Zsolt Jurányi

Egis Gyógyszergyár Nyrt., Budapeŝto, Budapest, Hungary

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Publications (12)23.78 Total impact

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    ABSTRACT: Synaptotoxic and neurotoxic effects of oßA are thought to be involved in the aetiopathology of Alzheimer?s disease. The molecular species of oßA underlying these pathologies as well as the respective mechanism(s) of action remain to be defined. This study aimed to devise an in vitro pharmacological screen for blockers of the neurotoxic effects of oßA. Neuron-enriched primary cultures of embryonic rat brain cortex were examined at various days after plating (DIV 15-25). Exogenous glutamate and NMDA (10-100 µM) caused marked cell death over 24h, which could be prevented by NMDA receptor antagonists. Inhibition of glutamate uptake by DHK (300µM) or TF-TBOA (15 nM) increased medium glutamate concentration significantly to 5-15 µM within 4 h and produced neurotoxicity by 24h. Exposure of the cells to oßA preparations resulted in the attachment of beta-amyloid immunoreactive material to the somatodendritic compartment of neurons, no labelling of glial cells was apparent. The oßA contained aggregates (>75K) that behaved as amyloid derived diffusible ligands. However, neurotoxic effects over 24h at up to 5µM nominal concentration of beta amyloid oligomer were inconsistent. When apparent, oßA neurotoxicity was significantly reduced by NMDA antagonists. Collectively, these data indicate that glutamate uptake systems are important for neuronal viability in neuron-enriched cultures and that oßA derived from synthetic beta-amyloid is not a reliable tool for pharmacological assays.
    No preview · Conference Paper · Jul 2014
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    ABSTRACT: 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.
    Full-text · Article · Dec 2010 · Neurochemical Research
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    ABSTRACT: Glycine is a critical factor in ischemia as reduced astrocytic and increased extracellular glycine levels aggravate the neurotoxic effect of glutamate and consequently, increase the extent of brain damage. Extracellular levels of glycine are primarily regulated by the plasma membrane glycine transporter 1. In the present study, we examined the effects of transient ischemia (1 h occlusion of the middle cerebral artery; followed by 0 h, 0.5 h, 1 h, 2 h, 4 h, 24 h or 48 h reperfusion) on immunoreactivity and mRNA expression of glycine transporter 1 in the rat forebrain. In control animals, glycine transporter 1-immunoreactivity was strong in diencephalic and certain telencephalic structures, moderate in the globus pallidus, and rather low in the cortex and striatum. In situ hybridization studies revealed a similar distribution pattern of glycine transporter 1 mRNA expression. One hour occlusion of the middle cerebral artery resulted in a significant decrease in ipsilateral glycine transporter 1-immunoreactivity and mRNA expression in a circumscribed region of the preoptic/hypothalamic area; both the immunoreactivity and mRNA exhibited further reductions with increasing reperfusion time. In contrast, the cerebral cortex and the globus pallidus showed an increase of glycine transporter 1-immunoreactivity after 0.5 h reperfusion; the elevation proved to be transient in the somatosensory cortex and remained sustained in the globus pallidus after longer reperfusion times. Western blot analysis of globus pallidus samples from the ipsilateral side confirmed higher glycine transporter 1 protein levels. These results suggest an elevated expression of the transporter protein facilitating the glial uptake of glycine from the extracellular space. However, glycine transporter 1 mRNA expression was not significantly different in the penumbra regions from the corresponding contralateral sites of the injury. Together, these findings indicate that post-translational mechanisms are of primary importance in elevating glycine transporter 1 protein levels following transient ischemia.
    No preview · Article · Mar 2008 · Neurochemistry International
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    ABSTRACT: Single neuron firing rate was recorded from dorsal raphe nucleus of anesthetized rats. The firing rate of raphe neurons varied from 4 to 8 discharge per second before drug administration and this neuronal activity was decreased by L-701,324 (2 mg/kg i.v. injection), a competitive antagonist of glycineB binding site of N-methyl-D-aspartate (NMDA) receptors. The glycine transporter type-1 (GlyT1) antagonists Org-24461 (10 mg/kg i.v.) and NFPS (3 mg/kg i.v.) reversed the inhibitory effect of L-701,324 on single neuron activity recorded from dorsal raphe nucleus of the rat. Org-24461 and NFPS both tended to increase the raphe neuronal firing rate also when given alone but their effect was not significant. This finding serves further evidence that glutamate released from axon terminals of the cortico-striatal projection neurons stimulates serotonergic neurons in the raphe nuclei and this effect is mediated at least in part by postsynaptic NMDA receptors. Thus, GlyT1 inhibitors are able to reverse the hypofunctional state of NMDA receptors, suggesting that these drugs may have beneficial therapeutic effects in neurological and psychiatric disorders characterized with impaired NMDA receptor-mediated transmission.
    No preview · Article · Feb 2008 · Neurochemistry International
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    ABSTRACT: Although levodopa is the current "gold standard" for treatment of Parkinson's disease, there has been disputation on whether AMPA receptor antagonists can be used as adjuvant therapy to improve the effects of levodopa. Systemic administration of levodopa, the precursor of dopamine, increases brain dopamine turnover rate and this elevated turnover is believed to be essential for successful treatment of Parkinson's disease. However, long-term treatment of patients with levodopa often leads to development of dyskinesia. Therefore, drugs that feature potentiation of dopamine turnover rate and are able to reduce daily levodopa dosages might be used as adjuvant in the treatment of patients suffering from Parkinson's disease. To investigate such combined treatment, we have examined the effects of two non-competitive AMPA receptor antagonists, GYKI-52466 and GYKI-53405, alone or in combination with levodopa on dopamine turnover rate in 6-hydroxydopamine-lesioned striatum of the rat. We found here that repeated administration of levodopa, added with the peripheral DOPA decarboxylase inhibitor carbidopa, increased dopamine turnover rate after lesioning the striatum with 6-hydroxydopamine. Moreover, combination of levodopa with GYKI-52466 or GYKI-53405 further increased dopamine turnover enhanced by levodopa administration while the AMPA receptor antagonists by themselves failed to influence striatal dopamine turnover. We concluded from the present data that potentiation observed between levodopa and AMPA receptor antagonists may reflect levodopa-sparing effects in clinical treatment indicating the therapeutic potential of such combination in the management of Parkinson's disease.
    Full-text · Article · Apr 2007 · Brain Research Bulletin
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    ABSTRACT: 2,3,5-Triphenyltetrazolium chloride (TTC) staining measures tissue viability used to evaluate infarct size. The goal of this study was to compare viability of neuronal tissue during the early phases of ischemia-reperfusion assessed either by perfusion of the brain with TTC solution transcardially, in vivo, or by staining brain slices, in vitro. The middle cerebral artery was occluded for 1 h in male SPRD rats and then reperfused for 0, 1, 4, 8, 16 and 24 h. Ischemic damage was evaluated by TTC staining, in vivo and in vitro, and by histology (Luxol Fast Blue and Fluoro-Jade staining, electron microscopy). Core volume of tissue injury measured in vivo was large at 0 h and steadily decreased by 50% (p<0.001) up to 16 h, but substantially increased from 16 to 24 h of reperfusion. In contrast, a significant core volume appeared at 4 h only, in vitro, and gradually increased up to 24 h. Core volume was larger in vivo than in vitro at all times except at 16 h when the opposite was observed. Evans blue administered intracardially stained TTC-negative areas at 1 and 24 h. Histology covered the evolution of serious tissue injury but also demonstrated some morphologically preserved neurons in the infracted area at 24 h. Formation of formazan from TTC can depend on both the staining method and the metabolic burden of the brain tissue causing uncertainties in the volume of ischemia-induced brain injury measured by TTC staining.
    Full-text · Article · Oct 2006 · Brain Research
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    ABSTRACT: Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain, loaded with [3H]serotonin ([3H]5-HT), superfused, and the electrically induced efflux of radioactivity was determined. The nonselective 5-HT receptor agonist 5-carboxamido-tryptamine (5-CT; 0.001 to 1 microM) inhibited the electrically stimulated [3H]5-HT overflow from raphe nuclei slices (IC50 of 3.34 +/- 0.37 nM). This effect of 5-CT on [3H]5-HT overflow was antagonized by the 5-HT7 receptor antagonist SB-258719 (10 microM) and the 5-HT(1B/1D) antagonist SB-216641 (1 microM), the IC50 values for 5-CT in the presence of SB-258719 and SB-216641 were 94.23 +/- 4.84 and 47.81 +/- 4.66 nM. The apparent pA2 values for SB-258719 and SB-216641 against 5-CT were 6.43 and 7.12, respectively. The inhibitory effect of 5-CT on [3H]5-HT overflow was weakly antagonized by 10 microM of WAY-100635, a 5-HT1A receptor antagonist (IC50 6.65 +/- 0.56 nM, apparent pA2 4.99). The antagonist effect of SB-258719 (10 microM) on 5-CT-evoked [3H]5-HT overflow inhibition was also determined in the presence of 1 microM SB-216641 or 1 microM SB-216641 and 10 microM WAY-100635, and additive interactions were found between the antagonists of 5-HT7 and 5-HT1 receptor subtypes. Addition of the Na+ channel blocker tetrodotoxin (1 microM) in the presence of SB-216641 (1 microM) and WAY-100635 (10 microM) attenuated the inhibitory effect of 5-CT on KCl-induced [3H]5-HT overflow. These findings indicate that 5-CT inhibits [3H]5-HT overflow from raphe nuclei slices of the rat by stimulation of 5-HT7 and 5-HT(1B/1D receptors, whereas the role of 5-HT1A receptors in this inhibition is less pronounced. They also suggest that 5-HT7 receptors are probably not located on serotonergic neurons and thus may serve as heteroreceptors in regulation of 5-HT release in the raphe nuclei. 5-CT (0.1 microM) also inhibited [3H]glutamate release, and SB-258719 (10 microLM) suspended this effect. We therefore speculated that the axon terminals of the glutamatergic cortico-raphe neurons may possess 5-HT7 receptors that inhibit glutamate release, which consequently leads to decreased activity of serotonergic neurons. The postulated glutamatergic-serotonergic interaction in the raphe nuclei was further evidenced by the finding that N-methyl-D-aspartate and AMPA enhanced [3H]5-HT release.
    Preview · Article · Sep 2004 · Neurochemical Research
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    ABSTRACT: The release of [3H]dopamine was measured in rat corticostriatal slice preparations that contained the striatum and the adjacent prefrontal cortex to maintained glutamatergic corticostriatal afferentation. These slices were prepared from either nontreated or 6-hydroxydopamine-pretreated rats. The slices were loaded with [3H]dopamine, submerged in a two-compartment bath so that the cortical region was contained in one compartment, the corpus callosum was passed through a silicone greased slot, and the striatal region was contained in the other compartment. The cortical and the striatal parts were superfused with Krebs-bicarbonate buffer independently. The release of [3H]dopamine was determined from the striatal part at rest and in response to electrical stimulation of the cortical area. Electrical stimulation of the cortical part increased the release of [3H]dopamine from the striatal part of the slices, and this release was found to be higher after lesion of the nigrostriatal dopaminergic pathway with 6-hydroxydopamine. Cortically evoked [3H]dopamine release was even higher in the presence of the dopamine precursor L-DOPA after 6-hydroxdopamine lesion. Perfusion of GYKI-53405, a noncompetitive AMPA receptor antagonist, in combination with L-DOPA further increased both basal and stimulation-evoked [3H]dopamine release, whereas GYKI-53405 by itself did not influence basal [3H]dopamine outflow from striatum. These findings indicate that, in parkinsonian striatum, the stimulatory effect of L-DOPA on dopamine release is potentiated by AMPA receptor blockade, and the antiparkinsonian effect of GYKI-53405 may be due to its L-DOPA sparing effect.
    No preview · Article · Feb 2004 · Critical Reviews in Neurobiology
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    ABSTRACT: Stroke or cerebrovascular accident reduces blood flow and decreases oxygen supply (ischemia) in brain tissue. This may be resulted from vascular obstruction when a blood vessel is blocked or by hemorrhage when bleeding occurs into the brain tissue. Decrease in oxygen supply shifts pH to acidosis and increases extracellular K+ concentration, which depolarizes neural cell membrane. Anoxic depolarization leads to excessive release of glutamate, which then activates various glutamate receptors in the synapse or the extrasynaptic space. Opening of ionotropic glutamate receptors (NMDA, AMPA and kainate receptors) causes influx of Na+ through the activated glutamate-gated ion channels. In response to anoxia, Ca2+ also enters the cells in excessive amounts via activated NMDA receptors and Ca2+-permeable AMPA receptors. This will lead to activation of several Ca2+-dependent intracellular signal transduction pathways (proteases, kinases, endonucleases, lipoxygeneses and nitric oxide synthase), which ultimately leads to neural death (Vizi et al., 1996; Parsons et al., 1998).
    No preview · Article · Feb 2004 · Advances in Experimental Medicine and Biology
  • Zsolt Juranyi · Michael J Zigmond · Laszlo G Harsing
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    ABSTRACT: A new method has been developed to investigate corticostriatal glutamatergic influence on [3H]dopamine release in striatum in complex corticostriatal slice preparation in vitro. Horizontal slices containing the striatum and the adjacent prefrontal cortex of rat brain were cut in a plane that maintains corticostriatal connections. After incubation with [3H]dopamine, slices were submerged in a two-compartment bath so that the cortical region was contained entirely in one compartment, corpus callosum passed through a silicone greased slot, and the striatal region was contained in the other compartment. A cannula was placed just above the striatal part of the slice and effluent was collected with a peristaltic pump, released tritiated materials were counted with a liquid scintillation counter. Electric field stimulation of cortex increased the release of [3H]dopamine in the striatum. Bicuculline (1 mM) increased the basal and stimulated release of [3H]dopamine in the striatum in response to cortical stimulation of cortex indicating the GABAergic control on dopamine release. This method allows investigation of the effect of cortical stimulation on glutamate-dopamine-GABA interactions in the striatum in vitro that might help to understand better the neurochemical background of schizophrenia or Parkinson's disease.
    No preview · Article · Jul 2003 · Journal of Neuroscience Methods
  • Zsolt Jurányi · Beáta Sperlágh · E.Sylvester Vizi
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    ABSTRACT: The objective of this study was to study how the outflow of []purines is altered during a brief period of ischemic-like conditions in superfused hippocampal slices and to show whether it is regulated by P2 purinoceptors and the nitric oxide (NO) pathway. The outflow of []purines increased in response to 5 min of combined hypoxia/hypoglycemia. High performance liquid chromatography analysis verified the efflux of []adenosine-triphosphate, []adenosine-diphosphate, []adenosine-monophosphate, []adenosine, []inosine, and []hypoxanthine in response to ischemic-like conditions. The P2 receptor antagonists suramin and pyridoxal-phosphate-6-azophenyl-2′-4′-disulphonic-acid-tetrasodium (PPADS) reduced significantly the []purine efflux evoked by ischemic-like conditions, showing that P2 purinoceptors are involved in the initiation of purine outflow. The NO synthase inhibitor N-nitro-l-arginine-methyl-ester (l-NAME) attenuated significantly the []purine outflow, evoked by ischemic-like conditions, while 7-nitroindazole (7-NI) caused only a mild decrease in the outflow. The NO donor sodium nitroprusside increased significantly the basal efflux of []purines. In summary, a brief period of combined hypoxia/hypoglycemia induced the efflux of ATP in addition to the outflow of other purines. Since P2 receptor antagonists decreased the []purine outflow evoked by ischemic-like conditions we propose that ATP, acting on P2 purinoceptors, is responsible for further efflux of purines after ischemic-like period. It seems likely that NO is also involved in the regulation of purine outflow, since inhibition of NO production attenuated the []purine outflow, evoked by ischemic-like conditions, while exogenous NO facilitated the basal outflow.
    No preview · Article · Apr 1999 · Brain Research
  • László Gábor Hársing · Zsolt Jurányi
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    ABSTRACT: Kortikostriátális agyszeletkészítményt fejlesztettünk ki, mely lehetővé teszi a Gluerg, GABAerg, DAerg neurotranszmisszió kölcsönhatásainak vizsgálatát a striátum állományában. A szuperfúziós rendszerben elkülönítve mértünk [3H]DA felszabadulást a striátum és a cortex állományából és a kéreg elektromos ingerlése [3H]DA felszabadulást váltott ki a striátumból. [3H]DA felszabadulást a potenciális antipszichotikum GlyT1 gátlók jelenlétében határoztuk meg. A GlyT1 gátlók potencírozzák a striátum NMDA receptorait, ezek a receptorok különböző neuronokban expresszálódhatnak, glicin iránti érzékenységük eltérő lehet. Közleményben foglaltuk össze a GlyT1 gátlók neurobiológiáját és medicinális kémiáját. [3H]5-HT felszabadulást vizsgáltunk patkány izolált rafe mag szeletben és meghatároztuk az 5-HT7 receptorok szerepet az e területről mérhető 5-HT felszabadulás szabályozásban. Az 5-HT7 receptorok a corticorafe Gluerg neuronok axon terminálisain expresszálódnak és heteroreceptorként vesznek részt a rafeból mérhető [3H]5-HT felszabadulás szabályozásában. Ezek a receptorok a rafe magban résztvésznek a Glu-5-HT neuronok közötti interakcióban és a rafe-kortikális 5-HTerg neuronok aktivitásának szabályozásában. A rafe neurotranszmisszióját review közleményben foglaltuk össze, bemutatva az 5-HT felszabadulásban az 5-HT1/2 receptor altípusok, valamint az 5-HT3/7 receptorok által megvalósuló gátlás és serkentés mechanizmusokat. E szabályzások alapját képezhetik a pszichózis 5-HT elméletének. | We have developed a corticostriatal slice preparation in order to study interactions between glutamatergic, GABAergic and dopaminergic neurons. Release of [3H]dopamine from striatum was induced by cortical stimulation. This release was studied after impairment of dopaminergic terminals by 6-OHDA and hypoxic insults and also in the presence of the glycine transporter-1 (GlyT1) inhibitor Org-24461, a potential antipsychotic agents. Results obtained indicate that GlyT1 inhibitors may exert their antipsychotic effects by potentiation of striatal NMDA receptors with different locations and sensitivity towards the receptor coagonist glycine. A detailed review was prepared to analyse the neurobiology and medicinal chemistry of GlyT1 inhibitors. Moreover, [3H]5-HT release from raphe nuclei slices was also determined to demonstrate the role of 5-HT7 receptors in the regulation of raphe nuclei 5-HT projection neurons. We showed that 5-HT7 receptors in the raphe nuclei are heteroreceptors and are expressed in the membrane of cortico-raphe glutamatergic axon terminals. Although these receptors regulate local glutamatergic-serotonergic interaction in the raphe nuclei they alter activity of raphe-cortical 5-HT neurons. The neurotransmission in the raphe has been reviewed demonstrating feedback inhibition and stimulation of raphe 5-HT release by various subtypes of 5-HT1/2 receptors and also by 5-HT3/7 receptors. These interactions may be the base for 5-HTergic theory of psychotic states.
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Publication Stats

259 Citations
23.78 Total Impact Points

Institutions

  • 2004-2010
    • Egis Gyógyszergyár Nyrt.
      Budapeŝto, Budapest, Hungary
    • Acheuron Hungary Ltd.
      Algyő, Csongrád, Hungary
  • 1999
    • Hungarian Academy of Sciences
      • Department of Pharmacology
      Budapeŝto, Budapest, Hungary