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Sto lat - czy naprawdę wszyscy chcemy żyć tak długo? Choroby neurodegeneracyjne jako nieodłączny element starzenia mózgu i próby poszukiwania efektywnych terapii

100%
Kreiner G.
Wszechświat
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2020
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tom 121
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nr 01-03
2

Genetic modeling of neurodegenerative diseases in mice

100%
Kreiner G.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr S
Neurodegenerative diseases are characterized by profound loss of certain neuronal populations and are associated with mitochondrial and proteasomal dysfunction, alteration of cellular defense mechanisms and oxidative stress. However, the exact molecular mechanisms of neurodegeneration remain to be unraveled and current pharmacotherapy provides only symptomatic cure. Although genetic mutations responsible for familial cases are known (e.g. in Alzheimer’s and Parkinson’s disease), genetic animal models often do not cover all the cardinal pathological features. This is also true for transgenic models of Huntington’s disease – one of the few neurodegenerative diseases with a known genetic cause. We applied a novel approach to generate mouse models of neurodegenerative diseases based on the activation of an endogenous suicide mechanism achieved by genetic ablation of the transcription initiation factor IA (TIF-IA). Loss of TIF-IA blocks the synthesis of ribosomal RNA leading to nucleolar disruption and p53-mediated apoptosis. We used conditional inactivation of the gene encoding TIF-IA by the Cre/loxP system to induce selective loss of different neuronal populations in mice. Deletion of TIF-IA leads to rapid loss of neuronal progenitors and progressive loss of postmitotic neurons. In dopaminergic neurons and striatal dopaminoceptive neurons nucleolar disruption results in mutants showing respectively the typical phenotype of either Parkinson’s disease (preferential degeneration of dopaminergic neurons in substantia nigra, depletion of dopamine in the striatum and typical motor dysfunctions) or Huntington’s disease (loss of medium spiny neurons in striatum, impairment of motion control and clasping behavior). In addition, cellular changes associated with nucleolar disruption recapitulate some events associated with neurodegeneration in response to oxidative stress. These mutant mice may contribute to the identification and validation of new therapeutic targets.
3

Similar action of the ECS and imipramine chronic treatments on subtypes of the alfa1 adrenoceptor

63%
Nalepa I., Kreiner G.
Acta Neurobiologiae Experimentalis
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1999
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tom 59
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nr 3
4

Disruption of nucleolar activity in dopaminergic neurons leads to progressive parkinsonism

51%
Schutz G., Parlato R., Rieker C., Kreiner G.
Acta Neurobiologiae Experimentalis
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2007
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tom 67
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nr 3
5

Depletion noradrenaline counteracts the increase of alpfaIA-adrenoceptor mRNA expression induced by treatment with antidepressant

51%
Kreiner G., Zelek-Molik A., Nalepa I.
Acta Neurobiologiae Experimentalis
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2001
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tom 61
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nr 3
6

Evaluation of transgenic mice conditionally lacking CREB in noradrenergic neurons as a novel tool for studying its role in the antidepressant drug action

51%
Rafa-Zablocka K., Kreiner G., Baginska M., Nalepa I.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: Most of the current antidepressants modulate levels of monoamines just after administration, however, only after prolonged therapy the clinical effect may be observed. Myriad attempts tried to identify molecular factors responsible for such a delayed response, the prominent example being the cyclic AMP response element binding protein (CREB). Many research suggest that chronically given antidepressants enhance CREB levels and activity. On the other hand, CREB knock-out mice showed rather antidepressant-like behavior, however, the compensatory effects of cAMP response element modulator (CREM) in absence of CREB were not taken into account. In our study we evaluated transgenic mice with selective ablation of CREB in noradrenergic cells, maintained in CREM deficient background (CrebDBHCreCrem-/-) for elucidation of the role of CREB in antidepressant treatment. METHODS: mRNA levels of neurotrophins and α1-adrenoceptors in CrebDBHCreCrem-/- mice were investigated in hippocampus and prefrontal cortex using qPCR method. Next mice were screened in behavioral tests like: open field (OF), tail suspension test (TST) and rotarod. Preliminary TST after acute desipramine (DMI) administration (20 mg/kg, ip) was executed. RESULTS: CrebDBHCreCrem-/- mutant mice did not show any abnormalities in their basal phenotype, moreover the mRNA levels of studied genes were not changed either. However, preliminary experiments revealed that CrebDBHCreCrem-/- show a treatment-resistant phenotype after acute DMI administration in TST, (effect absent in single mutants). CONCLUSIONS: Our results provide further evidence for the important role of CREM as a compensatory factor and indicate that these mice may represent an unique tool to dissect the role of CREB in the mechanism of antidepressants. Supported by statutory funds of the Institute of Pharmacology and 2014/13/B/NZ7/02293 grant. K. Rafa-Zabłocka is a holder of scholarship from the KNOW sponsored by MSHE, Poland.
7

The effects of trehalose administration on autophagy enhancement in mice with conditional and progressive degeneration of medial spiny neurons

51%
Kreiner G., Rafa-Zablocka K., Baginska M., Nalepa I.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: In neural cells, autophagy is proposed to serve as a surveillance mechanism which helps to clear protein aggregates, and loss of autophagy leads to neurodegeneration in mice. Our previous experiments, performed on genetically engineered mice with conditional and progressive neurodegeneration of medial spiny neurons (TIF-IAD1RCre mice) mimicking the typical progression of Huntington’s disease (HD), showed that the delayed onset of neurodegeneration observed in these mutants might be associated with temporary increased autophagy. The aim of current study was to evaluate a new strategy proposed recently for the anti-HD treatment, based on enhancing autophagy by administration of trehalose, a natural alpha-linked disaccharide. METHODS: Trehalose (2%) was dissolved in water and presented to the mice as a replacement for their water bottles for 1 or 2 months prior the experiments. The effects of trehalose were compared with groups receiving maltose (2%) as well as water (vehicle). The autophagy was determined by Western blot (WB) and immunohistochemistry (IHC) with use of anti-LC3B antibody. The animals were screened for their motor coordination by accelerated rotarod, and post-mortem for selected neurodegenerative markers by WB and IHC. RESULTS: Both control and mutant mice showed enhanced autophagy after trehalose administration as revealed by WB and IHC staining. Nevertheless, further analysis of quantitative assessment of several neurodegenerative markers by WB did not reveal any significant effects in attenuating the neurodegenerative process. There have been also no differences in behavioral phenotype. CONCLUSIONS: Our results provide additional evidence for stimulation of autophagy evoked by chronic administration of trehalose. However further study is needed, the enhancement of autophagy has not yet been proved to be neuroprotective in investigated model. Supported by 2011/03/B/NZ7/05949 grant financed by National Science Center (NCN).
8

Nifedipine modulates some changes induced by antidepressants in adrenergic transmission at the second messengers level

51%
Nalepa I., Kreiner G., Kowalska M., Vetulani J.
Acta Neurobiologiae Experimentalis
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1997
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tom 57
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nr 5
9

Denitryfikacja w bioreaktorze typu MEANDER z udzialem Thiobacillus denitrificans

51%
Pado R., Pawlowska-Cwiek L., Starzyk K., Kreiner G.
Biotechnologia
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1997
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nr 2
170-185
10

Changes of Galpha(q), Galpha(11) and Galpha(12) mRNA expression levels in rat prefrontal cortex and amygdala after reinstatement of cocaine-seeking behavior

45%
Zelek-Molik A., Kreiner G., Filip M., Wydra K., Nalepa I.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
|
nr S
Inhibition of monoamine transporters by a psychostimulant, cocaine, increases the monoamines availability at synaptic cleft and leads to the enhanced stimulation of monoaminergic postsynaptic receptors. G proteins represent the down-stream connectors from receptors to intracellular signalling. The aim of the study was to assess the expression of Gα(q), Gα(11) and Gα(12) mRNAs following reinstatement of cocaine-seeking behaviour in the prefrontal cortex (PFC) and the amygdala (AMY) of male Wistar rats using a “yoked” procedure and RT-PCR technique. We found that phases of cocaine-seeking behavior differently influenced the Gα subunits depending on the brain structure analyzed. Cocaine self-administered for 18 days induced a significant increase of mRNA levels of all Gα subunits (by ~23% for Gα12 and Gα11, and by 46% for Gαq vs yoked) in the PFC. After 10 days withdrawal from cocaine when no change in G proteins was observed, reinstatement induced by priming dose of the drug decreased G12 and Gq. The effect was more pronounced after combination of the cocaine with cue previously associated with cocaine self-administration and was noticed in G11 as well. In AMY, changes in the expression of Gα mRNAs induced by cocaine self-administration dependent on environmental cues paired with cocaine. Cocaine self-administration decreased (by ~24%) all G protein mRNAs while opposite effect was observed when cocaine self-administration was paired with cue stimulus. Withdrawal from cocaine induced 2-fold increase in mRNA level of three G proteins. On the contrary, the reinstatement induced by the cue decreased significantly Gα mRNAs to the same degree as did its combination with cocaine-priming. Our study provides the first evidence that alterations of G proteins mRNA expression can be conditioned by environmental stimuli paired with cocaine administration. Supported by statutory funds of the Institute of Pharmacology PAS.
11

Characterization of mice with genetically evoked selective degeneration of noradrenergic system and its possible influence on dopaminergic system

39%
Jurga A., Kreiner G., Rafa-Zablocka K., Baginska M., Parlato R., Schuetz G., Nalepa I.
Acta Neurobiologiae Experimentalis
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2013
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tom 73
|
nr 1
Parkinson’s Disease (PD) is characterized by an increased production of oxygen free radicals leading to alteration of the cellular constituents and subsequent dopaminergic cell loss within the region of substantia nigra (SN) and ventral tegmental area (VTA). However, it is well known that PD is not only associated with dopaminergic transmission. Involvement of extranigral structures in PD includes the noradrenergic system as well. Post-mortem studies of human brains revealed that neuronal loss associated with PD may proceed and is even greater in the region of locus ceruleus (LC) than SN/ VTA. In PD animal models, the loss of noradrenaline made worse the dopamine nigrostriatal damage and, in opposite, an enhanced noradrenaline level may have a neuroprotective role. The aim of this study was to determine whether genetically evoked, selective loss of noradrenergic neurons may have any long-term, negative impact on the dopaminergic system. We applied the conditional inactivation of the gene encoding transcription factor TIF-IA (essential for the regulation of rRNA synthesis) by the Cre-loxP system to induce the progressive and selective loss of noradrenergic neurons which was achieved by expressing Cre recombinase under dopamine beta-hydroxylase (DBH) promoter. Resulting TIFIADBHCre mice were born at expected rates, viable but showed clear signs of noradrenergic innervations failure e.g. ptosis, reduced locomotor activity, growth retardance and shorten life span. The animals were analyzed at 8 and 12 weeks of age. The selective loss of noradrenergic neurons was confirmed by immunofluorescent staining with the anti-tyrosine hydroxylase (TH) antibody. We observed approx. 90% reduction of TH positive cells in the LC of 8 weeks TIF-IADBHCre mice. The number of TH+ cells was not changed in the region of SN/VTA, neither in 8 nor 12 week old mutants. However, our preliminary data indicate that lack of the noradrenergic transmission may lead to enhanced expression of selected markers associated with neurodegeneration within the region of SN/VTA. Namely, we have found 1.4 fold up-regulation of mRNA encoding for glial fibrillary acidic protein (GFAP) as revealed by quantitative real-time PCR and increased level of oxidative stress shown by immunoblot detection of carbonyl groups by Western Blot in the SN/VTA of 12 weeks TIF-IADBHCre mice compared to control animals. If we provide additional evidences that selective noradrenergic degeneration affects functioning of dopaminergic neurons, TIF-IADBHCre mice may became a valuable, new model for study possible anti-PD treatment at early stages of the disease as dopaminergic neurons in these mice are not directly affected by the mutation. As for today, there are no experimental studies on a possible long-term negative impact of progressive noradrenergic degeneration on other neurotransmitter systems despite of clinically observed concomitant loss of SN/VTA and LC neurons in PD. This study was supported by the grant no 2011/03/B/NZ7/05949 financed by National Science Centre and statutory funds of the Institute of Pharmacology, Polish Academy of Sciences.
12

Impact of fear memory consolidation and retrieval on the mRNA expression of G proteins in mice brain

39%
Zelek-Molik A., Costanzi M., Rafa-Zablocka K., Kreiner G., Roman A., Cestari V., Nalepa I.
Acta Neurobiologiae Experimentalis
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2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Fear evoked signaling disturbances among hippocampus (HP), nuclei of amygdala (Amy) and prefrontal cortex (PFC) underlie anxiety related disorders, but their molecular mechanism remains elusive. Heterotrimeric G proteins (GP) based on intracellular activity of alpha subunit (Gα) are divided into four families: G(s) stimulating cAMP generation; G(i/o) inhibiting cAMP pathway; G(Q/11) increasing Ca++ level; G(12/13) activating monomeric GP-Rho. AIM(S): In the present study, the effects of fear memory consolidation and retrieval on the mRNA expression of Gα from all GP families were assessed in HP, Amy and PFC. METHOD(S): C57BL/6J mice were subject to 1-day fear conditioning (FC) procedure followed by contextual (CTX) or cued (Cs) retrieval test of freezing behavior. Morphine (1mg/kg/ip) injected immediately after FC was used to prevent fear consolidation process. RealTime PCR technique was adopted to measure mRNA expression of Gα subunits: 1 h after FC, 24 h later, 1 h after CTX or Cs retrieval test. RESULTS: In HP, the increased levels of Gα(s), (12) and (11) were observed 1 h after FC. The Gα(s) mRNA decreased (vs. control) when consolidation was stabilized as well after Cs retrieval. Elevated Gα(12) mRNA, as observed 1h after FC, returned to control level at fear memory stabilization and raised again with CTX retrieval. The increase in Gα(11) persisted 24 h after FC and after CTX (but not Cs) retrieval. In PFC, the CTX retrieval was accompanied by a decrease in Gα(i2) and (i3) mRNA levels. In Amy, no specific change to fear memory process was observed. CONCLUSIONS: FC evoked changes in Gα mRNA expression are observed mainly in HP and mostly connected to CTX learning. Results suggest that activated signaling pathways from Gα(s) and Gα(12) are necessary to begin fear memory consolidation process in HP while signal transduction via Gα(11) is implicated in maintenance of fear consolidation. FINANCIAL SUPPORT: Supported by statutory funds from the Institute of Pharmacology PAS.
13

The influence of conditional inactivation of GR in noradrenergic system on stress related behavior in mice

39%
Kreiner G., Chmielarz P., Kusmierczyk J., Parlato R., Schuetz G., Nalepa I.
Acta Neurobiologiae Experimentalis
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2011
|
tom 71
|
nr S
Depression is a mental disease affecting complex cognitive and emotional functions. Stress induced hyperactivity of hypothalamic-pituitary-adrenal system (HPA) is believed to be one of the major contributors to its pathology. The activity of HPA is controlled by glucocorticoid receptors (GR) which function may be impaired in depression, resulting in reduced GR-mediated negative feedback on the HPA-axis. Most of the compounds which modulate GR action also influence noradrenergic system by increasing noradreneline levels. The aim of this study was to investigate if conditional inactivation of GR in noradrenergic neurons of mice affects the animal behavior in stressful conditions. Selective ablation of GR in noradrenergic system was achieved using the Cre/loxP approach by crossing transgenic mice hosting the Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals harboring the floxed GR gene. Resulting GRDBHCre mutant mice were born at expected rates, viable and showed no obvious physical impairment regarding life span, weight gain and locomotor activity. Also plasma cortisol levels did not differ between mutant and control mice. Animals were screened for anxiety and depressive-like behavior in light/ dark box test (LDT) and tail suspension test (TST). Male mutant mice did not unveil any differences from their control littermates in basal state nor after acute restraint stress (2 hrs). However, both tests performed after chronic restraint stress (14 days, 2 hrs/day) revealed that GRDBHCre mice were resistant to this type of experimental procedure showing similar anxiety status and immobility time as non-stressed controls. Our mutant mice may represent an interesting tool to study the role of stress in depression in context of noradrenergic system which is important target for antidepressant therapy. This study was supported by grant POIG.01.01.02-12-004/09 (DeMeTer) financed by European Regional Development Fund.
14

Evaluation of transgenic mice with progressive degeneration of noradrenergic system towards the study of presymtomatic phase of Parkinson's disease

33%
Barut J., Chmielarz P., Jurga A., Baginska M., Parlato R., Domanskyi A., Nalepa I., Kreiner G.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
Parkinson’s disease (PD) is characterized by an inevitable loss of dopaminergic cells.However, examination of human brain tissues revealed that noradrenergic cell loss in the region of the locus coeruleus (LC) may proceed and may be even greater than dopaminergic degeneration. AIM(S): The aim of this study was to determine whether genetically evoked, selective loss of LC noradrenergic neurons in a progressive manner may negatively influence the dopaminergic system. Our mice models have progressive degeneration of the noradrenergic system, based on deletion of the gene Rrn3 encoding transcription factor TIF-IA, which is essential for the regulation of rRNA synthesis. METHOD(S): First, we applied the conditional inactivation of the Rrn3 by the Cre-loxP system expressing Cre recombinase under DBH promoter. TIF‑IADBHCre mice revealed ptosis, reduced locomotor activity, and a shortened life span associated with enhanced expression of various neurodegenerative markers within the dopaminergic system, including upregulation of micro- and astroglia, pro-inflammatory proteins, and enhanced level of oxidative stress. To limit mutations to the CNS, in a second model a Cre-dependent lentiviral vector carrying the Rrn3 deletion created by the CRISPR/Cas9 system was directly delivered to LC of DBHCre mice. RESULTS: Our construct was first successfully tested in vitro on primary dopamine neurons followed by in vivo stereotactic application. This approach seems to be successful as, in preliminary data, we observed the disintegration of nucleoli in transduced noradrenergic neurons in LC, which is the determinant of the functional impairment of the targeted TIF‑IA. CONCLUSIONS: To-date, there are no experimental studies on possible long-term negative impacts of progressive noradrenergic degeneration on other neurotransmitter systems, despite the clinically observed concomitant loss of SN/VTA and LC neurons in PD. If we provide additional evidence, mice with ongoing neurodegeneration of LC neurons may became a valuable tool for studying the presymptomatic phase of PD.
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