Kynurenines in the CNS: from endogenous obscurity to therapeutic importance

Stone, T.W.

doi:10.1016/s0301-0082(00)00032-0

Cited by 277 publications

(204 citation statements)

References 317 publications

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“…Based on these conclusions, it is unlikely that the increase in T/C ratio observed in KYN+PBCD-treated rats is attributable to KYNA-induced blockade of the glycine B receptor. It is also unlikely that KYNA's disruptive effects on auditory gating are related to its ability to compete with glutamate at the NMDA recognition site or AMPA/kainate receptors since the brain levels of KYNA attained in KYN+PBCD-treated rats (B20 mM) remained 1-2 orders of magnitude below its IC 50 values at these sites (Stone, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Neuroactive metabolites of tryptophan along the kynurenine pathway have been implicated in a variety of neurological and psychiatric diseases including Huntington's and Parkinson's disease, stroke, epilepsy and schizophrenia (Stone, 2001;Schwarcz and Pellicciari, 2002). In the brain, both QUIN and KYNA are derived from KYN, which enters the CNS via the same carrier system as tryptophan (Fukui et al, 1991;Guidetti et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, these cells serve as the primary source of QUIN and KYNA in the brain (Guillemin et al, 2001;Schwarcz and Pellicciari, 2002). To date, most hypotheses involving the kynurenine pathway have emphasized the potential pathophysiological significance of elevations in brain QUIN, a potent excitotoxin and NMDA receptor agonist (Stone, 2001). …”

Section: Discussionmentioning

confidence: 99%

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Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

Neuropsychopharmacol

127

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Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine B /NMDA and a-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine B site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine B receptor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

Neuropsychopharmacol

127

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“…The improved neuroprotective therapeutic profile of glycine B full antagonists could be due to their ability to reveal glycinesensitive desensitization 381 . Kynurenic acid is an endogenous glycine B antagonist but it seems unlikely that concentrations are sufficient to i n t e r a c t w i t h N M D A r e c e p t o r s u n d e r n o r m a l conditions 237,382 . However, concentrations are raised under certain pathological conditions 237,382 and interactions with other receptors such as α7 neuronal nicotinic have been reported at lower concentrations 237,382,383 .…”

Section: ) Glycinementioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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“…Such a pathway could modify the activation of NMDA receptors in response to external agents or events. One endogenous pathway which is known to include compounds capable of modifying NMDA receptor function is the kynurenine pathway of tryptophan oxidative metabolism (Stone, 1993(Stone, , 2001Stone and Darlington, 2002). This pathway -the major route of tryptophan metabolism -includes quinolinic acid, an agonist at NMDARs (Stone and Perkins, 1981) and kynurenic acid Protein expression was examined in embryos 5 and 24 hours after the administration of Ro61-8048 and in the brains of offspring at 21 days of age (P21), the time of weaning.…”

Section: Introductionmentioning

confidence: 99%

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

et al. 2013

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Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors.Rats were treated in late gestation with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5h of drug administration there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired-pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased.Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system. 3

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Kynurenines in the CNS: from endogenous obscurity to therapeutic importance

Cited by 277 publications

References 317 publications

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

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