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1

Excitotoxic neuronal injury in chronic homocysteine neurotoxicity studied in vitro: The role of MNDA and group I metabotropic glutamate receptors

100%
Zieminska E., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2006
|
tom 66
|
nr 4
Elevated homocysteine is a risk factor in cardiovascular diseases and neurodegeneration. Among the putative mechanisms of homocysteineevoked neurotoxicity, disturbances in methylation processes and NMDA receptor-mediated excitotoxicity have been suggested. Our previous studies demonstrated that group I metabotropic glutamate receptors along with NMDA receptors participate in acute homocysteine-induced neuronal damage. In this study, using propidium iodide staining, we tested whether the same mechanism may mediate chronic homocysteine neurotoxicity. Our results confirmed that the application of D,L-homocysteine in micromolar concentrations for 3 days induces neurodegeneration in primary cultures of cerebellar granule neurons. Uncompetitive NMDA receptor antagonist MK801, and mGlu1 or mGlu5 receptor antagonists (LY367385 and MPEP, respectively), given alone provided very limited neuroprotection. However, simultaneous application of the NMDA receptor antagonists MK-801, memantine or amantadine and MPEP almost completely prevented chronic homocysteine neurotoxicity. These findings suggest a novel therapeutic strategy to combat neurodegeneration induced by hyperhomocysteinemia comprising a combination of antagonists of group I metabotropic glutamate receptors and NMDA receptors.
2

Nicotinamide and 1-methylnicotinamide reduce homocysteine neurotoxicity in primary cultures of rat cerebellar granule cells

81%
Slomka M., Zieminska E., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2008
|
tom 68
|
nr 1
Nicotinamide is an important cofactor in many metabolic pathways and a known neuroprotective substance, while its methylated product, 1-methylnicotinamide, is a suspected neurotoxin. Homocysteine is a risk factor in Alzheimer’s disease and neurodegeneration, causing inhibition of methylation processes and inducing excitotoxicity. In this study, using primary cultures of rat cerebellar granule cells and propidium iodide staining, we investigated the neurotoxicity of nicotinamide and 1-methylnicotinamide, and their neuroprotective potential in acute and sub-acute homocysteine neurotoxicity. Our results demonstrated that nicotinamide and 1-methylnicotinamide applied for 24 h to cultures at concentrations of up to 25 mM had no effect on neuronal viability. Moreover, nicotinamide at concentrations of 5–20 mM and 1-methylnicotinamide at 1–10 mM applied to cells 24 h before, and for 24 h after an acute 30 min application of 25 mM D,L homocysteine, reduced neuronal damage. 1-Methylnicotinamide at concentrations of 250 and 500 µM showed neuroprotective activity during a sub-acute 24-h exposure to 2.5 mM D,L-homocysteine, while 5 and 25 mM nicotinamide also evoked neuroprotection. These findings do not support suggestions that 1-methylnicotinamide may act as an endogenous neurotoxic agent; rather, they indicate the neuroprotective ability of nicotinamide and 1-methylnicotinamide in homocysteine neurotoxicity. The exact mechanisms of this neuroprotection are unclear and require further investigation.
3

Interaction between indocyanine green and gadobutrol in cerebellar granule neurons cultures

81%
Zieminska E., Toczylowska B., Goch G., Liebert S.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
In experiments we used indocyanine green (ICG), and gadobutrol (Gad) contrast dyes. There is no information about parallel application of ICG and Gad, therefore we decided to study their toxicity using primary cerebellar granule cells culture (CGC). The aim of study was to assess the minimal ICG concentration which evokes neurotoxicity. 30 min exposition to 75 and 125 μM ICG resulted in neurotoxicity. We observed imbalance in calcium homeostasis (extra- and intracellular) after addition of ICG, which can be one of the mechanisms of ICG neurotoxicity. We measured absorbance and NMR spectra for 25–125 µM ICG concentrations in three solvents. Gad contrast media mixed with ICG were also measured and neurotoxicity of this mixture was examined. The shape of absorption and NMR spectra show differences between water, water with 2.3 mM Ca2+ and Locke25 for all analyzed ICG concentrations. Other possible mechanism of ICG neurotoxicity can be dose dependent oligomerization of ICG. We did not observe any toxic effect of Gad on CGC. Protective effect on surviving neurons after treatment of ICG, dependent on Gad dose and sequence of its administration (before > simultaneously > after addition of ICG) was observed. However, the mechanism of this phenomenon remains not clear. Supported by grant 2011/03/B/ST7/02576.
4

Tetrabromobisphenol A-induced oxidative stress in primary cultures of rat cerebellar granule cells:triggering role of CA2plus imbalance

81%
Zieminska E., Lenart J., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: Brominated flame retardant tetrabromobisphenol A (TBBPA) contaminates the environment and displays cytotoxic potential. The mechanism of its cytotoxicity in neurons encompasses interference with NMDA and ryanodine receptors (NMDARs and RyRs) resulting in increase in intracellular Ca2+ concentration (Ca2+i), and induction of oxidative stress, which may be primary, or secondary to rises in Ca2+i. The aim of this study was to assess the role of excitotoxicity and Ca2+ imbalance in TBBPA-evoked oxidative stress and cytotoxicity in neurons. METHODS: Using the primary cultures of rat cerebellar granule cells (CGC) we evaluated oxidative stress induced by an acute challenge with 10 or 25 µM TBBPA by measuring reactive oxygen species (ROS) production, intracellular glutathione (GSH) level, SOD-1 and SOD-2 level, catalase activity, and the level of Zn2+ in CGC. Zn2+ and Ca2+i were measured fluoromertically, moreover TBBPA toxicity 24 h after the exposure was evaluated using propidium iodide staining. The pharmacological tools included NMDARs antagonist MK-801, ryanodine with bastadin 12 inhibiting RyRs, and various free radical scavengers. RESULTS: TBBPA induced concentration-dependent decrease in CGC viability, increase in Ca2+i and Zn2+ level, in ROS production, decrease in GSH level, catalase activity and SOD-2 level. Co-application of NMDARs and RyRs inhibitors which completely prevented increase in Ca2+i, resulted in a significant, but not complete cytoprotection, and only partially reduced the oxidative stress in the CGC. Also administration of ROS scavengers provided only partial cytoprotection and reduction of oxidative stress. CONCLUSIONS: We conclude that the production of free radicals resulting secondarily from TBBPA-evoked excitotoxicity and increases in Ca2+ level together with oxidative stress possibly induced primarily by TBBPA, both participate in TBBPA cytotoxicity in cultured neurons. Supported by the NCN grant 2012/05/B/NZ7/03225.
5

Tetrabromobisphenol A directly interferes with activity of NMDA isolated cortical membranes

81%
Diamandakis D., Zieminska E., Salinska E., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: The results of early studies suggested a role of glutamate receptors in the mechanism of increases in intracellular Ca2+ concentration ([Ca2+]i ) and cytotoxicity induced by the brominated flame retardant, tetrabromobisphenol-A (TBBPA). Although now interest has focused mainly on TBBPA-induced Ca2+ release from intracellular stores, here we revisited the former issue and tested the involvement of NMDA receptors (NMDARs) in Ca2+ imbalance in neurons induced by TBBPA. METHODS: These effects were examined in primary cultures of rat cerebellar granule cells (CGC), and then, using isolated cortical membranes we checked whether TBBPA directly interacts with the agonist and modulatory sites of the NMDAR complex. On the 7th day in vitro CGC were treated with TBBPA at low µM concentrations. 45Ca uptake was detected and changes in [Ca2+]i , and plasma membrane potential were measured using fluorescent probes fluo-3 and oxonol VI, respectively. Moreover effects of TBBPA on specific binding of [3 H]MK-801, [3 H]glutamate and [3 H]glycine to isolated fraction of the rat brain cortex membranes were studied. RESULTS: The results demonstrated that TBBPA concentrationdependently increased 45Ca uptake and [Ca2+]i in CGC, and the increase was partially inhibited by NMDARs antagonist, MK-801. This effect was additive to glutamate-induced Ca2+ transients. TBBPA increased oxonol VI fluorescence in CGC reflecting depolarization of the cultured neurons. The binding assays demonstrated potentiation by TBBPA binding of [ 3 H]MK-801 in the presence of NMDA and glycine, with maximum at 20 µM TBBPA, which was inhibited by spermidine and antagonists of the polyamines’ site; inhibition by TBBPA of [ 3 H]glutamate binding, and no significant effect on [3 H]glycine binding. CONCLUSIONS: TBBPA directly enhances the activity of NMDARs in neuronal membranes by interfering with their modulatory sites, and by inducing depolarization of neurons. Supported by the NCN grant 2012/05/B/NZ7/03225
6

Neuroprotective potential of imethylnicotinamide in homocysteine-induced neurotoxicity in vitro

81%
Slomka M., Zieminska E., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
7

Pharmacological profiles of NMDA-induced eicosanoid release in rabbit hippocampus in vivo

81%
Zieminska E., Salinska E., Stafiej A., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
1995
|
tom 55
|
nr 5
8

Ryanodine receptors participate in the induction of mitochondrial permeability transition and excitotoxinc damage of cultured rat cerebellar granule cells

81%
Zieminska E., Gordon-Krajcer W., Matyja E., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2001
|
tom 61
|
nr 3
9

Complex mechanisms of tetrabromobisphenol A neurotoxicity in primary cultures of rat cerebellar granule cells

81%
Zieminska E., Stafiej A., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Tetrabromobisphenol A (TBBPA) is a brominated flame retardant considered as the environmental toxin affecting the brain. The exact molecular mechanisms of the TBBPA-induced neurotoxicity are unclear, however recent studies suggest a role of the NMDA receptor-mediated excitotoxicity and/or of calcium imbalance. To verify this hypothesis in the present study we examined relation between toxicity of TBBPA applied to cultured neurons at the micro molar concentration range and activation of the NMDA receptors as well as changes in the intracellular calcium homeostasis, oxidative stress and a decrease in the mitochondrial membrane potential. Experiments were performed using an in vitro model of the primary cultures of rat cerebellar granule cells at 7th day in vitro. To evaluate TBBPA neurotoxicity, the cells were exposed for 30 min to TBBPA, and neuronal viability was tested after 24 h with propidium iodide staining. Changes in calcium homeostasis were characterized by measuring 45Ca uptake and increases in fluorescence of calcium-sensitive probe fluo-3. Changes in the mitochondrial membrane potential and in free radical production were evaluated using the fluorescent probes rhodamine 123 and DCF, respectively. The results demonstrated that TPPBA in the concentration-dependent manner in the range of 25 - 100µM induced severe neurotoxicity. TBBPA in concentrations exceeding 5 µM triggered rise in the intracellular calcium level, which was sensitive to inhibitors of ryanodine receptors 2.5 µM bastadin 10 with 200 µM ryanodine, but not to 2ABP, which inhibits IP3 receptors. TBBPA in concentrations above 25µM activated 45Ca uptake, which was sensitive to uncompetitive NMDA receptor antagonist 0.5 µM MK-801. Moreover we observed accumulation of the reactive oxygen species and a drop in the mitochondrial membrane potential evoked by TBBPA applied at micro molar concentrations. The toxic effect of TPPBA in concentrations up to 10 - 15 µM was insensitive to antagonists of NMDA receptors and ryanodine receptors, MK-801 and bastadin 10 with ryanodine, respectively. This points to a role of the mechanism of TBBPA neurotoxicity other than excitotoxicity and calcium imbalance. Tentatively we identify it as the oxidative stress. Collectively, these data point to complexity of the mechanisms of toxic effects of TBBPA. Depending of TBBPA concentrations they comprise oxidative stress, the release of calcium from ryanodie sensitive stores in endoplasmic reticulum and activation of NMDA receptors. This work was supported by the Polish MNiSW grant N N401 024635.
10

Is the NMDA receptor involved in neurotoxicity of pvp-coated silver nanoparticles? Study on primary cultures of cerebellar granule cells

81%
Zieminska E., Stafiej A., Struzynska L.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
Silver nanoparticles (NAg) possess antibacterial properties thus are widely used in many applications in medicine, life sciences and biotechnology. Nanoparticles can be found in vertebrate brain, but little is known about their neurotoxicity. The aim of this study was to investigate how NAg can contribute to neuronal cell death. In the study primary cultures of rat cerebellar granule cells (CGC) were used. We tested hypothesis concerning the role of glutamatergic NMDA receptors in NAg-evoked neurotoxicity. In our study changes in intracellular calcium (Ca2+) homeostasis, uptake of 45Ca2+, reactive oxygen species (ROS) production, mitochondrial membrane potential and cells viability were investigated. We used commercially available 0.2% polyvinylpyrrolidone (PVP)-coated NAg <100 nm. To avoid sedimentation and agglomeration, before application to the CGC culture, NAg were sonicated with fetal calf serum. NAg were applied in concentration 2.5–75 µg/ml for 10, 30 min or 24 h, depending on experiment. As a pharmacological tool 0.5 µM MK801, a noncompetitive inhibitor of NMDA receptor, was used. After 10 min incubation in the presence of 25–75 µg/ ml NAg dose dependent increase of 45Ca2+ concentration was observed in neurons. This increase was comparable to that evoked by 100 µM glutamate and was completely abolished by MK801. Using fluorescent intracellular calcium indicator fluo3 we observed increase in intracellular calcium level by 200% compared to control, which was partially diminished by MK801. ROS production was measured using fluorescent dye DCF. After 30 min incubation with 75 µg/ml NAg the increase by about 35% over control level was observed and application of MK801 reduced it significantly. Changes in mitochondrial membrane potential were determined using rhodamine (R123). We observed significant decrease in mitochondrial potential during 30 min incubation with different concentrations of NAg and also in this case administration of MK801 was protective. Cells viability was assessed after 24 h incubation with NAg µg/ml alone or together with MK801. Application of MK801 increased neuronal survival from 50% up to 80%. Our results show that excitotoxicity via activation of NMDA receptor, followed by calcium imbalance, destabilization of mitochondrial function and ROS production, seems to be important mechanism involved in neurotoxicity evoked by NAg in cultured neurons. Supported by grant NN401619938.
11

Role of group 1 metabotropic glutamate receptors in homocysteine neurotoxicity

81%
Zieminska E., Stafiej A., Kozlowska H., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
12

Homocysteine neurotoxicity:involvement of calcium and mitochondrial alternations

81%
Zieminska E., Kozlowska H., Stafiej A., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2006
|
tom 66
|
nr 4
13

Acute cytotoxicity evoked by tetrabromobisphenol A in primary cultures of rat cerebellar granule cells outweighs the effects of polychlorinated biphenyls

81%
Zieminska E., Stafiej A., Toczylowska B., Lazarewicz J. W.
Polish Journal of Environmental Studies
|
2012
|
tom 21
|
nr 4
The aim of this study was to identify, among selected environmental toxins, the substance with the highest in vitro toxicity to neurons combined with the most marked induction of calcium imbalance, oxidative stress and mitochondrial dysfunction. Exposure of primary cultures of rat cerebellar granule cells for 30 min to polychlorinated biphenyls (PCBs) or brominated flame retardants (BFRs) at concentrations of 10-50 µM identified tetrabromobisphenol A as the compound with the highest toxicity. At a concentration of 25 µM, apart from the moderate activation of ⁴⁵Ca uptake, this BFR induced the most pronounced increase in intracellular Ca²⁺ concentration, depolarization of mitochondria, and activation of ROS production.
14

NMDA-induced mitochondrial permeability transition in rabbit brain: in vivo and in vitro study

81%
Zieminska E., Matyja E., Ziembowicz A., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
1999
|
tom 59
|
nr 3
15
Content available remote

Bastadin 12 and ryanodine reveal similarities between thapsigargin- and tetrabromobisphenol A-induced intracellular Ca2plus release in cultured cerebellar granule cells

81%
Zieminska E., Stafiej A., Toczylowska B., Lazarewicz J. W.
Journal of Physiology and Pharmacology
|
2014
|
tom 65
|
nr 5
16

Caspase 3 and homocysteine-induced excitotoxicity

81%
Zieminska E., Stafej A., Kozlowska H., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
17

Dysregulation of calcium homeostasis and oxidative stress: interrelated mediators of tetrabromobisphenol a toxicity in primary cultures of rat cerebellar granule cells

71%
Lazarewicz J. W., Zieminska E., Lenart J., Diamandakis D., Salinska E.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
There are alarming reports on cytotoxicity of the brominated flame retardant tetrabromobisphenol A (TBBPA) in the in vitro cellular models, that seem to be mediated by increases in the intracellular calcium concentration ([Ca2+] i) and oxidative stress. Still, the mechanisms of both these phenomena, their mutual cause‑and‑effect relationships and implication in the TBBPA-induced neuronal death are not clear. In our experiments the primary cultures of rat cerebellar granule cells (CGC) were acutely challenged with TBBPA. Such induced rises of [Ca2+]i appeared to result independently from the intracellular Ca2+ release via ryanodine receptors transformed into dysfunctional leak channels, and from Ca2+ influx mediated by NMDA receptors. These receptors seem to be activated indirectly, due to depolarization of neurons by TBBPA, which is mediated by the voltage-gated sodium channels and ionotropic glutamate receptors. TBBPA induced oxidative stress as evidenced by ROS production and decrease in GSH content and catalase activity. The pharmacological preventing of the TBBPA-induced rises in [Ca2+]i also entirely prevented oxidative stress induced by 10 µM TBBPA, while the effects of 25 µM TBBPA were only partially reduced. Application of free radical scavengers significantly reduced TBBPA‑induced oxidative stress, but did not interfere with rises in [Ca2+]i. This indicates that TBBPA-induced increase in [Ca2+]i is a primary and major event triggering oxidative stress, however at higher µM concentrations a Ca2+‑independent portion of oxidative stress emerges, and this effect seems to be directly induced by TBBPA. Furthermore, the separate application of inhibitors of TBBPA-induced Ca2+ transients and free radical scavengers, both provided a strong but incomplete cytoprotection, whereas combination of these substances completely prevented the death of neurons, showing that Ca2+ imbalance and oxidative stress are the triggers of acute TBBPA toxicity in CGC. FINANCIAL SUPPORT: This study was supported by the Polish National Science Centre grant no. 2012/05/B/ NZ7/03225.
18

Modulation of NMDA-evoked prostaglandin D2 release in rabbit hippocampus in vivo

71%
Lazarewicz J. W., Salinska E., Stafiej A., Ziembowicz A., Zieminska E.
Acta Neurobiologiae Experimentalis
|
1997
|
tom 57
|
nr 5
19

Glutathione and homocysteine toxicity in rat astrocytes in vitro

71%
Zieminska E., Wegrzynowicz M., Dybel A., Albrecht J., Lazarewicz J.
Acta Neurobiologiae Experimentalis
|
2007
|
tom 67
|
nr 3
20

Open-chain half bastadins mimic the effects of cyclic bastadins on calcium homeostasis in cultured neurons

71%
Zieminska E., Lazarewicz J. W., Couladouros E. A., Moutsos V. I., Pitsinos E. N.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 1
Controlled fl uctuations in intracellular calcium concentrations play an important role in many cellular processes such as muscle contraction, secretion, metabolism, and neuronal function. Ryanodine receptors (RyR) are intracellular ion channels that mediate the release of calcium ions from internal stores and have been suggested as pharmacological targets for heart disease and neurodegenerative diseases. Bastadins are an ever-growing family of marine natural products isolated from sponges. Seemingly subtle differences in their substitution pattern suffi ce to alter the response observed. To characterize bastadin-induced changes in calcium homeostasis we measured, using FLUO-3, a calciumsensitive fl uorescent probe, the ability of bastadin 5 (positive control) and the acyclic analogues 2a, b and 4 to increase the intracellular calcium concentration in cultured rat cerebellar granule cells. We monitored also the infl ux of extracellular calcium to neurons employing 45Ca isotope. The observed effect of the acyclic analogues on calcium accumulation decreased in order: 4>2b>2a. Addition of ryanodine to medium before application of bastadin abolished analyzed effects. This observation indicates that RyR are the primary targets for their pharmacological activity. Thus, the infl ux of extracellular calcium to bastadin-treated neurons appears to be a secondary effect resulting from the release of calcium from the ryanodine-sensitive pool. Constraining the catechol aryl ether moiety of bastadins by incorporation into a macrocyle is not necessary in order to mimic the effects of these marine natural products on neuronal calcium homeostasis. Simple, acyclic analogues that embody the ìwesternî or ìeasternî parts of bastadins were found to evoke comparable responses with bastadin 5.
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