieved by local perfusion of S -ESBA, a selective inhibitor of the astrocytic enzyme kynurenine aminotransferase II (KAT II), which catalyses the formation of KYNA from its precursor l -kynurenine. At 5 mm, S -ESBA caused a 30% reduction in extracellular KYNA levels, which was accompanied by a two-threefold increase in basal cortical ACh levels. Co-perfusion of KYNA in the endogenous range (100 nm), which by itself tended to reduce basal ACh levels, blocked the ability of S -ESBA to raise extracellular ACh levels. KYNA perfusion (100 nm) also prevented the evoked ACh release caused by d -amphetamine (2.0 mg/kg). This effect was duplicated by the systemic administration of kynurenine (50 mg/kg), which resulted in a significant increase in cortical KYNA formation. Jointly, these data indicate that astrocytes, by producing and releasing KYNA, have the ability to modulate cortical cholinergic neurotransmission under both basal and stimulated conditions. As cortical KYNA levels are elevated in individuals with schizophrenia, and in light of the established role of cortical ACh in executive functions, our findings suggest that drugs capable of attenuating the production of KYNA may be of benefit in the treatment of cognitive deficits in schizophrenia. [source] Altered kynurenine metabolism correlates with infarct volume in strokeEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2007L. G. Darlington Abstract Inflammation and oxidative stress are involved in brain damage following stroke, and tryptophan oxidation along the kynurenine pathway contributes to the modulation of oxidative stress partly via the glutamate receptor agonist quinolinic acid and antagonist kynurenic acid, and via redox-active compounds such as 3-hydroxyanthranilic acid. We have confirmed that following a stroke, patients show early elevations of plasma neopterin, S100B and peroxidation markers, the latter two correlating with infarct volume assessed from computed tomography (CT) scans, and being consistent with a rapid inflammatory response. We now report that the kynurenine pathway of tryptophan metabolism was also activated, with an increased kynurenine : tryptophan ratio, but with a highly significant decrease in the ratio of 3-hydroxyanthranilic acid : anthranilic acid, which was strongly correlated with infarct volume. Levels of kynurenic acid were significantly raised in patients who died within 21 days compared with those who survived. The results suggest that increased tryptophan catabolism is initiated before or immediately after a stroke, and is related to the inflammatory response and oxidative stress, with a major change in 3-hydroxyanthranilic acid levels. Together with previous evidence that inhibiting the kynurenine pathway reduces brain damage in animal models of stroke and cerebral inflammation, and that increased kynurenine metabolism directly promotes oxidative stress, it is proposed that oxidative tryptophan metabolism may contribute to the oxidative stress and brain damage following stroke. Some form of anti-inflammatory intervention between the rise of S100B and the activation of microglia, including inhibition of the kynurenine pathway, may be valuable in modifying patient morbidity and mortality. [source] Prokineticin 2 depolarizes paraventricular nucleus magnocellular and parvocellular neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2007Erik A. Yuill Abstract Blind whole-cell patch-clamp techniques were used to examine the effects of prokineticin 2 (PK2) on the excitability of magnocellular (MNC), parvocellular preautonomic (PA), and parvocellular neuroendocrine (NE) neurons within the hypothalamic paraventricular nucleus (PVN) of the rat. The majority of MNC neurons (76%) depolarized in response to 10 nm PK2, effects that were eliminated in the presence of tetrodotoxin (TTX). PK2 also caused an increase in excitatory postsynaptic potential (EPSP) frequency, a finding that was confirmed by voltage clamp recordings demonstrating increases in excitatory postsynaptic current (EPSC) frequency. The depolarizing effects of PK2 on MNC neurons were also abolished by kynurenic acid (KA), supporting the conclusion that the effects of PK2 are mediated by the activation of glutamate interneurons within the hypothalamic slice. PA (68%) and NE (67%) parvocellular neurons also depolarized in response to 10 nm PK2. However, in contrast to MNC neurons, these effects were maintained in TTX, indicating that PK2 directly affects PA and NE neurons. PK2-induced depolarizations observed in PA and NE neurons were found to be concentration-related and receptor mediated, as experiments performed in the presence of A1MPK1 (a PK2 receptor antagonist) abolished the effects of PK2 on these subpopulations of neurons. The depolarizing effects of PK2 on PA and NE neurons were also shown to be abolished by PD 98059 (a mitogen activated protein kinase (MAPK) inhibitor) suggesting that PK2 depolarizes PVN parvocellular neurons through a MAPK signalling mechanism. In combination, these studies have identified separate cellular mechanisms through which PK2 influences the excitability of different subpopulations of PVN neurons. [source] Respiratory responses evoked by blockades of ionotropic glutamate receptors within the Bötzinger complex and the pre-Bötzinger complex of the rabbitEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2005Donatella Mutolo Abstract The respiratory role of excitatory amino acid (EAA) receptors within the Bötzinger complex (BötC) and the pre-Bötzinger complex (pre-BötC) was investigated in ,-chloralose,urethane anaesthetized, vagotomized, paralysed and artificially ventilated rabbits by using bilateral microinjections (30,50 nL) of EAA receptor antagonists. Blockade of both N -methyl- d -aspartic acid (NMDA) and non-NMDA receptors by 50 mm kynurenic acid (KYN) within the BötC induced a pattern of breathing characterized by low-amplitude, high-frequency irregular oscillations superimposed on tonic phrenic activity and successively the disappearance of respiratory rhythmicity in the presence of intense tonic inspiratory discharges (tonic apnea). KYN microinjections into the pre-BötC caused similar respiratory responses that, however, never led to tonic apnea. Blockade of NMDA receptors by D(,)-2-amino-5-phosphonopentanoic acid (D-AP5; 1, 10 and 20 mm) within the BötC induced increases in respiratory frequency and decreases in peak phrenic amplitude; the highest concentrations caused tonic apnea insensitive to chemical stimuli. Blockade of non-NMDA receptors by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1, 10 and 20 mm) within the BötC produced only less pronounced increases in respiratory frequency. Responses to D-AP5 in the pre-BötC were similar, although less pronounced than those elicited in the BötC and never characterized by tonic apnea. In the same region, CNQX provoked increases in respiratory frequency similar to those elicited in the BötC, associated with slight reductions in peak phrenic activity. The results show that EAA receptors within the investigated medullary subregions mediate a potent control on both the intensity and frequency of inspiratory activity, with a major role played by NMDA receptors. [source] Cross-sample entropy statistic as a measure of complexity and regularity of renal sympathetic nerve activity in the ratEXPERIMENTAL PHYSIOLOGY, Issue 4 2007Tao Zhang In this study, we employed both power spectral analysis and cross-sample entropy measurement to assess the relationship between two time series, arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA), during a mild haemorrhage in anaesthetized Wistar rats. Removal of 1 ml of venous blood decreased BP (by 7.1 ± 0.7 mmHg) and increased RSNA (by 25.9 ± 2.4%). During these changes, the power in the RSNA signal at heart rate frequency was reduced but coherence between the spectra at heart rate frequency in RSNA and ABP remained unchanged. Cross-sample entropy was significantly increased (by 10%) by haemorrhage, revealing that there was greater asynchrony between ABP and the RSNA time series. Intrathecal administration of the glutamate receptor antagonist kynurenic acid (2 mm) almost halved (P < 0.01) the reflex increase in RSNA. Also during kynurenic acid block, haemorrhage failed to change total power, power at heart rate frequency, coherence at heart rate frequency, or the cross-sample entropy measurements. We conclude that the increase in asynchrony between ABP and RSNA during the reflex increase in RSNA was a consequence of an increase in synaptic input to the spinal renal neurones. The data show that the cross-sample entropy calculations can characterize the non-linearities of neural mechanisms underlying cardiovascular control and have a potential to reveal how some aspects of homeostatic regulation of kidney function is achieved by the autonomic nervous system. [source] Autism-like behavioral phenotypes in BTBR T+tf/J miceGENES, BRAIN AND BEHAVIOR, Issue 2 2008H. G. McFarlane Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms. [source] Association study between kynurenine 3-monooxygenase gene and schizophrenia in the Japanese populationGENES, BRAIN AND BEHAVIOR, Issue 4 2006N. Aoyama Several lines of evidence suggest that metabolic changes in the kynurenic acid (KYNA) pathway are related to the etiology of schizophrenia. The inhibitor of kynurenine 3-monooxygenase (KMO) is known to increase KYNA levels, and the KMO gene is located in the chromosome region associated with schizophrenia, 1q42-q44. Single-marker and haplotype analyses for 6-tag single nucleotide polymorphisms (SNPs) of KMO were performed (cases = 465, controls = 440). Significant association of rs2275163 with schizophrenia was observed by single-marker comparisons (P = 0.032) and haplotype analysis including this SNP (P = 0.0049). Significant association of rs2275163 and haplotype was not replicated using a second, independent set of samples (cases = 480, controls = 448) (P = 0.706 and P = 0.689, respectively). These results suggest that the KMO is unlikely to be related to the development of schizophrenia in Japanese. [source] Tryptophan metabolism and oxidative stress in patients with Huntington's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 3 2005N. Stoy Abstract Abnormalities in the kynurenine pathway may play a role in Huntington's disease (HD). In this study, tryptophan depletion and loading were used to investigate changes in blood kynurenine pathway metabolites, as well as markers of inflammation and oxidative stress in HD patients and healthy controls. Results showed that the kynurenine : tryptophan ratio was greater in HD than controls in the baseline state and after tryptophan depletion, indicating increased indoleamine dioxygenase activity in HD. Evidence for persistent inflammation in HD was provided by elevated baseline levels of C-reactive protein, neopterin and lipid peroxidation products compared with controls. The kynurenate : kynurenine ratio suggested lower kynurenine aminotransferase activity in patients and the higher levels of kynurenine in patients at baseline, after depletion and loading, do not result in any differences in kynurenic acid levels, providing no supportive evidence for a compensatory neuroprotective role for kynurenic acid. Quinolinic acid showed wide variations in blood levels. The lipid peroxidation data indicate a high level of oxidative stress in HD patients many years after disease onset. Levels of the free radical generators 3-hydroxykynurenine and 3-hydroxyanthranilic acid were decreased in HD patients, and hence did not appear to contribute to the oxidative stress. It is concluded that patients with HD exhibit abnormal handling of tryptophan metabolism and increased oxidative stress, and that these factors could contribute to ongoing brain dysfunction. [source] Dual effect of DL -homocysteine and S -adenosylhomocysteine on brain synthesis of the glutamate receptor antagonist, kynurenic acidJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2005E. Luchowska Abstract Increased serum level of homocysteine, a sulfur-containing amino acid, is considered a risk factor in vascular disorders and in dementias. The effect of homocysteine and metabolically related compounds on brain production of kynurenic acid (KYNA), an endogenous antagonist of glutamate ionotropic receptors, was studied. In rat cortical slices, DL -homocysteine enhanced (0.1,0.5 mM) or inhibited (concentration inducing 50% inhibition [IC50] = 6.4 [5.5,7.5] mM) KYNA production. In vivo peripheral application of DL -homocysteine (1.3 mmol/kg intraperitoneally) increased KYNA content (pmol/g tissue) from 8.47 ± 1.57 to 13.04 ± 2.86 (P < 0.01; 15 min) and 11.4 ± 1.72 (P < 0.01; 60 min) in cortex, and from 4.11 ± 1.54 to 10.02 ± 3.08 (P < 0.01; 15 min) in rat hippocampus. High concentrations of DL -homocysteine (20 mM) applied via microdialysis probe decreased KYNA levels in rabbit hippocampus; this effect was antagonized partially by an antagonist of group I metabotropic glutamate receptors, LY367385. In vitro, S -adenosylhomocysteine acted similar to but more potently than DL -homocysteine, augmenting KYNA production at 0.03,0.08 mM and reducing it at ,0.5 mM. The stimulatory effect of S -adenosylhomocysteine was abolished in the presence of the L -kynurenine uptake inhibitors L -leucine and L -phenyloalanine. Neither the N -methyl- D -aspartate (NMDA) antagonist CGS 19755 nor L -glycine influenced DL -homocysteine- and S -adenosylhomocysteine-induced changes of KYNA synthesis in vitro. DL -Homocysteine inhibited the activity of both KYNA biosynthetic enzymes, kynurenine aminotransferases (KATs) I and II, whereas S -adenosylhomocysteine reduced only the activity of KAT II. L -Methionine and L -cysteine, thiol-containing compounds metabolically related to homocysteine, acted only as weak inhibitors, reducing KYNA production in vitro and inhibiting the activity of KAT II (L -cysteine) or KAT I (L -methionine). The present data suggest that DL -homocysteine biphasically modulates KYNA synthesis. This seems to result from conversion of compound to S -adenosylhomocysteine, also acting dually on KYNA formation, and in part from the direct interaction of homocysteine with metabotropic glutamate receptors and KYNA biosynthetic enzymes. It seems probable that hyperhomocystemia-associated brain dysfunction is mediated partially by changes in brain KYNA level. © 2004 Wiley-Liss, Inc. [source] Structure elucidation and NMR assignments of two new pyrrolidinyl quinoline alkaloids from chestnut honeyMAGNETIC RESONANCE IN CHEMISTRY, Issue 5 2009Giangiacomo Beretta Abstract The complete 1H, 13C and 15N NMR spectral assignments of two new alkaloids isolated from chestnut honey and structurally related to kynurenic acid have been made using 1-D and 2-D NMR techniques, including COSY, HMQC and HMBC experiments. The new compounds have been identified as 3-(2,-pyrrolidinyl)-kynurenic acid and its ,-lactam derivative. Copyright © 2009 John Wiley & Sons, Ltd. [source] KYNURENINE PATHWAY METABOLISM IN PATIENTS WITH OSTEOPOROSIS AFTER 2 YEARS OF DRUG TREATMENTCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2006Caroline M Forrest ABSTRACT 1Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate. [source] | ||||||||||