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1

Early and delayed hypoxic postconditioning in the model of birth asphyxia in 7-day-old rats

100%
Makarewicz D., Salinska E.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Lack of the clinically applicable effective pharmacological neuroprotection in different forms of brain ischemia triggers increasing interest in alternative methods of therapy, including induction of brain tolerance by pre- and postconditioning. It is known for a long time that hypoxic preconditioning reduces brain damage in the rat model of perinatal asphyxia (Vannucci et al., 1998, Cantagrel et al., 2003). Recent data demonstrate that also postconditioning with moderate hypoxia delayed for 24 h after the insult results in a modest brain neuroprotection in adult mice (Leconte et al., 2009), however similar studies using the immature rats were never done. It has been suggested that similar mechanisms are involved in the induction of tolerance to brain ischemia by pre- and postconditioning, but timing may differ in both cases. Two temporal profiles of brain tolerance induced by preconditioning have been recognized: an early tolerance induced within minutes and depending on fast posttranslational modifications of proteins and a delayed one, developing after several hours to days and dependent on de novo protein synthesis (Kirino, 2002). It is not clear whether brain tolerance to hypoxia/ischemia induced by hypoxic postconditioning is also a two-phase phenomenon. The aim of this study was to evaluate efficacy of normo- and hypobaric postconditionig initiated 1, 3, or 6 hours after the insult in 7-day-old rats submitted to hypoxia-ischemia (H-I). H-I was induced by ipsilateral carotid occlusion followed by 75 min. exposure to hypoxia (7.2 - 7.4% O2 in N2). Hypoxic postconditionig was conducted under normobaric conditions at 10% O2 in N2 for 75 min, or in the hypobaric chamber set at 360 torr corresponding to 10 % O2 at the sea level. The post-conditioning was repeated once a day for 3 consecutive days. The brain damage was evaluated two weeks after H-I and expressed as ipsilateral hemisphere weight deficit in percent of the contralateral hemisphere. The results of this study demonstrated that both, normobaric or hypobaric postconditioning resulted in a significant neuroprotection only if initiated 1 h or 6 h after H-I, but not after 3 h. These results demonstrate for the first time efficacy of hypoxic postconditioning in the rat model of H-I and suggest that depending on timing of the hypoxic postconditioning the early and delayed tolerance may be achieved. Experiments are in progress verifying the role of mild oxidative stress in the mechanism of hypoxic postconditioning. Supported by the Ministry of Science and Higher Education grant #0039/B/P01/2008/35.
2

CDP-choline (citicoline) attenuates brain damage in a rat model of birth asphyxia

81%
Fiedorowicz M., Makarewicz D., Stanczak-Mrozek K. I., Grieb P.
Acta Neurobiologiae Experimentalis
|
2008
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tom 68
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nr 3
To estimate protective potential of citicoline in a model of birth asphyxia, the drug was given to 7-day old rats subjected to permanent unilateral carotid artery occlusion and exposed for 65 min to a hypoxic gas mixture. Daily citicoline doses of 100 or 300 mg/kg, or vehicle, were injected intraperitoneally for 7 consecutive days beginning immediately after the end of the ischemic-hypoxic insult, and brain damage was assessed by gross zorphology score and weight deficit two weeks after the insult. Caspase-3, α-fodrin, Bcl-2, and Hsp70 levels were assessed at 0, 1, and 24 h after the end of the hypoxic insult in another group of rat pups subjected to the same insult and given a single dose of 300 mg/kg of citicoline or the vehicle. Citicoline markedly reduced caspase-3 activation and Hsp70 expression 24 h after the insult, and dose-dependently attenuated brain damage. In the context of the well-known excellent safety profile of citicoline, these data suggest that clinical evaluation of the efficacy of the drug in human birth asphyxia may be warranted.
3

Effect of methylnicotinamide on MMPs activity after neonatal cerebral hypoxia-ischemia

81%
Dragun P., Makarewicz D., Zalewska T., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
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2006
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tom 66
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nr 4
4

Neuroprotective potential of mGluR agonist ABHxD-I and calcium stabiliser dantrolene in the model of perinatal asphyxia in rats

81%
Makarewicz D., Wroblewski T., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2001
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tom 61
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nr 3
5

Ligands of metabotropic glutamate receptors are neuroprotective in rat model of perinatal asphyxia

81%
Makarewicz D., Wroblewski J. T., Danysz W., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2005
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tom 65
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nr 3
6

Neonatal cerebral hypoxia-ischemia:involvement of FAK-dependent pathway

81%
Ziemka-Nalecz M., Makarewicz D., Zalewska T.
Acta Neurobiologiae Experimentalis
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2005
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tom 65
|
nr 3
7

NMDA receptor antagonists MK-801 and memantine induce tolerance to oxygen and glucose deprivation in primary cultures of rat cerebellar granule cells

81%
Slomka M., Kuszczyk M., Lazarewicz J. W., Makarewicz D.
Acta Neurobiologiae Experimentalis
|
2014
|
tom 74
|
nr 4
Preconditioning is an experimental strategy for reducing ischemic brain damage. There are reports that brief exposure of neurons to NMDA-receptor antagonists may be an adequate preconditioning stressor. We studied effects of preconditioning of the cerebellar granule cells (CGC) in primary culture by 30-minute exposure to NMDA receptor antagonists 0.5 ^M MK-801 or 5 ^M memantine. CGC were challenged with oxygen and glucose deprivation (OGD) or excitotoxic glutamate and cell viability was tested 24 h later using calcein/ethidium homodimer-1 staining. We studied glutamate-induced increases in 45Ca uptake and in the intracellular Ca2+ level assessed with the fluorescent probe fluo-3. The number of living cells in OGD-treated cultures decreased by 42%. Preconditioning with MK-801 or memantine 24 h earlier reduced cell death to 8% and 30% and 48 h earlier to 27% and 33%, respectively. Pretreatment with MK-801 followed by the standard MK-801 wash out was slightly cytoprotective in a glutamate excitotoxicity test performed immediately; the protection increased significantly 24 h after preconditioning. In both cases the extensive wash out of MK-801 after preconditioning resulted in loss of cytoprotection. The increase in the intracellular Ca2+ level evoked by glutamate was decreased 24 h after preconditioning and even halved in the neuronal cultures 48 h after preconditioning with MK-801 and memantine. Glutamate-induced 45Ca uptake in these cells was decreased by 18%, irrespective of the time laps after preconditioning. These results demonstrate that preconditioning of CGC with NMDA receptor antagonists induces prolonged tolerance to OGD, which is accompanied by the reduction of glutamate-evoked calcium fluxes. The causal relationship between these effects may be suggested.
8

Upregulation of IGF-1B (MGF) in neonatal stroke

71%
Majewska M., Beresewicz M., Makarewicz D., Gorecki D. C., Zablocka B.
Acta Neurobiologiae Experimentalis
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2006
|
tom 66
|
nr 4
9

NMDA receptor antagonists - a novel approach at the phenomenon of neuroprotection

71%
Makarewicz D., Duszczyk M., Kuszczyk M., Lazarkiewicz J., Salinska E.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Alternative methods of the therapy in the brain ischemia such as preconditioning seem more interesting because of the lack of the clinical applicable effective pharmacological neuroprotection. The role of NMDA receptor activation in triggering of this phenomenon was suggested, but it is not clear. Our recent in vitro studies (Kuszczyk et al. 2010) disclosed tolerance to the excitotoxic challenge by preconditioning with different NMDA receptor antagonists including MK-801 and memantine. The aim of the present study was to check if NMDA receptor antagonism induces also brain tolerance in vivo in different models of experimental brain ischemia. They included hypoxia-ischemia (H-I) in 7-dayold rats and 3-min global forebrain ischemia of Mongolian gerbils. In the neonatal rats exposure to 7% O2 in N2 was used for hypoxic preconditioning (H-P) as a positive control, while for pharmacological preconditioning two NMDA receptor antagonists MK-801 (3 mg/kg) and memantine (5 mg/kg) were injected i.p. Gerbils were pretreated with MK-801. The animals were preconditioned 24, 48, 72 and 96 hours before the insults, and the brain damage or deficit of CA1 pyramidal neurons was evaluated two weeks later. Our results demonstrated that MK-801 administered in all studied time points almost completely reduced brain damage compared to the H-I group, while H-P and preconditioning with memantine were less effective. In gerbils MK-801 was effective only 24 h before global ischemia. These data demonstrate for the first time ischemic tolerance induced by MK-801 and memantine preconditioning in vivo. Known neuroprotective effects of the NMDA receptor antagonists in various models of brain ischemia may be partially ascribed to induced tolerance. We consider a role of mild oxidative stress and enhanced production of trophic factors in its mechanisms. Supported by the MNiSW grant #0664/B/ P01/2010/38.
10

Neuroprotective potential of 1-methyl-1,2,3,4,-tetrahydroisochinoline in brain ischemia: role of NMDA receptor antagonism

61%
Duszczyk M., Kuszczyk M., Makarewicz D., Salinska E., Antkiewicz-Michaluk L., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Various endogenous teterahydroisochinoline derivatives present in the mammalian brain have been considered as neurotoxic substances. However 1-methyl-1,2,3,4-tetrahydroisochinoline (1MeTIQ) is known for its mild neuroprotective potential of the unclear mechanism. On the one hand 1MeTIQ exhibits anti-dopaminergic activity and reduces the neurotoxic effects of MPTP and rotenone, decreasing also the behavioral effects of MK-801 in rats in vivo. On the other hand the results of our previous study demonstrated that 1MeTIQ in vitro prevents glutamate-induced excitotoxicity in cultured neurons suggesting that this effect may be ascribed to its inhibitory effect on NMDA receptors. It is well known that the antagonists of NMDA receptors provide neuroprotection in brain ischemia, however the anti ischemic properties of 1MeTIQ were not tested previously. The aim of our present study was to verify in vitro putative antagonistic effects of 1MeTIQ on the NMDA receptors and to evaluate its neuroprotective potential in the animal models of brain ischemia. The receptor binding experiments using membranous fractions isolated from the rat brain cortex confirmed that 1MeTIQ in high micro molar concentrations inhibits in a concentration-dependent manner the specific binding of [3H] MK-801, while the binding of [3H]glutamate remains unaffected. The hypothesis that 1MeTIQ may be attributed to NMDA receptor antagonists acting as channel blockers was also supported by the results of experiments utilizing primary cultures of rat cerebellar granule cells submitted to acute NMDA and glutamate excitotoxicity. Under these conditions 1MeTIQ applied at high micro molar concentrations provided a pronounced neuroprotection and significantly inhibited generation of the calcium signal. The in vivo ischemic experiments demonstrated that application of 1MeTIQ in the dose of 50 mg/kg 30 min before the insult in the model of global forebrain ischemia in Mongolian gerbils or its repeated application in the same dose after hypoxia-ischemia in the rat model of perinatal asphyxia provided significant neuroprotection. In the gerbils treated with 1MeTIQ we observed the morphological and behavioral symptoms of neuroprotection and the postischemic hypothermia characteristic for medication of brain ischemia with the NMDA receptor antagonists. Collectively these data offer new arguments confirming the hypothesis that 1MeTIQ acts as a weak uncompetitive antagonist of NMDA receptors, providing the neuroprotection under various excitotoxic and ischemic conditions both in vitro and in vivo.
11

Neuroprotective potential of methylnicotinamide versus liicotinamide in vivo and in vitro

61%
Slomka M., Makarewicz D., Zieminska E., Duszczyk M., Stafiej A., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2006
|
tom 66
|
nr 4
12
Content available remote

Matrix metalloproteinases activity during the evolution of hypoxic-ischemic brain damage in the immature rat. The effect of 1-methylnicotinamide (MNA)

61%
Dragun P., Makarewicz D., Wojcik L., Ziemka-Nalecz M., Slomka M., Zalewska T.
Journal of Physiology and Pharmacology
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2008
|
tom 59
|
nr 3
441-455
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix and carry out key functions during brain development. Apart from a physiological role, excessive activation of MMPs in brain tissue has been postulated to represent a pathway for cell death arising from ischemia. To evaluate the possible involvement of MMPs in the perinatal brain asphyxia, we exposed 7-day-old rats to hypoxia-ischemia (HI). Unilateral HI was administered by ligation of the common carotid artery followed by hypoxia (7.4% O2/92.6% N2) for 65 minutes. This insult is known to produce brain damage confined to the cerebral hemisphere ipsilateral to the arterial occlusion in > 90% of animals. HI resulted in a significant elevation of MMP-2 and MMP-9 activity in the ipsilateral forebrain. The maximum activation was found at 48 hours and 7-14 days after the insult. These results suggest that early and late induction of MMPs may play a role in neuronal death as well as in repair processes. The treatment of animals subjected to HI with 1-methylnicotinamide (MNA), the anti-inflammatory agent, led to the inhibition of MMP-9 in an acute phase of ischemic damage and to the activation of MMP-2 in the later stages after injury. The timing of MMPs modulation by MNA may indicate its possible therapeutic implications.
13

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

61%
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.
14

Pretreatment is not mandatory for neuroprotection with 1alpha,25-dihydroxyvitamin D3 in perinatal hypoxic-ischemic rat brain damage in vivo and in excitotoxic injury of primary neuronal cell cultures

51%
Makarewicz D., Kajta M., Zieminska E., Jantas D., Domin H., Lason W., Kutner A., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 1
Previous in vivo and in vitro studies demonstrated neuroprotective potential of pretreatment with 1α, 25-dihydroxyvitamin D3 (calcitriol). The aim of present study was to determine effectiveness of calcitriol administered in vivo after brain ischemic episode in the rat model of perinatal asphyxia, or co-applied with some delay during 24 h exposure to glutamate of the mice hippocampal, cortical and cerebellar neuronal cultures at 7th and 12th day in vitro. In some experiments calcitriol was given after acute exposure to glutamate of the rat cerebellar neurons. Our results demonstrated, that in the 7 day old rat pups submitted to hypoxia ñ ischemia acute application of calcitriol in one dose of 2 μg/kg 30 min after termination of the insult or sub-chronic, 7-day post-treatment with calcitriol effectively diminished brain damage. The rate of such accomplished neuroprotection exceeded that achieved by hypoxic preconditioning, used as the reference neuroprotective method. Moreover the results of our in vitro experiments revealed the ability of calcitriol to reduce excitotoxicity in a way dependent on origin of neuronal cells, stage of their development and duration of excitotoxic insult. Calcitriol was neuroprotective when it was applied together with glutamate or even with up to 6 h delay during 24-h excitotoxic challenge to the hippocampal and neocortical, but not cerebellar neuronal cultures. In addition calcitriol inhibited glutamate-induced caspase-3 activity in hippocampal cultures. We ascribe these protective effects of calcitriol to a rapid, possibly non-genomic modulation by this compound of the mechanisms that are instrumental in its direct neuroprotective action. The study was supported by Polish MNSW Scientifi c Network Fund no 26/E-40/SN-0023/2007
15

Enhanced NMDA-evoked mobilisation of intracellular Ca2+ in the hippocampus of developing rats in vivo

51%
Makarewicz D., Salinska E., Puka-Sundvall M., Alaraj M., Skangiel-Kramska J., Jablonska B., Bona E., Hagberg H., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
1999
|
tom 59
|
nr 3
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