Biomedical subjects

Waldemar A Turski

Publications and source records attributed to Waldemar A Turski.

At least 19 recordsLinked to original sources

PubMed2006

NMDA antagonists exert distinct effects in experimental organophosphate or carbamate poisoning in mice.

Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures.

Animals↗

PubMed2006

Lithium-methomyl induced seizures in rats: a new model of status epilepticus?

Behavioral, electroencephalographic (EEG) and neuropathological effects of methomyl, a carbamate insecticide reversibly inhibiting acetylcholinesterase activity, were studied in naive or lithium chloride (24 h, 3 mEq/kg, s.c.) pretreated male Wistar rats. In naive animals, methomyl with equal potency produced motor limbic seizures and fatal status epilepticus. Thus, the CD50 values (50% convulsant dose) for these seizure endpoints were almost equal to the LD50 (50% lethal dose) of methomyl (13 mg/kg). Lithium pretreated rats were much more susceptible to convulsant, but not lethal effect of methomyl. CD50 values of methomyl for motor limbic seizures and status epilepticus were reduced by lithium pretreatment to 3.7 mg/kg (a 3.5-fold decrease) and 5.2 mg/kg (a 2.5-fold decrease), respectively. In contrast, lithium pretreatment resulted in only 1.3-fold decrease of LD50 value of methomyl (9.9 mg/kg). Moreover, lithium-methomyl treated animals developed a long-lasting status epilepticus, which was not associated with imminent lethality observed in methomyl-only treated rats. Scopolamine (10 mg/kg) or diazepam (10 mg/kg) protected all lithium-methomyl treated rats from convulsions and lethality. Cortical and hippocampal EEG recordings revealed typical epileptic discharges that were consistent with behavioral seizures observed in lithium-methomyl treated rats. In addition, convulsions induced by lithium-methomyl treatment were associated with widespread neurodegeneration of limbic structures. Our observations indicate that lithium pretreatment results in separation between convulsant and lethal effects of methomyl in rats. As such, seizures induced by lithium-methomyl administration may be an alternative to lithium-pilocarpine model of status epilepticus, which is associated with high lethality.

Animals↗

PubMed2006

Enhancement of brain kynurenic acid production by anticonvulsants--novel mechanism of antiepileptic activity?

In this study, we describe the effect of antiepileptic drugs on the production of kynurenic acid in rat cortical slices, and on the activity of kynurenic acid biosynthetic enzymes, kynurenine aminotransferases (KATs I and II) in the brain tissue. Phenobarbital, felbamate, phenytoin and lamotrigine (all at 0.5-3.0 mM) enhanced kynurenic acid production in vitro, and stimulated the activity of KAT I. In contrast, vigabatrin, gabapentin and tiagabine inhibited kynurenic acid synthesis in cortical slices with IC(50) of 3.9 (2.8-7.9), 3.7 (2.5-5.4) and 7.5 (3.5-14.3) mM, respectively. Vigabatrin, gabapentin and tiagabine reduced also the activity of KAT I with IC(50) of 1.6 (1.1-2.4), 0.1 (0.01-0.15), 0.9 (0.7-1.2) mM, and the activity of KAT II with IC(50) values of 6.0 (4.8-7.5), 0.2 (0.1-0.3) and 2.0 (1.5-2.6) mM, respectively. In conclusion, the enhancement of kynurenic acid formation displayed by carbamazepine, phenytoin, phenobarbital, felbamate and lamotrigine seems to be a novel mechanism, synergistic with other actions of these drugs, and potentially valuable in terms of better control of epilepsy.

Animals↗

PubMed2006

Effect of glutamate receptor antagonists and antirheumatic drugs on proliferation of synoviocytes in vitro.

One of the most striking features of inflammatory arthritis is the hyperplasia of synovial fibroblasts. It is not known whether the massive synovial hyperplasia characteristic of rheumatoid arthritis is due to the proliferation of synovial fibroblasts or to defective apoptosis. It has been found that glutamate receptor antagonists inhibit proliferation of different human tumour cells and the anticancer potential of glutamate receptor antagonists was suggested. Here, we investigated the effect of glutamate receptor antagonists and selected antirheumatic drugs on proliferation of synoviocytes in vitro. Experiments were conducted on rabbit synoviocytes cell line HIG-82 obtained from American Type Culture Collection (Menassas, VA, USA). Cell proliferation was assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated. Glutamate receptor antagonists, 1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (CFM-2), riluzole, memantine, 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), dizocilpine, ketamine and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.014, 0.017, 0.065, 0.102, 0.15, 0.435 and 1.16, respectively. Antirheumatic drugs, celecoxib, diclofenac, nimesulide, sulfasalazine, naproxen and methotrexate, inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.0043, 0.034, 0.044, 0.096, 0.385 and 1.123, respectively. Thus, the antiproliferative potential of glutamate receptor antagonists is comparable to that of antirheumatic drugs.

Animals↗

PubMed2006

Ammonia at pathophysiologically relevant concentrations activates kynurenic acid synthesis in cultured astrocytes and neurons.

The synthesis of the NMDA receptor glycine site antagonist kynurenic acid (KYNA) from exogenously added kynurenine was measured in cultured cerebral cortical neurons, cortical astrocytes and an oligodendroglial cell line OLN-93, incubated for 2 h in the presence or absence of ammonium acetate ("ammonia") at 0.1-10 mM concentration. In neurons ammonia stimulated KYNA synthesis to approximately 160-170% of control at 0.1-1.0mM, did not produce any effect at 2.5 and 5 mM, and inhibited the synthesis to approximately 80% of control at 10mM concentration. In astrocytes, a stimulation to approximately 200% of control occurred in the whole ammonia concentration range. No effect of ammonia was noted in OLN-93 cells. Increased KYNA synthesis may represent a cytoprotective response of astrocytes and neurons against the NMDA receptor-mediated cytotoxic activity of ammonia.

Ammonia↗

PubMed2005

Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons.

The present study characterizes the synthesis of kynurenic acid (KYNA) from exogenously added kynurenine and its regulation by extrinsic factors, in cultured cerebral cortical neurons and, for comparison, in astrocytes incubated under identical conditions. The neuronal culture showed positive immunostaining for both kynurenic acid aminotransferase (KAT) isoforms I and II. Neurons synthesized KYNA at a rate about 2.3 times higher than astrocytes. Neuronal, but not astrocytic, KYNA synthesis was lowered approximately 30% by ionotropic glutamate receptor agonists [(R,S)-3-hydroxy-5-methoxyloxasole-4-propionic acid (AMPA; 100 microM) and N-methyl-D-aspartic acid (NMDA; 100 microM)] and depolarizing agents [KCl (50 mM) and 4-aminopyridine (4-AP; 10 microM)]. Neuronal and astrocytic synthesis alike were vulnerable to inhibition exerted by the aminotransferase inhibitor aminooxyacetic acid (AOAA), glutamate (IC50: 31 and 85 microM, respectively), substrates of the L-amino transport system [leucine (Leu); IC50: 19 and 42 microM, respectively] and 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH; IC50: 19 and 28 microM, respectively). Glutamine (Gln), which is a metabolic precursor of glutamate in astrocytes and L-system substrate in both cell types, inhibited KYNA synthesis both in neurons and in astrocytes (IC50: 268 and 318 microM, respectively). alpha-Ketoisocaproic acid (KIC), a Leu transamination product that is produced mainly in astrocytes and shuttled to neurons to modulate intraneuronal concentration of glutamate, stimulated KYNA synthesis in neurons but did not affect the synthesis in astrocytes. In conclusion, this study is the first to demonstrate active, regulation-prone KYNA synthesis in neurons.

Animals↗

PubMed2005

Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in oligodendrocyte cell line (OLN-93).

In the present study we demonstrate for the first time that both kynurenine aminotransferase (KAT) isoforms I and II are present in the permanent immature rat oligodendrocytes cell line (OLN-93). Moreover, we provide evidence that OLN-93 cells are able to synthesize kynurenic acid (KYNA) from exogenously added L-kynurenine and we characterize its regulation by extrinsic factors. KYNA production in OLN-93 cells was depressed in the presence of aminotransferase inhibitor, aminooxyacetic acid and was not affected by depolarizing agents such as 50 mM K+ and 4-aminopyridine. Glutamate agonists, L-glutamate and D,L-homocysteine significantly decreased KYNA production. Selective agonist of ionotropic glutamate receptors Amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropionic acid (AMPA) lowered KYNA production in OLN-93 cell line, whereas N-methyl-D-aspartate (NMDA) had no influence on KYNA production. Furthermore, KYNA synthesis in OLN-93 cells was decreased in a concentration-dependent manner by amino acids transported by L-system, L-leucine, L-cysteine and L-tryptophan. The role of KYNA synthesis in oligodendrocytes needs further investigation.

Amino Acids↗

PubMed2005

Effect of pesticides on kynurenic acid production in rat brain slices.

Kynurenic acid (KYNA) is a broad spectrum antagonist of ionotropic glutamate receptors, preferentially active at the strychnine-insensitive glycine allosteric site of the N-methyl-D-aspartate (NMDA) receptor, and a noncompetitive antagonist of alpha7 nicotinic receptor. Animal studies showed that it possesses anticonvulsant and neuroprotective properties. Its involvement in the pathophysiology of various brain disorders was suggested. In this study, the effect of pesticides on KYNA production in brain cortical slices was investigated. Pyrethroids, deltamethrin and fenpropathrin significantly lowered KYNA production. Methomyl, bensultap, fipronil, diquat and MCPA were ineffective in this regard. In view of this data, the inhibition of KYNA synthesis appear to merit further investigation as a potential factor contributing to the toxicology of pyrethroids.

Animals↗

PubMed2004

Ethosuximide and valproate display high efficacy against lindane-induced seizures in mice.

Both lindane (gamma-hexachlorocyclohexane), an organochlorine ectoparasiticide and pentylenetetrazol, used as a model of experimental epilepsy, produce convulsive seizures resulting from the blockade of the gamma-aminobutyric acid (GABAA) receptor. In the present study we established the protective effects of ethosuximide and valproate against seizures induced by lindane and compared them with the well-known protective effects of these drugs against pentylenetetrazol-induced seizures in mice. Both ethosuximide and valproate afforded complete and dose-dependent protection against seizures induced by lindane. However, the potencies of these drugs were lower than those obtained against pentylenetetrazol seizures. Nevertheless, the protective efficacy of ethosuximide and valproate against experimentally induced lindane seizures may suggest possible efficacy of these drugs against seizures in lindane-poisoned patients.

Animals↗

PubMed2004

Carbamazepine enhances brain production of kynurenic acid in vitro.

Disturbed formation of kynurenic acid, an endogenous antagonist of glutamate ionotropic receptors, might contribute to the pathogenesis of seizures. Here, the effect of anticonvulsant drug, carbamazepine on the production of kynurenic acid was studied. Carbamazepine (0.5-3 mM) enhanced kynurenic acid synthesis in rat cortical slices and also increased the activity of kynurenine aminotransferase (KAT) I at 0.1-3.0 mM concentration. Thus, anticonvulsant drugs, such as carbamazepine, might act partially via stimulation of kynurenic acid production.

Analysis of Variance↗

PubMed2004

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 alpha-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.

Animals↗

PubMed2004

Kynurenic acid synthesis in cerebral cortical slices of rats with progressing symptoms of thioacetamide-induced hepatic encephalopathy.

Increased ammonia is a major pathogenic factor in hepatic encephalopathy (HE), a neurologic syndrome associated with glutamatergic dysfunction. Previous studies have shown that in rat cerebral cortical slices or a glia-derived cell line, acute treatment with ammonia in vitro and in vivo inhibits the production of a broad-spectrum antagonist of excitatory amino acid receptors, kynurenic acid (KYNA). The present study analyzed KYNA synthesis in cerebral cortical slices obtained from rats with progressing HE symptoms accompanying acute liver failure induced by one, two, or three intraperitoneal administrations of thioacetamide (TAA) at 24-hr intervals. KYNA synthesis was found decreased to 83% of control 24 hr after one administration of TAA and unaffected after two TAA injections, when moderate hyperammonemia was associated by metabolic and bioelectric activation of the central nervous system, but was not accompanied by typical HE symptoms. KYNA synthesis was elevated to 155% of control after three TAA administrations, a period in which the rats showed advanced HE symptoms including stupor or coma. KYNA synthesis at the advanced HE stage was inhibited by glutamate in a degree comparable to that observed in control slices. The elevation of KYNA synthesis was associated with increased activity of a kynurenine aminotransferase (KAT) isomer, KAT-II. KYNA synthesis did not differ from control 21 days after the third TAA administration when HE symptoms receded. The results suggest that alterations of KYNA synthesis may contribute to the imbalance between neural excitation and inhibition at different stages of HE.

Animals↗

PubMed2004

Expression of kynurenine aminotransferases in the rat retina during development.

The study investigates the cellular expression of kynurenine aminotransferases (KAT I and II) in the rat retina during development. At P1 (the day of birth) and P7 (the 7th day after birth), KAT I expression was observed in the inner plexiform layer (IPL), the fiber layer (FL), and in vertically running processes in the ganglion cell layer (GCL) (but not in the cell bodies). At P14 (the 14th day after birth) a strong KAT I immunoreactivity was observed in Müller cell endfeet. KAT II was expressed in the IPL, the FL, and in cells in the GCL at P1 and P7. From P14 on, KAT II expression in the IPL decreased. Double labeling revealed that KAT I was expressed in Müller cell endfeet, whilst KAT II both on retinal ganglion cells (RGC) and Müller cell endfeet. In conclusion, KAT I and II are present in the rat retina during development. The heterogeneity of the KAT developmental profiles possibly reflects a neuromodulatory role in the retinal differentiation.

Animals↗

PubMed2004

Age-dependent decrease of retinal kynurenate and kynurenine aminotransferases in DBA/2J mice, a model of ocular hypertension.

The study examines age-dependent changes of kynurenic acid (KYNA) content and kynurenine aminotransferases (KAT I and KAT II) celluar expression in the retinas of DBA/2J mice. Retinas were obtained from DBA/2J mice of different ages (3, 6 and 11 months). C57BL6 mice were used as controls. As measured with HPLC, KYNA content decreased (p < 0.01) in the retinas of 6-month-old DBA/2J mice and continued to decrease (p < 0.0074) in the retinas of 11-month-old animals compared to the controls. Immunohistochemistry showed that expression of both KAT I and KAT II decreased markedly in the retinas of 11-month-old DBA/2J mice compared to controls. The impairment in KYNA biosynthesis in the retinas of DBA/2J mice may be one of the mechanisms of retinal neurodegeneration related to ocular hypertension.

Aging↗

PubMed2004

Geographical Information System (GIS) as a tool for monitoring and analysing pesticide pollution and its impact on public health.

Geographical Information System (GIS) combines information from cartography sources (i.e. maps), earthbound surveys, remote sensing (i.e. aerial and satellite imagery) and creates overlapping layers that can be accessed, transformed, and manipulated interactively in one spatial structure. Thanks to the great flexibility of GIS, its possible applications are countless. For example, dynamic databases created by GIS can manage information from various sources and make spatial correlations with epidemiological data about temporal distribution of environmentally-related diseases. GIS has also been increasingly used to monitor, analyse and model pesticide migration in the environment. GIS analysis has proved to be a valuable tool in environmental and public health studies yielding important results that may ultimately help prevent excessive or uncontrolled exposure to xenobiotics, including pesticides. Despite its obvious advantages GIS technology is still not commonly used for such studies, particularly in the developing countries where the knowledge about GIS technology and its accessibility is limited. The presented review briefly explains the basic features of GIS and discusses exemplary studies where this technology has been successfully used for monitoring and analysing pesticide pollution and its impact on public health.

Databases, Factual↗

PubMed2003

L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II.

In the present study the effect of endogenous sulphur-containing amino acids, L-cysteine sulphinate, L-cysteate, L-homocysteine sulphinate and L-homocysteate, on the production of glutamate receptor antagonist, kynurenic acid (KYNA), was evaluated. The experiments comprised the measurements of (a). KYNA synthesis in rat cortical slices and (b). the activity of KYNA biosynthetic enzymes, kynurenine aminotransferases (KATs). All studied compounds reduced KYNA production and inhibited the activity of KAT I and/or KAT II, thus acting most probably intracellularly. L-Cysteine sulphinate in very low, micromolar concentrations selectively affected the activity of KAT II, the enzyme catalyzing approximately 75% of KYNA synthesis in the brain. L-Cysteine sulphinate potency was higher than other studied sulphur-containing amino acids, than L-aspartate, L-glutamate, or any other known KAT II inhibitor. Thus, L-cysteine sulphinate might act as a modulator of KYNA formation in the brain.

Amino Acids, Sulfur↗

PubMed2003

Alterations of kynurenic acid content in the retina in response to retinal ganglion cell damage.

The present study is the first to examine the modulation of retinal kynurenic acid (KYNA) content in response to N-methyl-D-aspartate (NMDA)-induced cell death in adult rat retinal ganglion cells (RGC). Adult Brown Norway rats were intravitreally injected with NMDA or PBS. Surviving RGC were retrogradely labeled with fluorogold and counted in wholemounts of retinas 2, 7 and 14 days after injection. Retinal KYNA content was measured by HPLC at the same time points. RGC numbers decreased significantly 2, 7 and 14 days after NMDA injection if compared to control retinas. KYNA concentration increased significantly two days after NMDA-injection. However, 7 and 14 days after injection retinal KYNA content was found markedly decreased in NMDA-treated eyes as compared to controls. It is conceivable that KYNA deficiency is causally related to the pathology of excitotoxic retinal diseases.

Animals↗

PubMed2003

Ontogenic changes of kynurenine aminotransferase I activity and its expression in the chicken retina.

Kynurenine aminotransferases are key enzymes for the synthesis of kynurenic acid (KYNA), an endogenous glutamate receptor antagonist. The study described here examined ontogenic changes of kynurenine aminotransferase I (KAT I) activity and its expression in the chicken retina. KAT I activity measured on embryonic day 16 (E16) was significantly higher than at all other stages (E12, P0 and P7). Double labeling with antibodies against glutamine synthetase showed that on P7 KAT I was expressed in Müller cell endfeet and their processes in the inner retina. Since KAT I activity is high in the late embryonic stages, it is conceivable that it plays a neuromodulatory role in the retina during the late phase of embryogenesis.

Animals↗