Disease relevance of Kynurenate

• Kynurenic acid, a broad-spectrum antagonist at excitatory amino acid receptors, was used as treatment (300 mg/kg; 3 doses at 4-hour intervals) before and after focal cerebral ischemia in rats (n = 54) [1].
• Synaptic transmission between dorsal root ganglion and dorsal horn neurons in culture: antagonism of monosynaptic excitatory postsynaptic potentials and glutamate excitation by kynurenate [2].
• Preischemia but not 1 hour postischemia treatment with kynurenate attenuated infarction size (p less than 0.001) and improved neurological outcome (p less than 0.001) studied at 24 hours after injury [1].
• Kynurenic acid is an endogenous substance that inhibits EAA receptors and may therefore influence important physiologic and pathologic processes [3].
• Kynurenic acid, an antagonist of excitatory amino acid receptors as well as the excitotoxic effects of quinolinic acid, was also increased in the CSF of SAIDS macaques, but to a significantly lesser degree than was quinolinic acid (kynurenic acid, 1.8-fold; quinolinic acid, 15.6-fold) [4].
• Incubation of monocytes with pertussis toxin prior to use in flow experiments significantly reduced the KYNA-induced monocyte adhesion, suggesting that adhesion is triggered by a G(i)-mediated process [5].

Psychiatry related information on Kynurenate

• Increased kynurenic acid levels in Huntington's disease [6].
• Muscimol and kynurenic acid had the same effects: when compared to saline controls, freezing immobility and ultrasonic vocalizations were reduced and replaced by marked locomotor activity, and the increase in heart rate was enhanced; however, the increase in arterial blood pressure remained the same [7].
• Decreased serum and red blood cell kynurenic acid levels in Alzheimer's disease [8].
• Therefore, this study tested the hypothesis that water deprivation increases excitatory amino acid (EAA) drive of the rostral ventrolateral medulla (RVLM), by determining whether bilateral microinjection of kynurenate (Kyn; 2.7 nmol) into the RVLM decreases arterial pressure more in water-deprived than water-replete rats [9].
• This effect was observed with doses at which kynurenic acid does not affect responding in the self-stimulation test by itself [10].
• 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 [11].

High impact information on Kynurenate

• This review summarizes the mechanism of action of these various agents, the development of glutamate receptor antagonists from kynurenic acid and the range of their potential uses in neurology and psychiatry [12].
• The amphetamine-induced release of dopamine, monitored by the inhibition of oxygen consumption, was blocked by L-2-amino-4-phosphonobutyric acid and kynurenic acid [13].
• The "L-MAN" EPSPs were blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid (D-APV) as well as the broad-spectrum glutamate receptor antagonist kynurenic acid but were relatively unaffected by the non-NMDA receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) [14].
• Perfusion of 1 mM kynurenic acid (Kyn) into either the ventral tegmental area (VTA) or NAS blocked lever pressing for mPFC stimulation [15].
• Single-unit action potentials were recorded from the inferior colliculus before and after local injection of the excitatory amino acid antagonist kynurenic acid into the DNLL [16].

Chemical compound and disease context of Kynurenate

• Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid [17].
• In contrast, intrathecal injections of glutamate receptor antagonists resulted in a dose-dependent depression of the strychnine evoked hyperesthesia with the ordering of activity being MK-801, AP-5, kynurenic acid, SKF10047 and ketamine [18].
• 5. In ventilated rats, bilateral microinjection into RVL of kynurenate, but not xanthurenate, abolished resting activity and chemoreflex excitation of phrenic nerve activity, whilst in spontaneously breathing rats, kynurenate microinjection into RVL produced apnea and silenced phrenic nerves [19].
• Because kynurenic acid (KYNA) is an antagonist of NMDA receptors, we hypothesize that KYNA and its synthesizing enzyme, KAT, may play a role in the prevention of migraine attacks [20].
• The effects of treatment with indole-pyruvic acid, an endogenous metabolite of tryptophan converted into kynurenic acid in the brain, were studied in rats after transient forebrain ischemia induced by the 4-vessel occlusion procedure [21].

Biological context of Kynurenate

• 2-Amino-5-phosphonovaleric acid, kynurenic acid, and other acidic amino acid antagonists reversibly decrease the amplitudes of spontaneously occurring synaptic potentials without affecting their frequency, indicating subsynaptic blockade [22].
• The EPSP in these young embryos was unaffected by picrotoxin and strychnine, but responded to APV and kynurenate in a manner similar to that at later stages [23].
• This component was followed by a kynurenic acid (KYNA)-sensitive postsynaptic response, most likely comprised of Ca(2+)-mediated action potentials occurring at the proximal pole of the Purkinje cell dendrites and evoked by climbing fiber inputs [24].
• 4. A structural analog of XA, kynurenic acid (C10H6NO3), also activated gametogenesis but only at higher concentrations and with less effect [25].
• NTS microinjection of kynurenate (ionotropic antagonist) inhibited both the cardiac and sympathetic baroreflex gains (16 +/- 5% and 59 +/- 11% of control, respectively) [26].

Anatomical context of Kynurenate

• The results obtained in vitro with AP4, kynurenic acid, and amino acid uptake inhibitors were confirmed in vivo by bathing segments of the rat spinal cord in situ with solutions containing antagonists and uptake inhibitors [27].
• In contrast, no effect was seen in the inferior colliculus ipsilateral to the kynurenic acid injection [28].
• In such minisclices local application of either kynurenic acid or 6-cyano-7-nitroquinoxaline-2-3-dione (CNQX) to the proximal basilar dendrites abolished the synchronized discharges of electrographic seizures [29].
• The blockade of synaptic transmission by kynurenate appeared to result from a postsynaptic action on dorsal horn neurons [2].
• The release of intracerebrally synthesized kynurenic acid into the extracellular fluid (ECF), where it may act at EAA receptors, has not been established in vivo [3].

Associations of Kynurenate with other chemical compounds

• Blocking synaptic transmission with either Ca(2+)-free EGTA perfusate or kynurenic acid (an excitatory amino acid antagonist) blocked the optical signal, indicating that it resulted from postsynaptic activation of the cells and was not due to presynaptic fiber volleys or transmitter release alone [30].
• When administered to rats, m-NBA significantly increases the concentration of kynurenine and kynurenic acid in the brain as well as in blood and in the liver. m-NBA has also been shown to increase the concentration of kynurenic acid in hippocampal extracellular fluid [31].
• In three rhesus macaques (Macaca mulatta) with septicemia, both CSF and serum quinolinic acid concentrations were markedly elevated and were accompanied by increases in CSF kynurenic acid levels that were of a smaller magnitude [32].
• Quinolinate (QUIN) and kynurenate (KYNA), two endogenous neuroactive metabolites of the kynurenine pathway of tryptophan degradation, have been proposed to modulate excitotoxic neuronal death in HD [33].
• These results suggest that brain synaptic membranes treated with Triton X-100 are useful in evaluating the strychnine-insensitive and kynurenate-sensitive binding sites of glycine, which are functionally linked to N-methyl-D-aspartate- sensitive receptor channels [34].

Gene context of Kynurenate

• Targeted deletion of the kynurenine aminotransferase ii gene reveals a critical role of endogenous kynurenic acid in the regulation of synaptic transmission via alpha7 nicotinic receptors in the hippocampus [35].
• Plasma concentrations of formyl-kynurenine, kynurenine, and kynurenic acid were elevated in KO mice (but not HZ mice) relative to WT mice, further suggesting that there must be enzymes other than Afmid (possibly in the kidney) capable of metabolizing formyl-kynurenine into kynurenine [36].
• Tat-induced depolarizations and cytotoxicity were blocked by the excitatory amino acid antagonist kynurenate [37].
• The broad-spectrum EAA receptor antagonist kynurenic acid (KYN) completely abolished ASP effects on CRH and AVP release in vitro [38].
• Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons--possible involvement of endogenous kynurenic acid [39].

Analytical, diagnostic and therapeutic context of Kynurenate

• Indeed, analogues of the amino acid receptor antagonist kynurenic acid are now in, or are about to enter, clinical trials for stroke and related disorders [12].
• We studied the synthesis and release of kynurenic acid in the rat striatum using intracerebral microdialysis coupled with high performance liquid chromatography and fluorescence detection [3].
• In addition to their blockade of PGi-evoked activity, kynurenic acid and DGG exerted a similar, simultaneous blockade of the characteristic excitation of LC neurons evoked by electrical stimulation of the hindpaw [40].
• No change in MAP was observed in response to kynurenic acid microinjection into the RVLM in either group [41].
• In a microdialysis experiment in rats, 16 dose dependently increased kynurenic acid concentration in the extracellular hippocampal fluid [42].

References