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1

Alternative methods of neuroprotection in brain ischemia

100%
Lazarewicz J.
Acta Neurobiologiae Experimentalis
|
2009
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tom 69
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nr 3
Learning of cellular and molecular mechanisms of the ischemic neuronal damage led to development of pharmacological methods of neuroprotection targeted at these mechanisms. They were effective in animal stroke models, but none of them passed clinical trials. Thus the alternative experimental neuroprotective strategies emerge. Preclinical studies demonstrated that mild hypothermia signifi cantly improves the outcome in the animal models of stroke and brain injury. This method of still unclear mechanism has been successfully used in specifi c clinical conditions and has been tested in several trials. It is hoped that moderate hypothermia soon may be introduced as an alternative method of stroke treatment. Ischemic preconditioning is a way of inducing tolerance to brain ischemia by preceding the injurious ischemia with the sub-lethal stressors like short ischemia, mild hypoxia, heating or pharmacological treatment. The exact mechanisms of activation and induction of brain tolerance to ischemia by preconditioning are not clear. Recently post-conditioning, i.e. neuroprotective effect of the post-treatment with sub-lethal stressors after injurious ischemia has been demonstrated, pointing to a therapeutic potential of such a treatment, still being tested at the preclinical level.
2

Common mechanisms of interacellular calcium release by TBBPA and thapsigargin in cultured neurons

51%
Ziemianska E., Stafiej A., Lazarewicz J.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Tetrabromobisphenol A (TBBPA) is a brominated flame retardant and the environmental toxin affecting the brain. The molecular mechanisms of the TBBPA-induced neurotoxicity are still unclear although recent studies suggest a role of calcium imbalance. It has been hypothesized that TBBPA may act as an intracellular calcium releaser from the stores in endoplasmic reticulum. To verify this hypothesis in the present study we examined changes in the intracellular calcium homeostasis induced by TBBPA, and their pharmacological modulation. 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 using the calcium-sensitive fluorescent probe fluo-3. The results demonstrated that TPPBA 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. The same features were disclosed for the effects of thapsigargin, that is a recognized inhibitor of the calcium pump SERCA and a well known calcium releaser. TPPBA in the concentration-dependent manner in the range of 2.5 - 100 µM induced severe neurotoxicity. The toxic effect of TPPBA in concentrations up to 10 - 15 µM was insensitive to antagonists of ryanodine receptors, bastadin 10 with ryanodine. Collectively, these results indicate that TBBP-A like thapsigargin is a calcium releaser destabilizing the ryanodine receptors, however this effect does not explain the mechanism of TBBPA neurotoxicity. This work was supported by the MNiSW grant N N401 024635.
3

Analysis of putative toxic interaction of L-methylnicotinamide with dopaminergic neurons

51%
Slomka M., Ziembowicz A., Lazarewicz J.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
It has been proposed that in the Parkinson’s disease exo- or endogenous N-methyl-compounds like 1-methylnicotinamide (MNA) could be accumulated by dopaminergic neurons and induces neurotoxic effects, as happens with MPP+. The aim of this study was to test this hypothesis by comparing direct effects of MPP+ or MNA application into the striatum of 7 day old rat pups and to the substantia nigra (SN) of the adult rats. Microinjections of tested substances in doses: MPP+ (20 and 100 μg) and MNA (20, 40, 80 μg), were made unilaterally. Effects of MNA and MPP+ on pups’ striatum were evaluated by TTC staining and the lesion volume was calculated using the ImageJ program. In the SN of adult rats alterations in the level of tyrosine hydroxylase (TH) immunostaining were examined at the 5th day after MPP+ or MNA injection, utilizing antibody specifi c to TH. Moreover the coronal sections (20 μm thick) of the SN were examined to evaluate MNA- or MPP+-induced glial activation with the glia-specifi c lectin. Using these methods we did not observe any toxic effect of MNA. MPP+ induced statistically signifi cant damages in the striatum of rat pups, whereas there was no lesion after MNA injection. Also in the SN of adult rats MPP+ caused 50% loss of TH-positive neurons and doubled the number of activated glial cells, while MNA injection had no visible effect. Summing up, present data did not demonstrate any toxic effects of MNA on dopaminergic neurons in the rat brain in vivo.
4

Glutathione and homocysteine toxicity in rat astrocytes in vitro

45%
Zieminska E., Wegrzynowicz M., Dybel A., Albrecht J., Lazarewicz J.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
|
nr 3
5

Glutamate transporters in rat brain exposed to polychlorinated biphenyls and polibrominated flame retardants

45%
Sulkowski G., Struzynska L., Dabrowska-Bouta B., Albrecht J., Lazarewicz J.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
Polychlorinated biphenyl (PCB) congeners and polibrominated fl ame retardants (BFRs) are environmentally occurring toxins that exhibit a broad range of adverse biological effects including neurotoxicity. Due to their stability and lipophilic character, they persist in the environment and accumulate in brain of animals and humans contributing to induction of neurological disorders. The mechanisms by which PCBs and BFRs cause neurotoxic effects are still not completely understood. However, it is postulated that glutamate excitotoxicity may be involved. The main glutamate transporters GLT-1 and GLAST are membrane-bound proteins localized in glial cells. The clearance of synaptically released glutamate by these proteins protects neurons from excitotoxicity. The aim of the study was to establish whether the chronic exposure to these substances may infl uence the expression and activity of main glutamate transporters in rat brain. Aroclor 1254 (PCBs) and tetrabromobisphenol A (BFRs) were administered by oral gavage, which resembles the human exposure through the food chain, for two weeks. Signifi cant changes in the expression of glutamate transporters were observed, especially in the case of GLT-1. The effect was more pronounced for Aroclor 1254. The results suggest that GLT-1 is a molecular target of this toxin that may, almost partially, contribute to PCBs-induced excitotoxicity. This study was supported by grant nr NN401024635 from Polish Ministry of Science and Higher Education.
6

The role of low molecular weight thiols in thimerosal toxicity - an in votro study

39%
Zieminska E., Toczylowska B., Wojcik J., Stafiej A., Bal W., Lazarewicz J.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
Thimerosal (TH), an ethylmercury complex of thiosalicylic acid has been used as preservative in vaccines. Inspired by a known high affi nity of mercury for thiol groups, we examined whether the presence of L-cysteine (Cys), D,L-homocysteine (Hcy), Nacetyl cysteine (NAC), L-methionine (Met) and glutathione (GSH) in extracellular space could infl uence the viability, intracellular calcium concentration ([Ca2+]i ) and mitochondrial membrane potential in rat cerebellar granule cells. The cells were exposed to 500 nM TH for 48 h or 15 μM TH for 10 min. The loss of cells viability could be prevented partially or wholly, in a dose-dependent manner, by 60, 120 or 600 μM Cys, Hcy, NAC and GSH, but not by Met. The elevation in [Ca2+]i and mitochondrial potential induced by 25 μM TH were abolished by all compounds studied, except for Met, at 600 μM. The loss of the ethylmercury moiety from TH as a result of interaction with thiols studied was monitored by 1 Hand 199Hg-NMR spectroscopy. This extracelullar process may be responsible for the neuroprotection seen in cerebellar cell culture, but also provides a molecular pathway for redistribution of TH derived toxic ethylmercury in the organism.
7

Hyperbaric preconditioning combined with post-ischemic hyperbaric therapy prevents ischemia-evoked damage to CA1 hippocampal neurons of Mongolian gerbils

39%
Malek M., Gamdzyk M., Duszczyk M., Ziembowicz A., Sobczuk A., Lazarewicz J., Salinska E.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Lack of the clinically effective pharmacological neuroprotection in different forms of brain ischemia increased the interest in alternative methods of therapy, like hypothermia or induction of brain tolerance by pre- and post-conditioning. The hyperbaric oxygen (HBO) therapy (2.5 atm) applied after ischemia or traumatic brain injury is one of the proposed but still controversial methods. The aim of this study was to find whether HBO and hyperbaric air (HBA) preconditioning followed by hyperbaric treatment applied for 60 min at different times after 3 min forebrain ischemia in gerbils will give a significant protection. The effects of both treatments on brain temperature and animal behaviour were also examined. A telemetric system to measure brain temperature was used and for behavioural observations a nest building test. The density of viable CA1 pyramidal neurons was also quantified. Our results show that HBO preconditioning combined with HBO postischemic therapy significantly reduced ischemia-evoked increase of brain temperature. HBA was also effective. Both treatments significantly increased gerbils’ ability to build a nest in comparison to untreated animals. The best effect was observed when postischemic therapy was applied 1 h after ischemia, but it was also effective 3 h after ischemia. Morphological analysis showed that HBO preconditioning combined with HBO postischemic treatment applied 1 h after ischemia significantly reduced neuronal damage in CA1 region of hippocampus resulting in 85% of surviving neurons compared to 18% of surviving CA1 neurons in the brains of animals subjected to ischemia but not treated with HBO. Our results show that HBO preconditioning combined with HBO therapy after forebrain ischemia in gerbils gives morphological protection which is accompanied by good behavioral results. Apart from inducing tolerance mediated by mild oxidative stress, HBO may affect blood oxygenation and other factors instrumental in brain protection.
8

Involvement of group I metabotropic glutamate receptors in forming hyptoxic brain tolerance induced in rats by hypobaric preconditioning

39%
Belyakow A., Semenov D., Tjulkova E., Glushchenko T., Salinska E., Samoilov M., Lazarewicz J.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
The assumption that hypoxic tolerance induced by preconditioning with moderate hypobaric hypoxia (MHH) includes modifi cation of intracellular Ca2+ (Ca2+ i ) transients by modulation of glutamate receptors (GluR) activity was tested. Superfused rat brain slices were prepared 24 hours after three MHH sessions equivalent to 5 000 m above see level and tested by application of selective agonists of different subtypes of GluR. Ca2+ i level in response to the agonists was increased in comparison with the control ones. The most prominent Ca2+ level shifts were recorded in response to stimulation of group I metabotropic glutamate receptors (ImGluRs). The modifi ed pattern of the responses showed striking prevalence of signal pathways responsible for Ca2+ release from intracellular stores against modulation of Ca2+ entry. The selective antagonism of both 1 and 5 subtypes of ImGluRs in vivo during MHH did not suppress the preconditioning effi ciency, tested in the slices by severe (10 min) anoxia 24 hours after. Moreover by immunocytochemical and Western-blotting methods we found no valid distinctions in a peptide expression of these ImGluRs subtypes between control and MHHpreconditiond rats. Thus it can be supposed that the changed pattern of Ca2+ response to the agonist and mechanisms of brain tolerance induced by MHH are determined by a shift in balance of different glutamatergic signal pathways controlling the dynamics of Ca2+ i level rather than by modifi cation of the agonist reception.
9

Differential efficacy of mild normobaric hypoxia in inducing ischemic tolerance in two models of brain ischemia in vivo

39%
Duszczyk M., Makarewicz D., Malek M., Ziembowicz A., Lazarewicz J., Salinska E.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Induction of short ischemic episodes after the stroke can be neuroprotective. Hypoxia was also suggested as the factor producing neuroprotection in the animal brain. Therefore in our studies we aimed to test if normobaric hypoxia (10% of oxygen) induced after ischemia could prevent neuronal loss. The model of hypoxia-ischemia (H-I) in 7-days old rats and the model of global forebrain ischemia in Mongolian gerbils were used. 7-days old rats were subjected to H-I and the first of three episodes of postconditioning hypoxia was induced 1, 3 or 6 hours after H-I episode. After ischemia gerbils were subjected to three trials of 1h hypoxia applied every 24 hours. The first episode was induced immediately, 2.5 h or 6 h after the ischemic insult. The morphological and behavioral effects of the postconditioning were evaluated. In the model of H-I on rats, the assessment of brain mass deficit revealed that normobaric hypoxia induced signifficant neuroprotection when applied 1 h or 6 h after H-I but not 2.5 h. In the global forebrain ischemia model normobaric hypoxia itself was harmless and the number of pyramidal neurons evaluated in CA1 region was the same as in the sham group. The neuroprotective effect of normobaric hypoxia postconditioning was observed when hypoxia was induced immediately after ischemia but not 2.5 or 6 hours after the insult. The behavioral evaluation showed only small improvement in nest-building test in postconditioned animals. Presented data show that normobaric hypoxia postconditioning produces the neuroprotective effect, however the therapeutic window of this treatment varies according to the model of brain ischemia. Supported by MSHE grant NN401003935.
10

Alternations of brain cell metabolism in conditions of hypoxia

27%
Broniszewska-Ardelt B., Domanska-Janik K., Dabrowiecki Z., Gromek A., Ksiezak H., Lazarewicz J., Majewska D., Pastuszko A., Rafalowska U., Rossowska M., Strosznajder J., Wroblewski J., Zaleska M.
Acta Neurobiologiae Experimentalis
|
1976
|
tom 36
|
nr 6
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