Administration Of Kynurenic Acid Research Articles

Kynurenic Acid Acts as a Signaling Molecule Regulating Energy Expenditure and Is Closely Associated With Metabolic Diseases.

Kynurenic acid (KYNA) is an important bio-active product of tryptophan metabolism. In addition to its well-known neuroprotective effects on mental health disorders, it has been proposed as a bio-marker for such metabolic diseases as atherosclerosis and diabetes. Emerging evidence suggests that KYNA acts as a signaling molecule controlling the networks involved in the balance of energy store and expenditure through GPR35 and AMPK signaling pathway. KYNA plays an important role in the pathogenesis and development of several endocrine and metabolic diseases. Exercise training promotes KYNA production in skeletal muscles and increases thermogenesis in the long term and limits weight gain, insulin resistance and inflammation. Additionally, KYNA is also present in breast milk and may act as an anti-obesity agent in infants. Although we are far from fully understanding the role of KYNA in our body, administration of KYNA, enzyme inhibitors or metabolites may serve as a potential therapeutic strategy for treating metabolic diseases. The present review provides a perspective on the current knowledge regarding the biological effects of KYNA in metabolic diseases and perinatal nutrition.

Intrastriatal Quinolinic Acid Administration Impairs Redox Homeostasis and Induces Inflammatory Changes: Prevention by Kynurenic Acid

Kynurenic acid (KYNA) and quinolinic acid (QUIN) are metabolites formed in the degradation of tryptophan (Trp). QUIN is a selective NMDA receptor antagonist and may exert neurotoxic effects, whereas KYNA is an agonist of glutamatergic and cholinergic receptors and presents antioxidant properties. KYNA/QUIN ratio is decreased in several central nervous system disorders, but the mechanisms involved are not well elucidated. In the present study, we try to determine the neuroprotective capacity of KYNA on the QUIN effects in redox homeostasis changes (H2DCF oxidation, superoxide dismutase/catalase (SOD/CAT) ratio, glutathione peroxidase (GPx) activity, sulfhydryl content, and nitrite levels), as well as on inflammatory parameters (levels of TNF-α, IL-1β, and IL-6). KYNA and QUIN effects on the activities of Na+,K+-ATPase and acetylcholinesterase (AChE) were also evaluated. Thirty-day-old male Wistar rats underwent stereotactic surgery and received intrastriatal injections as follows: group 1-control (PBS-injected), group 2-KYNA (100μM), group 3-QUIN (150nM), and group 4-KYNA + QUIN (KYNA-injected followed QUIN-injected). Results demonstrated that the KYNA administration was able to prevent the increase in reactive oxygen species, SOD/CAT ratio, and pro-inflammatory cytokines (IL-1β and IL-6) and the decrease in GPx activity, sulfhydryl content, and nitrite levels caused by QUIN. KYNA was also able to partially prevent the decrease in Na+,K+-ATPase activity and the increase in AChE activity caused by QUIN. This study may help in the elucidation of neuroprotective effects of KYNA against oxidative and inflammatory insults caused by QUIN in the striatum of young male Wistar rats.

Organ-differential responses to ethanol and kynurenic acid, a component of alcoholic beverages in gene transcription

Excessive alcohol (ethanol) use has long been known to affect human health negatively. However, the underlying molecular basis is incompletely understood. Moreover, consumption of alcohol is often mixed with kynurenic acid (KYNA), an abundant tryptophan metabolite produced during fermentation. The combined effect of ethanol and KYNA on host gene expression has not been investigated. The current study used mice as the model to interrogate the impact of ethanol and/or KYNA on global gene transcription. Adult male mice were administered with 2 g/kg ethanol and/or 0.1 mg/kg KYNA by gavage once a day for a week. Three organs: brain, kidney, and liver were collected and their total RNAs extracted for transcriptome sequencing and quantitative real-time PCR. Gene ontology, Kyoto encyclopedia of genes, and genomes pathway analyses revealed that alcohol affects the three organs differentially. Furthermore, the gene expression profile from alcohol and KYNA co-administration was significantly different from that of alcohol or KYNA administration alone. Strikingly, Indolamine 2,3-dioxygenase 1, a rate-limiting enzyme in tryptophan metabolism, was significantly increased in the brain after a combined exposure of alcohol and KYNA, suggesting that Trp metabolism was skewed towards the kynurenine pathway in the brain. Our systemic analysis provides new insights into the mechanism whereby alcohol and KYNA affects organ functions.

Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery

It is usually assumed that kynurenic acid (KYNA) modifies neuronal function because it antagonizes the glycine site of the NMDA receptors and/or the neuronal cholinergic α7 nicotine receptors. It is not clear, however, whether the basal levels of KYNA found in brain extracellular spaces are sufficient to interact with these targets. Another reported target for KYNA is GPR35, an orphan receptor negatively coupled to G(i) proteins. GPR35 is expressed both in neurons and other cells (including glia, macrophages and monocytes). KYNA affinity for GPR35 in native systems has not been clarified and the low-affinity data widely reported in the literature for the interaction between KYNA and human or rat GPR35 have been obtained in modified expression systems. Possibly by interacting with GPR35, KYNA may also reduce glutamate release in brain and pro-inflammatory cytokines release in cell lines. The inhibition of inflammatory mediator release from both glia and macrophages may explain why KYNA has analgesic effects in inflammatory models. Furthermore, it may also explain why, KYNA administration (200mg/kg ip×3 times) to mice treated with lethal doses of LPS, significantly reduces the number of deaths. Finally, KYNA has been reported as an agonist of aryl hydrocarbon receptor (AHR), a nuclear protein involved in the regulation of gene transcription and able to cause immunosuppression after binding with dioxin. Thus, KYNA has receptors in the nervous and the immune systems and may play interesting regulatory roles in cell function.

Cortical kynurenic acid bi-directionally modulates prefrontal glutamate levels as assessed by microdialysis and rapid electrochemistry

Using two in vivo methods, microdialysis and rapid in situ electrochemistry, this study examined the modulation of extracellular glutamate levels by endogenously produced kynurenic acid (KYNA) in the prefrontal cortex (PFC) of awake rats. Measured by microdialysis, i.p. administration of KYNA's bioprecursor l-kynurenine dose-dependently elevated extracellular KYNA and reduced extracellular glutamate (nadir after 50 mg/kg kynurenine: 60% decrease from baseline values). This dose-dependent decrease in glutamate levels was also seen using a glutamate-sensitive microelectrode array (MEA) (31% decrease following 50 mg/kg kynurenine). The kynurenine-induced reduction in glutamate was blocked (microdialysis) or attenuated (MEA) by co-administration of galantamine (3 mg/kg i.p.), a drug that competes with KYNA at an allosteric potentiating site of the α7 nicotinic acetylcholine receptor. In separate experiments, extracellular glutamate levels were measured by MEA following the local perfusion (45 min) of the PFC with kynurenine (2.5 μM) or the selective KYNA biosynthesis inhibitor S-ethylsulfonylbenzoylalanine (S-ESBA; 5 mM). In agreement with previous microdialysis studies, local kynurenine application produced a reversible reduction in glutamate (nadir: −29%), whereas perfusion with S-ESBA increased glutamate levels reversibly (maximum: +38%). Collectively, these results demonstrate that fluctuations in the biosynthesis of KYNA in the PFC bi-directionally modulate extracellular glutamate levels, and that qualitatively very similar data are obtained by microdialysis and MEA. Since KYNA levels are elevated in the PFC of individuals with schizophrenia, and since prefrontal glutamatergic and nicotinic transmission mediate cognitive flexibility, normalization of KYNA levels in the PFC may constitute an effective treatment strategy for alleviating cognitive deficits in schizophrenia.

A novel kynurenic acid analogue: a comparison with kynurenic acid. An in vitro electrophysiological study

Kynurenic acid is an endogenous product of the tryptophan metabolism, and as a broad-spectrum antagonist of excitatory amino acid receptors may serve as a protective agent in neurological disorders. The use of kynurenic acid as a neuroprotective agent is rather limited, however, because it has only restricted ability to cross the blood-brain barrier. Accordingly, new kynurenic acid analogues which can readily cross the blood-brain barrier and exert their complex anti-excitotoxic activity are greatly needed. Such a novel analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride, has been developed and tested. In an in vitro electrophysiological study, in which its properties were compared with those of kynurenic acid, the new analogue behaved quite similarly to kynurenic acid: in the micromolar range, its administration led to a decrease in the amplitudes of the field excitatory postsynaptic potentials in the CA1 region of the hippocampus, while in nanomolar concentrations it did not give rise to inhibition, but, in fact, facilitated the field excitatory postsynaptic potentials. Moreover, the new analogue demonstrated similar protective action against PTZ-induced facilitation to that observed after kynurenic acid administration. The findings strongly suggest that the neuroactive effects of the new analogue are comparable with those of kynurenic acid, but, in contrast with kynurenic acid, it readily crosses the blood-brain barrier. The new analogue may therefore be considered a promising candidate for clinical studies.

Kynurenic acid actions in brain and periphery

Abstract. Kynurenic acid (KYNA) is commonly considered a non-competitive NMDA receptor antagonist. It has been recently shown that KYNA also antagonizes the alpha 7 nicotine receptors and reduces glutamate and dopamine release in the rat striatum. Finally, it has been demonstrated that KYNA interacts with GPR35, an orphan receptor negatively coupled to Gi proteins. We noticed that in a macrophage cell line (RAW 264.7) KYNA reduces the LPS-induced release of pro-inflammatory cytokines. In mice treated with lethal doses of LPS, a septic shock model, KYNA administration (200 mg/kg i.p.x 3 times) significantly reduced the mortality rate. Thus KYNA has receptors both in the nervous and peripheral tissues where it may play an interesting regulatory role in cell activation and survival.

Kynurenic acid inhibition of an experimental epileptogenic focus in the rat hippocampus

Kynurenic acid introduced in an epileptogenic focus through an electrochemotrode before the creation of the focus was found to reduce the intensity of epileptiform discharges between seizures and of electrographic correlates of seizures on the electroencephalogram. Administration of kynurenic acid led to the appearance of a slow Θ-rhythm dominating in all the leads.

Cardiorespiratory effects produced by blockade of excitatory amino acid receptors in cats

The aim of our study was to determine the role of excitatory amino acids in controlling cardiorespiratory activity. For this purpose we administered an antagonist of both N-methyl-D-aspartate (NMDA) and non-NMDA receptors (kynurenic acid), and an antagonist of the NMDA receptor complex (dizocilpine, more commonly known as MK-801) i.v. to chloralose-anesthetized cats while monitoring tracheal air flow, tidal volume, respiratory rate, inspiratory and expiratory durations, end tidal CO 2, arterial blood pressure and heart rate. Administration of kynurenic acid in doses of 350 and 500 mg/kg produced respiratory depression as reflected by decreases in respiratory minute volume and increases in end tidal CO 2. Inspiratory duration was increased with both doses and apnea (occurring during expiration) was observed with the high dose. Apnea was preceded by an apneustic pattern of breathing. Both doses resulted in an increase in blood pressure and, with the high dose, a later decrease in blood pressure was noted. Dizocilpine in doses ranging from 0.03 to 1 mg/kg produced dose-related decreases in respiratory minute volume, and increases in end tidal CO 2. In addition, dizocilpine produced increases in inspiratory duration, an apneustic pattern of breathing and apnea (occurring during inspiration). Effects on blood pressure were similar to those observed with kynurenic acid. It is concluded that blockade of excitatory amino acid receptors results in pronounced effects on cardiorespiratoty activity.

Inhibition of rostral VLM by baroreceptor activation is relayed through caudal VLM

Experiments were done to test the hypothesis that inhibition of neurons in the rostral ventrolateral medulla (RVLM) elicited by stimulation of the nucleus tractus solitarii (NTS) is relayed through the caudal ventrolateral medulla (CVLM). We recorded activity from 56 spontaneously firing units in the right RVLM of urethan-anesthetized and artificially ventilated rats. Eleven of these units were classified as cardiovascular neurons, because they were silenced by baroreceptor activation (1-3 micrograms phenylephrine iv) and showed rhythmicity of their spontaneous activity in synchrony with the cardiac cycle. Single pulses (0.1 ms, 30-75 microA) delivered 1/s to depressor sites in the ipsilateral NTS inhibited the activity of all these cardiovascular neurons. Microinjection of the glutamate antagonist kynurenic acid (0.15 M, 50 nl) into the ipsilateral CVLM blocked the inhibitory response of RVLM units to the administration of phenylephrine and increased the firing frequency of cardiovascular neurons in the RVLM by 43%. Moreover, kynurenic acid administration attenuated the inhibitory response of cardiovascular neurons in the RVLM to NTS stimulation. Finally, stimulation of the NTS that elicited depressor responses under control conditions produced a pressor response after kynurenic acid administration. The remaining 45 RVLM neurons were barosensitive but lacked cardiac cycle-related rhythmicity. These results provide direct evidence for the existence of a tonic inhibitory pathway from NTS to RVLM that is relayed through the CVLM probably by a glutamatergic projection from NTS to CVLM.