Jolanta Parada-Turska

Excitatory amino acid antagonists and memory: Effect of drugs acting at N- methyl-D-aspartate receptors in learning and memory tasks

The role of N-methyl-D-aspartate (NMDA) receptors in memory processes was examined using a Y-shaped maze and a step-through passive avoidance task in mice. In the Y-maze, the total number of arm entries, which represents locomotor activity and alternation behaviour, thought to reflect working memory, were measured. Competitive NMDA antagonists, CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylate) and CPP (3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphate), impaired spontaneous alternation at doses which reduced locomotion of mice. N-Methyl-D-aspartate prevented the impairment of alternation and decrease of locomotor activity produced by CGS 19755 and CPP. These results suggest that NMDA-dependent processes are involved in the mechanisms of working memory. In contrast, the non-competitive NMDA antagonist, MK 801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) dramatically enhanced the total number of arm entries, while reducing alternation behaviour, N-Methyl-D-aspartate had no effect on MK 801-induced enhancement of locomotor activity and impairment of alternation. In the passive avoidance task, mice were trained to avoid entry into the dark compartment. At doses which impaired working memory in the alternation task, CPP, CGS 19755 and MK-801 reduced acquisition, when administered before training. N-Methyl-D-aspartate antagonized the effect of CPP, CGS 19755 and MK-801. Neither CPP nor MK-801 affected retention, when administered immediately after training or before testing retention. N-Methyl-D-aspartate had no effect on retention with high-intensity shock, but facilitated retention with low-intensity shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Excitatory amino acid antagonists protect mice against seizures induced by bicuculline

The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the gamma-aminobutyric acidA (GABAA) antagonist bicuculline (BIC) were tested in mice. 3-[+/-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists. gamma-D-Glutamylaminomethylsulphonate (gamma-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v. administration with a CD50 of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (ED50 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), gamma-D-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABAA agonist, blocked BMI-induced seizures with an ED50 of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CD50 of 2.2 mg/kg (range 1.9-2.5) for clonus and CD50 of 2.4 mg/kg (range 2.2-2.7) for tonus.2+ the pathogenesis of seizures triggered by bicuculline in mice.

Kynurenic Acid in the Digestive System—New Facts, New Challenges

This review provides information on the most recent findings concerning presence, origin, and role of kynurenic acid (KYNA), a tryptophan metabolite, in the digestive system. KYNA is an antagonist of both the ionotropic glutamate receptors and the alpha7 nicotinic acetylcholine receptor, as well as an agonist of G-protein coupled GPR35 receptor. Since the GPR35 receptor is mainly present in the gastrointestinal tract, researchers have concentrated on the digestive system in recent years. They have found that KYNA content increases gradually and significantly along the gastrointestinal tract. Interestingly, the concentration of KYNA in the lumen is much higher than in the wall of intestine. It has been documented that KYNA may have a positive influence on the number of pathologies in the gastrointestinal tract, in particular ulcers, colon obstruction, or colitis. Future studies might determine whether it is advisable to supplement KYNA to a human organism.

Retigabine: the newer potential antiepileptic drug

Retigabine represents an antiepileptic drug possessing a completely different mechanism of action when compared to the existing classical and newer antiepileptic drugs. In the therapeutic range, retigabine enhances potassium currents, very likely via destabilization of a closed conformation or stabilization of the open conformation of the potassium Kv7.2-7.3 channels. There are also data indicating that this drug may be a GABA enhancer. Kainate-induced status epilepticus in rats resulted in massive apoptosis in the pyriform cortex and hippocampal area - retigabine inhibited neurodegeneration only in the former brain structure. The metabolism of retigabine has nothing to do with cytochrome P450 enzymes and the drug undergoes glucuronidation and acetylation. Randomized, placebo-controlled multicenter studies have shown that retigabine produced a considerable improvement as an add-on drug in patients with partial drug-resistant epilepsy. The most prominent adverse effects due to retigabine combined with the existing antiepileptic treatment were dizziness, somnolence and fatigue. The preclinical data indicate that this antiepileptic drug may possibly be applied in patients with neuropathic pain and affective disorders. Initial clinical data suggest that retigabine may be also effective in Alzheimers disease or stroke.

Kynurenic acid production in cultured bovine aortic endothelial cells. Homocysteine is a potent inhibitor.

Kynurenic acid (KYNA) is a broad-spectrum antagonist at all subtypes of ionotropic glutamate receptors, but is preferentially active at the strychnine-insensitive glycine allosteric site of the N-methyl-d-aspartate (NMDA) receptor and is also a non-competitive antagonist at the alpha7 nicotinic receptor. KYNA occurs in the CNS, urine, serum and amniotic fluid. Whilst it possesses anticonvulsant and neuroprotective properties in the brain, its role in the periphery, however, is unknown. In this study we demonstrated the presence of kynurenine aminotransferase (KAT) I and II in the cytoplasm of bovine aortic endothelial cells (BAEC). BAEC incubated in the presence of the KYNA precursor l-kynurenine synthesized KYNA concentration- and time-dependently. KYNA production was inhibited by the aminotransferase inhibitor aminooxyacetic acid but was not affected by a depolarising concentration of K+ or by 4-aminopyridine. The glutamate agonists l-aspartate and l-glutamate depressed KYNA production significantly. The selective ionotropic glutamate receptor agonists α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropionic acid (AMPA) and NMDA were ineffective in this respect. d,l-Homocysteine and l-homocysteine sulphinic acid lowered KYNA production in BAEC. Further investigations are needed to assess the role and importance of KYNA in vessels and peripheral tissues.

Parthenolide Inhibits Proliferation of Fibroblast-Like Synoviocytes In Vitro

Parthenolide is a bioactive constituent of an aromatic herb Feverfew (Tanacetum parthenium). It has been found that both parthenolide and extract of feverfew have anti-inflammatory and antinociceptive properties. Moreover, they demonstrate antiproliferative activities on different human tumour cells. The massive hyperplasia of synovial fibroblasts is the one of the most striking features of rheumatoid arthritis. It is not known whether this is due to the proliferation of synovial fibroblasts or to defective apoptosis. We investigated the effect of parthenolide on the proliferation of rabbit synoviocytes cell line HIG-82, rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and human skin fibroblasts (HSF) in vitro. Cell proliferation was assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 5′-bromo-2′-deoxy-uridine methods. Parthenolide inhibited proliferation of HIG-82 and human RA-FLS. The proliferation of HSF was inhibited less effectively. The antiproliferative potential of parthenolide was demonstrated.

Effect of kynurenic acid on the viability of probiotics in vitro.

Probiotics are bacteria that are commercially available as dietary supplements. One of the important properties of probiotics is their ability to survive in the intestine. Recent evidence has identified kynurenic acid (KYNA) as a bactericidal constituent of intestinal fluid. These data led us to study the influence of KYNA on the viability of selected probiotics. We found that KYNA supported the growth of bacteria in the probiotics Acidolac (Lactobacillus acidophilus, Bifidobacterium) and Lakcid Forte (Lactobacillus rhamnosus) or retarded the growth of bacteria from the Acidolac, BioGaia (Lactobacillus reuteri Protectis), Dicoflor (Lactobacillus rhamnosus GG), Lacium (Lactobacillus plantarum) and Trilac (Lactobacillus acidophilus, Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium animalis subsp. lactis) probiotics depending on its concentration. KYNA did not affect the viability of bacteria from the probiotic Linex (Lactobacillus acidophilus LA-5, Bifidobacterium animalis subsp. lactis BB-12). Our results suggest a potential role of KYNA in the regulation of bacterial growth in the digestive system.

Kynurenic acid in synovial fluid and serum of patients with rheumatoid arthritis, spondyloarthropathy, and osteoarthritis.

Objective. Previously we demonstrated that kynurenic acid (KYNA), an endogenous metabolite of kynurenine, is present in the synovial fluid of patients with rheumatoid arthritis (RA). KYNA inhibits proliferation of synoviocytes in vitro. The goal of our study was to compare KYNA concentrations in synovial fluid and blood of patients with RA, inflammatory spondyloarthropathies (SpA), and osteoarthritis (OA). Methods. Serum and synovial fluid samples were obtained from 189 patients with RA, 56 patients with SpA, and 32 patients with OA. KYNA was separated using a high-performance liquid chromatography system and measured fluorometrically. Results. KYNA concentration in synovial fluid obtained from patients with RA and SpA was significantly lower than that in patients with OA (p < 0.05). The concentration of KYNA in serum of patients with RA, SpA, and OA did not differ among all groups studied. The positive correlation between KYNA content in synovial fluid and serum was found in patients with RA (p < 0.05). Univariate linear regression analysis demonstrated that fibrinogen was significantly associated with KYNA in synovial fluid (p < 0.05), and red blood cell counts, morning stiffness, and pain scores were significantly associated with KYNA level in serum (all p < 0.05). Multivariate regression analysis revealed correlation between the following independent variables: hemoglobin level, hematocrit, red blood cell count in conjunction with age and KYNA content in synovial fluid. A lack of correlation was observed between KYNA content in synovial fluid of patients with RA and other clinical and laboratory measures of disease activity. Conclusion. Our data show a local deficit of KYNA in inflammatory states.

Plasma Kynurenic Acid Concentration in Patients Undergoing Cardiac Surgery: Effect of Anaesthesia

Increases in plasma kynurenic acid (KYNA) concentration relate to the severity of inflammation. The aim of this study was to analyse changes in plasma KYNA concentration and neutrophil/lymphocyte ratio (NLR) in cardiac surgery patients. Additionally, the effect of anaesthesia was analysed. Adult cardiac surgery patients under intravenous general anaesthesia were studied. Additionally, some patients received sevoflurane (SEV) prior to cardiopulmonary bypass. Plasma KYNA concentration and NLR were measured before anaesthesia, just after surgery and on postoperative days 1, 2 and 3. Patients were assigned to two groups: patients who did not receive SEV (NonSEV group) and patients who received SEV (SEV group). Forty-three patients were studied. Twenty-four of them received SEV. KYNA increased immediately after surgery and remained elevated through postoperative day 3 in the NonSEV group, whereas it was similar to the preoperative concentration in the SEV group. NLR increased immediately after surgery in both groups, and higher values were noted in the NonSEV group than in the SEV group at postoperative days 2 and 3. Plasma KYNA concentration correlated with NLR in the NonSEV group. Cardiac surgery caused an increase in NLR. Plasma KYNA increased in the NonSEV group and correlated with NLR. Administration of SEV inhibited the increase in KYNA, most likely due to its anti-inflammatory properties.

Carotid surgery affects plasma kynurenic acid concentration: a pilot study.

Background An increase in plasma kynurenic acid (KYNA) concentration has been observed following surgery, inflammation, and cerebral pathologies. The aim of the present study was to analyze the changes in plasma KYNA concentration in patients undergoing carotid surgery (CS). Material/Methods Adult patients undergoing elective carotid endarterectomy (CEA) or carotid angioplasty with stent placement (CAS) were studied. Plasma KYNA concentrations were analyzed before surgery and at 4 time points after CS. The amount of inflammation was measured as neutrophil-lymphocyte ratio (NLR). Results Forty patients (10 female and 30 male) aged 55–86 years of age were evaluated in this study. In patients with unstable carotid plaque, the plasma KYNA concentration was higher than in patients with stable carotid plaque. Moreover, the NLR was significantly higher in patients with unstable carotid plaque undergoing CEA than in patients undergoing CAS. Plasma KYNA concentration increased after surgery in patients undergoing CEA and CAS. There was a strong correlation between plasma KYNA concentration and NLR in patients with postoperative neurological disorders. Conclusions CS increases plasma KYNA concentration, and changes in plasma KYNA concentration can indicate neurologic outcomes in patients undergoing CS.