Tuberculosis in prehistory in Eastern Central Europe (Hungary) - Chronological and geographical distribution.

Tuberculosis (TB) has long been a major scourge of humankind. Paleopathological and paleomicrobiological studies have revealed the past presence of the disease on a large spatial and temporal scale. The antiquity of the disease has extensively been studied in the Carpathian Basin, given its dynamic population and cultural changes since prehistory. These studies, however, have mainly focused on the populations living during the Common Era. The aim of this paper is to present the published and the recently discovered cases of prehistoric TB, from the Neolithic (6000-4500/4400 BCE) to the Bronze Age (2600/2500-800 BCE) Central Carpathian Basin (Hungary). We summarize 18 published cases and present new cases dating to the Neolithic period and introduce 3 newly discovered Bronze Age cases of TB. Despite extensive research, TB has not yet been identified from the Copper and Iron Ages in the Carpathian Basin. Considering the state of TB research, and supplemented by our prehistoric dataset, the spatio-temporal pattern of the disease can be further elucidated, thus advancing future molecular and paleopathological studies. Our dataset offers comprehensive spatial and temporal information on the spread of the disease in the Carpathian Basin, along with a detailed biological profile of the demonstrated cases and extensive paleopathological descriptions of the observed lesions, complemented by photographic evidence. This invaluable resource paves the way for enhanced understanding and progress in the field.

Utilization of acute vascular imaging and neurointervention for acute ischaemic stroke patients in 20 Hungarian stroke centers.

BACKGROUND AND PURPOSE: Acute mortality rate of stroke in Hungary is significantly higher than in Western Europe, which is likely to be partially attributable to suboptimal treatment. METHODS: We examined the use of acute vascular imaging and mechanical thrombectomy for acute ischaemic stroke patients. We collected data on 20 consecutive patients from Hungarian stroke centers before 31st August 2016. RESULTS: Out of the reported 410 patients, 166 (40.4%) underwent CT angiography and 44 (10.7%) had mechanical thrombectomy. CONCLUSION: Only about 1/3 of acute ischaemic stroke patients eligible for thrombectomy actually had it. The underlying reasons include long onset-to-door time, low utilization of acute vessel imaging and a limited neuro-intervention capacity needing improvement.

Stress and Salivary Glands.

Salivary glands produce a bicarbonate-rich fluid containing digestive and protective proteins and other components to be delivered into the gastrointestinal tract. Its function is under strict control of the autonomic nervous system. Salivary electrolyte and fluid secretion are primarily controlled by parasympathetic activity, while protein secretion is primaily triggered by sympathetic stimulation. Stress activates the hypothalamic - pituitary - adrenal axis. The peripheral limb of this axis is the efferent sympathetic/adrenomedullary system. Stress reaction, even if it is sustained for long, does not cause obvious damage to salivary glands. However, stress induces dramatic changes in the constituents of secreted saliva. Since salivary protein secretion is strongly dependent on sympathetic control, changes in saliva can be utilized as sensitive stress indicators. Some of the secreted compounds are known for their protective effect in the mouth and the gut, while others may just pass through the glands from blood plasma because of their chemical nature and the presence of transcellular salivary transporting systems. Indeed, most compounds that appear in blood circulation can also be identified in saliva, although at different concentrations. This work overviews the presently recognized salivary stress biosensors, such as amylase, cortisol, heat shock proteins and other compounds. It also demonstrates that saliva is widely recognised as a diagnostic tool for early and sensitive discovery of salivary and systemic conditions and disorders. At present it may be too early to introduce most of these biomarkers in daily routine diagnostic applications, but advances in salivary biomarker standardisation should permit their wide-range utilization in the future including safe, reliable and non-invasive estimation of acute and chronic stress levels in patients.

[Non-contrast brain ct based systemic thrombolysis of two wake up ischemic stroke patients in rural settings]. / Ébredési ischaemiás stroke esetek szisztémás thrombolysise natív koponya-CT-vizsgálatra alapozva egy vidéki kórházban.

Background and presentation - Conventionally the acute ischemic stroke patients who wake up with symptomes (WUS - wake up stroke) cannot benefit from systemic thrombolysis due to the uncertainty of the exact onset time of the cerebrovascular event. Perfusion brain imaging could be used as patient selection tool but the method is not available in many settings. Simple non-contrast CT scan is easily accessible and reliable as it shows the different stages of the evolving ischemia with high accuracy. Early brain CT scan results of WUS patients have the same characteristics as the ones who are surely within therapeutic window. The intravenous thrombolysis with recombinant tissue plasminogen activator (rTPA) of WUS patients seems to be similarly successful as the ones with known onset time, the treatment does not come with excess complications, higher rate of symptomatic intracranial hemorrhage was not found in previous reports. Purpose - In this report we present two systemic thrombolysis cases of acute ischemic stroke patients who woke up with stroke symptoms. Methods - In 2014 and 2015 we performed systemic thrombolysis for one wake up stroke patients, respectively. Both patients had large vessel occlusion. Indication was based on favourable non-contrast brain CT scan results. Results - Treatment of these two patients with rTPA proved to be safe, no hemorrhage occurred after treatment. Conclusion - We presented two acute ischemic stroke patients with symptomes at early wake up who were treated intravenously with recombinant tissue plasminogen activator based on non-contrast CT alone without complications and some moderate improvement at 90 days in the settings of a rural town hospital in a middle income country.

[Psychiatric disorders in epilepsy: clinical phenomena]. / Pszichiátriai zavarok epilepsziában: klinikai jelenségek.

The frequent psychiatric comorbidity in epilepsy compromises the quality of life of those affected, further increasing their suicide risk and the high burden of stigmatisation. Out of adulthood epilepsies, mesio-temporal lobe epilepsy carries the highest cognitive and psychiatric risk, making mental health comorbidities its inherent features. The pathomechanism of the epilepsy-related mental health symptoms and conditions appears to be related to undetected subclinical seizures, postictal exhaustion and inhibition, and the non-REM sleep related interictal epileptic activity. In our work we try to present some of the typical psychiatric syndromes and conditions seen in epilepsy. We aim to highlight the difficulties of treatment on the borderline of neurology and psychiatry.

Ictal analgesia in temporal lobe epilepsy - The mechanism of seizure-related burns.

Seizure-related injuries have major impact in the excess mortality and morbidity of epilepsy patients. Experimental data suggest that analgesia may develop during seizures contributing to the severity of seizure-related accidents, especially burns. We aimed to identify those seizure-types that may lead to burn-injuries by seizure-related analgesia. In our tertiary epilepsy centre, we asked 100 epilepsy patients having a history of seizure-related injury, to complete our burn-and-pain questionnaire. Fifty-one patients completed the survey; their epileptology data were collected and those with a seizure-related burn were interviewed. Forty-two out of the 51 patients (82%) had partial epilepsy and 9 (18%) had idiopathic generalised epilepsy. Twenty-six persons (51%) reported decreased pain perception during or after seizures in general. Twelve patients (23%) had suffered one or more seizure-related burn. Five of them fell onto a hot surface or fire accidentally, during generalized tonic-clonic seizures. Seven out of the 12 burnt patients (58%) grasped a hot object or reached into boiling fluid during complex partial seizures; without experiencing-, or reacting in response to pain. These patients had temporal lobe epilepsy, 5 of them had left temporal seizure onset. Our hypothesis based on the circumstantial analysis of our patients' burn-injuries; is that temporal lobe seizures may cause ictal/postictal analgesia. It may be caused by the seizure-related epileptic facilitation of the periaqueductal gray matter; the central pain-inhibiting structure of the brain. Seizure-related endogenous opioid-release my have a contributory role in inhibiting pain-perception. Ictal analgesia warrants better burn-prevention in temporal lobe epilepsy patients. Understanding the mechanism of ictal analgesia and specifying those seizures-types prone to cause it; may help indentifying human pain-inhibiting pathways.

Sarcosine-Based Glycine Transporter Type-1 (GlyT-1) Inhibitors Containing Pyridazine Moiety: A Further Search for Drugs with Potential to Influence Schizophrenia Negative Symptoms.

We have synthesized a novel series of N-substituted sarcosines, analogues of NFPS (N-[3-(biphenyl-4- yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine), as type-1 glycine transporter (GlyT-1) inhibitors. Several compounds incorporated a diazine ring inhibited recombinant hGlyT-1b expressed permanently in CHO cells and GlyT-1 in rat brain synaptosomal preparations. A structure-activity relationship for the newly synthesized compounds was obtained and discussed on the ground of their GlyT-1 inhibitory potencies. Replacement of the biphenyl-4-yloxy moiety in NFPS with a 5-pyridazinylphenoxy moiety (compounds 3, 4, 5, and 6) or a 2-phenyl-5- pyridazinyloxy moiety (compounds 10, 11, and 12) afforded compounds exhibiting potent inhibition on GlyT-1 activity. The GlyT-1 inhibitory properties of NFPS analogues, in which sarcosine was closed into a ring forming (methylamino)pyridazine-3-(2H)-one, were markedly reduced (compounds 13 and 14). The pyridazine-containing GlyT-1 inhibitors with in vitro GlyT-1 inhibitory potency also enhanced extracellular glycine concentrations in conscious rat striatum as was measured by microdialysis technique. In contrast to NFPS, sarcosine-based pyridazine containing GlyT-1 inhibitors failed to evoke compulsive running behavior whereas they inhibited phencyclidine- induced hypermotility in mice. It is believed that increase of extracellular concentrations of glycine by inhibition of its reuptake may probably influence positively glutamate N-methyl-D-aspartate (NMDA)-type ionotropic receptors in the central nervous system. This may have importance in the treatment of neuropsychiatric disorders associated with hypofunctional NMDA receptor-mediated glutamatergic neurochemical transmission. Thus, impaired NMDA receptor functions have been shown to be involved in the development of the negative symptoms and the cognitive deficit of schizophrenia and the treatment of these symptoms is the possible clinical indication of GlyT-1 inhibitors including those containing pyridazine moiety.

Critical role of extracellular vesicles in modulating the cellular effects of cytokines.

Under physiological and pathological conditions, extracellular vesicles (EVs) are present in the extracellular compartment simultaneously with soluble mediators. We hypothesized that cytokine effects may be modulated by EVs, the recently recognized conveyors of intercellular messages. In order to test this hypothesis, human monocyte cells were incubated with CCRF acute lymphoblastic leukemia cell line-derived EVs with or without the addition of recombinant human TNF, and global gene expression changes were analyzed. EVs alone regulated the expression of numerous genes related to inflammation and signaling. In combination, the effects of EVs and TNF were additive, antagonistic, or independent. The differential effects of EVs and TNF or their simultaneous presence were also validated by Taqman assays and ELISA, and by testing different populations of purified EVs. In the case of the paramount chemokine IL-8, we were able to demonstrate a synergistic upregulation by purified EVs and TNF. Our data suggest that neglecting the modulating role of EVs on the effects of soluble mediators may skew experimental results. On the other hand, considering the combined effects of cytokines and EVs may prove therapeutically useful by targeting both compartments at the same time.

Temporal alteration of spreading depression by the glycine transporter type-1 inhibitors NFPS and Org-24461 in chicken retina.

We used isolated chicken retina to induce spreading depression by the glutamate receptor agonist N-methyl-d-aspartate. The N-methyl-d-aspartate-induced latency time of spreading depression was extended by the glycine(B) binding site competitive antagonist 7-chlorokynurenic acid. Addition of the glycine transporter type-1 inhibitors NFPS and Org-24461 reversed the inhibitory effect of 7-chlorokynurenic acid on N-methyl-d-aspartate-evoked spreading depression. The glycine uptake inhibitory activity of Org-24461, NFPS, and some newly synthesized analogs of NFPS was determined in CHO cells stably expressing human glycine transporter type-1b isoform. Compounds, which failed to inhibit glycine transporter type-1, also did not have effect on retinal spreading depression. These experiments indicate that the spreading depression model in chicken retina is a useful in vitro test to determine activity of glycine transporter type-1 inhibitors. In addition, our data serve further evidence for the role of glycine transporter type-1 in retinal neurotransmission and light processing.

Liquid-phase synthesis of cobalt oxide nanoparticles.

Various liquid-phase syntheses of CoO and Co3O4 nanoparticles have been studied. The experiments focus on two synthesis routes: the coprecipitation and the sol-gel methods combined with thermal decomposition. The effect of synthesis route, the type of precursors (cobalt nitrate/chloride) and precipitation agent (carbonate, hydroxide, oxalic acid, and ammonia), the chemical compositions, pH, application of surfactants (PDMS, Triton X-100, NaDS, NaDBS, TTAB, ethyl acetate, citric acid), and the heat treatments on the properties of particles were investigated. The particle size and distribution have been determined by dynamic light scattering (DLS). The phases and the morphology of products have been analysed by XRD and SEM. The coprecipitation technique is less able to shape the particles than sol-gel technique. PDMS can be applied efficiently as surfactant in preparation methods. The finest particles (around 85 nm) with narrow polydispersity (70-100 nm) and spherical shape could be achieved by using sol-gel technique in medium of 1-propanol and ethyl acetate.

Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone.

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.

2,3-benzodiazepine-type AMPA receptor antagonists and their neuroprotective effects.

AMPA receptors are fast ligand-gated members of glutamate receptors in neuronal and many types of non-neuronal cells. The heterotetramer complexes are assembled from four subunits (GluR1-4) in region-, development- and function-selective patterns. Each subunit contains three extracellular domains (a large amino terminal domain, an agonist-binding domain and a transducer domain), and three transmembrane segments with a loop (pore forming domain), as well as the intracellular carboxy terminal tail (traffic and conductance regulatory domain). The binding of the agonist (excitatory amino acids and their derivatives) initiates conformational realignments, which transmit to the transducer domain and membrane spanning segments to gate the channel permeable to Na+, K+ and more or less to Ca2+. Several 2,3-benzodiazepines act as non-competitive antagonists of the AMPA receptor (termed also negative allosteric modulators), which are thought to bind to the transducer domains and inhibit channel gating. Analysing their effects in vitro, it has been possible to recognize a structure-activity relationship, and to describe the critical parts of the molecules involved in their action at AMPA receptors. Blockade of AMPA receptors can protect the brain from apoptotic and necrotic cell death by preventing neuronal excitotoxicity during pathophysiological activation of glutamatergic neurons. Animal experiments provided evidence for the potential usefulness of non-competitive AMPA antagonists in the treatment of human ischemic and neurodegenerative disorders including stroke, multiple sclerosis, Parkinson's disease, periventricular leukomalacia and motoneuron disease. 2,3-benzodiazepine AMPA antagonists can protect against seizures, decrease levodopa-induced dyskinesia in animal models of Parkinson's disease demonstrating their utility for the treatment of a variety of CNS disorders.

Synthesis of conformationally constrained glutamic acid homologues and investigation of their pharmacological profiles.

Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (+/-)-1 and (+/-)-2 on their activity/selectivity profiles. We therefore synthesized new derivatives (+/-)-3-(+/-)-6, which are homologues of glutamic acid containing three additional carbon units. Moreover, because the potency of NMDA antagonists can be markedly increased by replacing the distal carboxylate with the bioisosteric phosphonate group, we also prepared the corresponding phosphonate derivatives (+/-)-7-(+/-)-10. All new compounds were submitted to binding assays with iGluRs, and derivatives (+/-)-3-(+/-)-6 were also tested in second messenger assays at representative mGluR subtypes. All the applied structural modifications were detrimental to the interaction with NMDA receptors. Conversely, structural variation of the nonselective mGluR ligand (+/-)-2 led to derivative (+/-)-5, which behaved as a selective group I metabotropic receptor antagonist. Notably, upon i.c.v. administration in DBA/2 mice, amino acid (+/-)-5 produced a significant protection against audiogenic seizures, whereas it was inactive after i.p. administration.

The new 2,3-benzodiazepine derivative EGIS-8332 inhibits AMPA/kainate ion channels and cell death.

We observed in vitro neuroprotective and AMPA/kainate receptor antagonist effects of the new 2,3-benzodiazepine derivative EGIS-8332 (R,S-1-(4-aminophenyl)-7,8-methylenedioxy-4-cyano-4-methyl-3-N-acetyl-5H-3,4-dihydro-2,3-benzodiazepine) using the lactate dehydrogenase (LDH) release assay and patch clamp recordings on primary cultures of rat embryonic telencephalon neurons exposed to AMPA/kainate receptor agonists. EGIS-8332 potently decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and quisqualate induced LDH release (IC(50)=5.2+/-0.4 and 7.4+/-1.3 microM, respectively) from the cells. Whole-cell patch clamp studies carried out on the ionotropic glutamate receptors N-methyl D-aspartate (NMDA), as well as AMPA (and kainate) in cultured telencephalon neurons verified that EGIS-8332 blocked steady state responses to AMPA and kainate (IC(50)=1.7+/-0.4 and 6.2+/-1.6 microM, respectively), but hardly influenced currents evoked by NMDA. EGIS-8332 also inhibited kainate-evoked response in CHO cells expressing the flop variant of GluR1 receptor and, in cerebellar Purkinje cells at similar efficiency. The stereoselectivity of the inhibitory site is established by the clearly dissimilar inhibitory potency of the enantiomer components of EGIS-8332 differing in the configuration of methyl and cyano substituents on carbon C(4): the R(-) enantiomer was found to be the efficient species. This finding suggests that the inhibitory interaction between the channel protein and drug is promoted by presence of the C(4) methyl group. The inhibition of the AMPA/kainate ion channels by EGIS-8332 is non-competitive, not use dependent, and depends neither on the closed/open state of the channel, nor the membrane potential. These findings suggest an allosteric mechanism for the inhibition. These in vitro observations suggest that the compound might be useful in the treatments of certain acute and chronic neurological syndromes initiated by derangements of ionotropic glutamate receptor function.

Acoustic and electroacoustic spectroscopy of water-in-diluted-bitumen emulsions.

Water-in-oil emulsions of Athabasca bitumen diluted with toluene have been studied using the latest advances in acoustic and electroacoustic spectroscopy. From the sound attenuation spectra of emulsions, the water droplet size distribution is measured. The electrical surface charge density of the water droplets is obtained from the colloid vibration current. In the case of freshly prepared water-in-oil emulsions, the droplet size increased while the surface charge density decreased with time. The time-dependent relaxation of the surface charge ranges from several hours to 3 days, and it is probably due to the slow adsorption/desorption kinetics of bituminous components at the water-oil interface. This study illuminates the contribution of the electrostatic interactions to the stability of water-in-oil emulsions.

Adsorption of bituminous components at oil/water interfaces investigated by quartz crystal microbalance: implications to the stability of water-in-oil emulsions.

Silica-gel-coated QCM crystals oscillating in a thickness shear mode are used to measure adsorption of bituminous components in water-saturated heptol (1/1 vol ratio of a heptane/toluene mixture) at the oil/water interface. In addition to the viscoelasticity of the adsorbed film, the effects of the bulk liquid density and viscosity as well as the liquid trapped in interfacial cavities are taken into account for the calculation of adsorbed mass. Asphaltenes in heptol adsorb continuously at the oil/water interface, while resins (the surface-active species in maltenes) show adsorption saturation in the same solvent. For Athabasca bitumen in heptol, two adsorption regimes are observed depending on concentration. At low concentrations, a slow, non-steady-state, and irreversible adsorption takes place. At high concentrations, a steady-state adsorption with limited reversibility results in a quick adsorption saturation. The threshold concentration between these adsorption regimes is 1.5 wt % and 8 wt % for oil/water and oil/gold interfaces, respectively. The threshold concentration, the total adsorbed amount, and the flux of non-steady-state adsorption depend on the resin-to-asphaltene ratio. The threshold concentration is related to the earlier reported critical bitumen concentration characterizing the rigid-to-flexible transition of the interfacial film. We propose a new mechanism based on the change of the effective resin-to-asphaltene ratio with dilution to explain both the adsorption behavior and emulsion stability.

Adsorption isotherms of associating asphaltenes at oil/water interfaces based on the dependence of interfacial tension on solvent activity.

In the Gibbs adsorption equation, the application of solvent activity for the calculation of the surface/interfacial excess is proposed for nonideal or associating or pseudocomponents such as asphaltenes. For the aforementioned systems, only the mass-based phenomenological interfacial excess can be determined based on interfacial tension versus activity data. The use of the mole fraction is compared to the use of the activity when the adsorbed amount of associating asphaltenes is calculated at a water/toluene interface. Langmuir-type isotherms describe the adsorption of asphaltenes at toluene/water interfaces. Asphaltenes were treated to remove the resins and natural surfactants using cyclic precipitation and dissolution of asphaltenes at a fixed aliphatic/aromatic ratio. Different fractions of asphaltenes were obtained by changing the aliphatic/aromatic ratio of the precipitating solvent. The limiting molar masses of asphaltenes measured by vapor pressure osmometry are different for fractions precipitated at different heptane to toluene ratios. The mass-based adsorbed amounts at the water/toluene interface, at a 0.1 asphaltene-to-toluene mass-ratio, varied in the range of 0.8-2.8 mg/m(2), depending on the molar mass of asphaltenes.

Comparison of the AMPA antagonist action of new 2,3-benzodiazepines in vitro and their neuroprotective effects in vivo.

PURPOSE: AMPA receptor-mediated excitotoxicity is thought to be a critical process in diseases accompanied by neuronal cell loss following a hypoxic/anoxic state of the central nervous system. It has been suggested that blockade of AMPA receptors might result in significant protection of neurons against cellular damage. For testing the hypothesis, in vitro efficacy and in vivo neuroprotective action of new 2,3-benzodiazepine (2,3BDZ) AMPA antagonists have been compared. METHODS: 2.3BDZs were tested on kainate-evoked whole-cell currents in cultured neurons as well as on population spikes (PS) in rat hippocampal slices. Data were correlated with those obtained from the spreading depression (SD) experiments in chicken retina. Compounds were also examined in the gerbil bilateral carotid occlusion model (BCO), where percentage decrease of ischemia-related hypermotility (HM), impaired spatial memory (SA), and hypoxia-induced hippocampal CA1 neuronal cell death (CA1) were evaluated. RESULTS: Certain structural modifications of classical 2,3BDZs resulted in increased in vitro activity and improved in vivo efficacy. In particular, the halogen-substituted compounds EGIS-9879 and EGIS-9883 showed the highest neuroprotective efficacy (84% and 47% protection in CA1, 71% and 82% decrease in HM, respectively; 4 x 5 mg/kg i.p.) in BCO. PS and SD were correlated to the decrease of neuronal loss in the CA1 area. Lack of significant correlation was found between PS and CA1 (r = 0.437, p = 0.079) or SD and CA1 (r = 0.380, p = 0.146). CONCLUSIONS: Several new 2.3BDZ AMPA receptor antagonists have been synthesized at EGIS Pharmaceuticals characterized by remarkable in vitro and corresponding in vivo neuroprotective properties.

The glycine transporter-1 inhibitors NFPS and Org 24461: a pharmacological study.

The in vitro and in vivo pharmacology of two glycine transporter-1 (GlyT1) inhibitors, N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-propyl]sarcosine (NFPS) and R,S-(+/-)N-methyl-N-[(4-trifluoromethyl)phenoxy]-3-phenyl-propylglycine (Org 24461), was studied. NFPS and Org 24461 inhibited the uptake of [3H]glycine in hippocampal synaptosomal preparation with IC(50) values of 0.022 and 2.5 microM. Neither NFPS nor Org 24461 (0.1 microM) showed significant binding to alpha-1, alpha-2, and beta-adrenoceptors, D(1) and D(2) dopamine receptors, and 5-HT(1A) and 5-HT(2A) serotonin receptors in membranes prepared from rat brain or to cloned 5-HT(6) and 5-HT(7) receptors. At 10 microM concentrations, binding affinity was measured for NFPS to 5-HT(2A) and 5-HT(2C) serotonin receptors and alpha-2 adrenoceptors and for NFPS and Org 24461 to 5-HT(7) serotonin receptors. Glycine (0.1 mM) and sarcosine (5 mM) increased [3H]glycine efflux from superfused rat hippocampal slices preloaded with [3H]glycine. NFPS and Org 24461 (0.1 mM) did not influence [3H]glycine efflux, however, they inhibited glycine-induced [3H]glycine release. These findings indicate that NFPS and Org 24461 selectively inhibit glycine uptake without being substrates of the transporter protein. Several antipsychotic tests were used to characterize antipsychotic effects of NFPS and Org 24461 in vivo. These compounds did not alter apomorphine-induced climbing and stereotypy in a dose of 10 mg/kg p.o. in mice and did not induce catalepsy in a dose of 10 mg/kg i.p. in rats. The ID(50) values of NFPS were 21.4 mg/kg and higher than 30 mg/kg i.p. for inhibition of phencyclidine (PCP)- and D-amphetamine-induced hypermotility in mice and these values were 2.5 and 8.6 mg/kg i.p. for Org 24461. NFPS and Org 24461 did not exhibit anxiolytic effects in light-dark test in mice, in the meta-chlorophenylpiperazine (mCPP)-induced anxiety test (minimal effective dose or MED was higher than 3 mg/kg i.p.) and in the Vogel conflict drinking test in rats (MED was higher than 10 mg/kg i.p.). Both NFPS and Org 24461 (1-10 mg/kg i.p.) reversed PCP-induced changes in EEG power spectra in conscious rats. These data support the view that GlyT1 inhibitors may have potential importance in treatment of negative symptoms of schizophrenia.