Expression Of Kynurenine Aminotransferases Research Articles

Kynurenine Pathway as a New Target of Cognitive Impairment Induced by Lead Toxicity During the Lactation

The immature brain is especially vulnerable to lead (Pb2+) toxicity, which is considered an environmental neurotoxin. Pb2+ exposure during development compromises the cognitive and behavioral attributes which persist even later in adulthood, but the mechanisms involved in this effect are still unknown. On the other hand, the kynurenine pathway metabolites are modulators of different receptors and neurotransmitters related to cognition; specifically, high kynurenic acid levels has been involved with cognitive impairment, including deficits in spatial working memory and attention process. The aim of this study was to evaluate the relationship between the neurocognitive impairment induced by Pb2+ toxicity and the kynurenine pathway. The dams were divided in control group and Pb2+ group, which were given tap water or 500 ppm of lead acetate in drinking water ad libitum, respectively, from 0 to 23 postnatal day (PND). The poison was withdrawn, and tap water was given until 60 PND of the progeny. The locomotor activity in open field, redox environment, cellular function, kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) levels as well as kynurenine aminotransferase (KAT) and kynurenine monooxygenase (KMO) activities were evaluated at both 23 and 60 PND. Additionally, learning and memory through buried food location test and expression of KAT and KMO, and cellular damage were evaluated at 60 PND. Pb2+ group showed redox environment alterations, cellular dysfunction and KYNA and 3-HK levels increased. No changes were observed in KAT activity. KMO activity increased at 23 PND and decreased at 60 PND. No changes in KAT and KMO expression in control and Pb2+ group were observed, however the number of positive cells expressing KMO and KAT increased in relation to control, which correlated with the loss of neuronal population. Cognitive impairment was observed in Pb2+ group which was correlated with KYNA levels. These results suggest that the increase in KYNA levels could be a mechanism by which Pb2+ induces cognitive impairment in adult mice, hence the modulation of kynurenine pathway represents a potential target to improve behavioural alterations produced by this environmental toxin.

Kynurenine aminotransferase isoforms display fiber-type specific expression in young and old human skeletal muscle.

Conversion of kynurenine (KYN) to kynurenic acid (KYNA) is the main pathway for free tryptophan degradation in skeletal muscle and has emerged as an important mechanism of how exercise is linked to promotion of mental health. Metabolism of KYN to KYNA mainly depends on the expression of kynurenine aminotransferases (KATs) that is under control of the mitochondria biogenesis regulator PGC-1α. We therefore hypothesized that expression of KATs would vary between muscle fibers that differ in mitochondrial content, i.e. oxidative type I vs more glycolytic type II muscle fibers. Moreover, we tested the hypothesis that KAT expression differs with age. Single muscle fibers were isolated from biopsies taken from the vastus lateralis muscle in young and old healthy subjects. In young and old subjects the abundance of KAT I, KAT III and KAT IV was greater in Type I than Type II fibers without age-dependent difference in the KAT isoform expressions. The link to mitochondrial content was further seen as the expression of KAT IV correlated to mitochondrial cytochrome c oxidase IV (COX IV) abundance in both fiber types. In conclusion, we describe for the first time the expression pattern of KAT isoforms with respect to specific fiber types and age in human skeletal muscle.

Expression of kynurenine aminotransferase I as a prognostic factor in the context of the occurrence of neurological symptoms during chemotherapy.

e22081Background: Neurological symptoms in the course as well as after completed chemotherapy are one of the most frequently reported complications affecting the quality of life of patients. Method...

Central Nervous System Infection with Borna Disease Virus Causes Kynurenine Pathway Dysregulation and Neurotoxic Quinolinic Acid Production.

ABSTRACTCentral nervous system infection of neonatal and adult rats with Borna disease virus (BDV) results in neuronal destruction and behavioral abnormalities with differential immune-mediated involvement. Neuroactive metabolites generated from the kynurenine pathway of tryptophan degradation have been implicated in several human neurodegenerative disorders. Here, we report that brain expression of key enzymes in the kynurenine pathway are significantly, but differentially, altered in neonatal and adult rats with BDV infection. Gene expression analysis of rat brains following neonatal infection showed increased expression of kynurenine amino transferase II (KATII) and kynurenine-3-monooxygenase (KMO) enzymes. Additionally, indoleamine 2,3-dioxygenase (IDO) expression was only modestly increased in a brain region- and time-dependent manner in neonatally infected rats; however, its expression was highly increased in adult infected rats. The most dramatic impact on gene expression was seen for KMO, whose activity promotes the production of neurotoxic quinolinic acid. KMO expression was persistently elevated in brain regions of both newborn and adult BDV-infected rats, with increases reaching up to 86-fold. KMO protein levels were increased in neonatally infected rats and colocalized with neurons, the primary target cells of BDV infection. Furthermore, quinolinic acid was elevated in neonatally infected rat brains. We further demonstrate increased expression of KATII and KMO, but not IDO, in vitro in BDV-infected C6 astroglioma cells. Our results suggest that BDV directly impacts the kynurenine pathway, an effect that may be exacerbated by inflammatory responses in immunocompetent hosts. Thus, experimental models of BDV infection may provide new tools for discriminating virus-mediated from immune-mediated impacts on the kynurenine pathway and their relative contribution to neurodegeneration.IMPORTANCE BDV causes persistent, noncytopathic infection in vitro yet still elicits widespread neurodegeneration of infected neurons in both immunoincompetent and immunocompetent hosts. Here, we show that BDV infection induces expression of key enzymes of the kynurenine pathway in brains of newborn and adult infected rats and cultured astroglioma cells, shunting tryptophan degradation toward the production of neurotoxic quinolinic acid. Thus, our findings newly implicate this metabolic pathway in BDV-induced neurodegeneration. Given the importance of the kynurenine pathway in a wide range of human infections and neurodegenerative and neuropsychiatric disorders, animal models of BDV infection may serve as important tools for contrasting direct viral and indirect antiviral immune-mediated impacts on kynurenine pathway dysregulation and the ensuing neurodevelopmental and neuropathological consequences.

MP80-02 EFFECTS OF ALPHA-1A/D ADRENOCEPTOR ANTAGONIST ON BLADDER OVERACTIVITY AND REMODELING IN RATS WITH SPINAL CORD INJURY

INTRODUCTION AND OBJECTIVES: Detrusor overactivity threatens the renal function of patients with spinal cord injury. Suppressing N-methyl-D-aspartate receptors is known to improve detrusor overactivity in rats with spinal cord injury, whereas kynurenic acid, the endogenous antagonist of N-methyl-D-aspartate receptors, is irreversibly synthesized by kynurenine aminotransferases. METHODS: In this study, we evaluated if replication-defective herpes simplex virus vectors mediated gene transfer of human kynurenine aminotransferase II could treat detrusor overactivity by injecting the vectors into the rat bladder wall at one week after spinal cord injury. At three weeks after injection, we evaluated the cystometry and the gene expression of kynurenine aminotransferase II in L6-S1 dorsal root ganglia. RESULTS: The results showed the vectors are transported to L6-S1 dorsal root ganglia and up-regulate the expression of kynurenine aminotransferase II, improve detrusor overactivity and voiding efficiency. We also proved N-methyl-D-aspartate receptors were blocked by the kynurenic acid in the extracellular solution or the vector-mediated gene transfer of kynurenine aminotransferase II in cultured rat neurons of L6-S1 dorsal root ganglia by whole-cell patch clamp to explore the mechanisms of gene therapy. CONCLUSIONS: Therefore, replication-defective herpes simplex virus vectors mediated kynurenine aminotransferase II inhibits detrusor overactivity in spinal cord injured rats, possibly through suppressing N-methyl-D-aspartate receptors in bladder afferent pathways.

Herpes simplex virus vector-mediated gene transfer of kynurenine aminotransferase improves detrusor overactivity in spinal cord-injured rats

Detrusor overactivity threatens the renal function of patients with spinal cord injury. Suppressing N-methyl-D-aspartate receptors is known to improve detrusor overactivity in rats with spinal cord injury, whereas kynurenic acid, the endogenous antagonist of N-methyl-D-aspartate receptors, is irreversibly synthesized by kynurenine aminotransferases (KATs). In this study, we investigated whether replication-defective herpes simplex virus vector-mediated gene transfer of human KAT II could treat detrusor overactivity by injecting the vectors into the rat bladder wall 1 week after spinal cord injury. Three weeks after injection, we evaluated the cystometry and gene expression of KAT II in L6-S1 dorsal root ganglia. The results showed that the vectors are transported to L6-S1 dorsal root ganglia and upregulate the expression of KAT II, and that they also improve the detrusor overactivity and voiding efficiency. We also proved that N-methyl-D-aspartate receptors were blocked by kynurenic acid in the extracellular solution or the vector-mediated gene transfer of KAT II in cultured rat neurons of L6-S1 dorsal root ganglia by whole-cell patch clamp to explore the mechanisms of gene therapy. Therefore, replication-defective herpes simplex virus vector-mediated KAT II inhibits detrusor overactivity in spinal cord-injured rats, possibly by suppressing N-methyl-D-aspartate receptors in bladder afferent pathways.

109. Enhanced kynurenic acid levels and cytokine-induced production of 3-hydroxykynurenine in fibroblasts from bipolar or schizophrenic patients

Recent studies suggest that cytokine-related disturbances of kynurenine metabolism are involved in the pathogenesis of schizophrenia and bipolar disorder. Here, we examined the production of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK) and the expression of kynurenine pathway enzymes under basal conditions and in the presence of pro-inflammatory cytokines in fibroblast cultures from patients with schizophrenia or bipolar disorder. Higher baseline production of KYNA and 3-HK was demonstrated in fibroblasts obtained from patients as compared with control subjects. Following exposure to interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)1-beta, IL6, or combinations, 3-HK levels, but not KYNA, increased in the fibroblast cultures. After treatments with cytokines the mRNA expression of kynurenine aminotransferase (KAT) enzymes were decreased and kynurenase (KYNU) increased, kynurenine-3-monooxygenase (KMO) levels were not affected. Interaction analyses showed that cells from patients with schizophrenia or bipolar disorder respond differently to pro-inflammatory cytokines in terms of L-kynurenine metabolism as compared to control individuals. Potential associations with two polymorphisms in the KMO allele were also investigated. The single nucleotide polymorphisms (SNPs) rs1053230 and rs2275163 both had effects on KYNA levels but these SNPs did not explain the case-control differences in KYNA or 3-HK levels. In conclusion, our results provide evidence that the kynurenine pathway is abnormally affected by cytokine exposure in fibroblast cultures obtained from patients with schizophrenia or bipolar disorder.

The l‐kynurenine–probenecid combination reduces neuropathic pain in rats

l-Kynurenine has antinociceptive effects in acute and inflammatory pain. This study determined the effect of l-kynurenine and its metabolite (kynurenic acid) on rats subjected to neuropathic pain. L5/L6 spinal nerve ligation induced tactile allodynia as measured with von Frey filaments using the up-down method. High-performance liquid chromatography and Western blot analysis determined kynurenic acid levels and expression of kynurenine amino transferase II (KAT II), respectively. l-Kynurenine (50-200 mg/kg, i.p.) or probenecid (100 mg/kg, i.p.) did not affect allodynia in neuropathic rats. In contrast, l-kynurenine (50-200 mg/kg, i.p.) in combination with probenecid (100 mg/kg, i.p.), an inhibitor of organic anion transport, reversed allodynia. Furthermore, intrathecal kynurenic acid (1-30 μg) reversed allodynia. Probenecid (100 mg/kg, i.p.) supplementation enhanced the maximal antiallodynic effect of intrathecal kynurenic acid (10 μg). Only the combined administration of l-kynurenine (200 mg/kg)/probenecid (100 mg/kg) increased the kynurenic acid concentration in cerebrospinal fluid. KAT II is expressed in dorsal root ganglia and dorsal spinal cord. KAT II expression was unchanged by the spinal nerve ligation or l-kynurenine/probenecid combination. The kynurenine/probenecid combination did not affect motor activity. l-Kynurenine produces its antiallodynic effect in the central nervous system through kynurenic acid. This effect may result from blockade of N-methyl-d-aspartate receptors. KAT II is expressed in dorsal root ganglion and dorsal spinal cord. Combined l-kynurenine and probenecid therapy has the potential to reduce neuropathic pain in humans.

Expression of kynurenine aminotransferase in the subplate of the rat and its possible role in the regulation of programmed cell death.

The neurons of the transient subplate zone, considered important for the prenatal development of the cerebral cortex, were shown here to express kynurenine aminotransferase (KAT)-I from embryonic day (E) 16 until postnatal day (P) 7 in the rat. No other cells of brain tissue exerted KAT-I immunoreactivity during this period. From P3 on, the neurons of the subplate gave rise to KAT-I immunoreactive, varicose axons, which entered the thalamus and terminated around thalamic nerve cells that are devoid of KAT-I immunoreactivity. Other subplate markers displayed a different expression pattern during development. Thus, subplate neurons displayed parvalbumin (PV) immuno-reactivity from E16 to P10 and an intense NPY immunoreaction from P7 to P1. They also exhibited nitric oxide synthase immunoreactivity from E16 to P10, whereas on the surface of the subplate neurons, the alpha7 subunit of the nicotinic acetylcholine receptor (nAChR) was present from P1 to P10. The cells of Cajal-Retzius were nAChR-immunoreactive during this period. Between P1 and P7, the perikarya of subplate neurons also showed an intense immuno-reaction with the N-methyl-D-aspartate (NMDA) receptor subtype R2A. After the first postnatal week, many of the KAT-I positive subplate neurons display a gradual decrease of immunoreactivity and undergo programmed cell death. Since KAT-I persists in the subplate through the period E16-P7, we conclude that KAT-I is a useful and reliable subplate marker in the rat. Since it is assumed that migration of nerve cells is regulated by NMDA receptors, and since kynurenic acid--the only naturally occurring NMDA receptor antagonist--is synthesized by KAT, we suggest that a temporary breakdown of the delicate equilibrium between NMDA and KAT might induce abnormal neuronal migration, giving rise to developmental abnormalities.