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1

Effects of estrone on quisqualate-induced toxicity in primary cultures of rat cortical neurons

100%

Kajta M., Marszal M., Kubera M., Lason W.

Journal of Physiology and Pharmacology

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2005

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tom 56

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nr 2

Estrogens exert protective effects against neurotoxic changes induced by over-activation of ionotrophic glutamate receptors, whereas little is known about their interaction with changes mediated by metabotropic glutamate receptors. We evaluated effects of estrone on quisqualate (QA)-induced toxicity in neuronal cell cultures on 7 and 12 day in vitro (DIV). Twenty four hour exposure to QA (150 µM and 300 µM) significantly decreased cell survival in 7 day old cultures, but the 12 day old cultures were more resistant to its toxicity. DNQX (10 µM), an AMPA/kainate receptor antagonist, partly attenuated the toxic effects of QA, whereas LY 367 385 (100 µM), a selective mGluR1alpha antagonist, completely reversed the above effect. QA did not activate, but suppressed spontaneous caspase-3-like activity. Estrone (100 nM and 500 nM) attenuated QA-mediated neurotoxic effects independently of estrogen receptors, as indicated with ICI 182, 780 and without affecting the caspase-3-like activity. At early stage of development in vitro (7 DIV) toxic effects of QA were more profound and mediated mainly by metabotropic glutamate receptors of group I, whereas later (12 DIV) they were mediated mostly by ionotropic AMPA/kainate receptors. The toxic effects of QA were partly accompanied by anti-apoptotic action against spontaneous caspase-3-like activity, possibly due to modulation of neuronal plasticity.

2

Inhibition of c-JUN-JNK and MLK pathway activation blocks DNA damage-induced death in embryonic cortical neurons

100%

Ghahremani M. H., Keramaris E., Bazenet C., Ham J., Slack R. S., Park D. S.

Cellular and Molecular Biology Letters

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2003

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tom 08

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nr 2A

3

Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons

84%

Leskiewicz M., Jantas D., Budziszewska B., Lason W.

Journal of Physiology and Pharmacology

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2008

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tom 59

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nr 3

457-475

Some neurosteroids show neuroprotective action in in vitro and in vivo studies, but their interaction with apoptotic/necrotic processes has been only partially unraveled. The aim of the present study was to examine the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL) and allopregnanolone (Allo) on staurosporine-, glutamate-, and NMDA-induced damage in primary cortical neuronal culture. DHEA, DHEAS and PGL (0.1 and 1 µM) inhibited the staurosporine-evoked LDH release and decreased the number of apoptotic cells as shown by Hoechst`s staining, whereas Allo was without effect. The neurosteroids affected neither the staurosporine-evoked changes in caspase-3 activity nor the decrease in mitochondrial membrane potential. It was also shown that protective effects of DHEA, DHEAS and PGL against staurosporine-induced LDH release were attenuated by extracellular signal-regulated kinase (ERK) - mitogen-activated protein kinase (MAPK) inhibitor – PD 98059 (5 µM) but not by phosphatidylinositol-3-kinase (PI3-K) inhibitors such as LY 294002 (1 µM) or wortmannin (10 nM). The involvement of ERK2-MAPK in protective effects of neurosteroids was confirmed by Western blot study. Further study demonstrated that glutamate-induced cell damage was attenuated by DHEA, DHEAS, and PGL, but not by Allo. None of the steroids influenced NMDA-induced LDH release. The results of the present in vitro studies suggest that excitatory neurosteroids DHEA, DHEAS and PGL at physiological concentrations participate in the inhibition of cortical neuronal degeneration elicited by staurosporine and glutamate, whereas the most potent positive modulator of GABAA receptor - Allo - has no effect. Moreover, neurosteroids appear to attenuate the staurosporine-induced cell damage in a caspase-3 independent way and their neuroprotective mechanism of action involves the increase in ERK-MAPK phosphorylation.

4

Effects of p53 inhibitor on survival and death of cells subjected to oxidative stress

84%

Strosznajder R. P., Jesko H., Banasik M., Tanaka S.

Journal of Physiology and Pharmacology. Supplement

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2005

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tom 56

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nr 4

215-221

Our previous data indicate that ischemia and amyloid beta peptide (Abeta) cause an oxidative damage to macromolecules. In the present study we investigated the role of p53 protein in cell survival and death after administration of Abeta. The experiments were carried out on pheochromocytoma cells (PC-12) and cortical primary neurons in culture. The cortical neurons were exposed (48 h, 10 µM) to the action of a short Abeta25-35 neurotoxic fragment and the involvement of p53 was evaluated after addition of the p53 inhibitor pifithrin-alpha. Changes in cell morphology were evaluated by 4', 6-diamidino-2-phenylindole staining and the concentration-dependent effect of pifithrin-alpha on cells viability was determined. Additionally, we studied the effect of pifithrin-alpha on neuronal survival in vivo after a 5-min global brain ischemia followed by 7 days' reperfusion in gerbils. We found that Abeta enhanced apoptotic cell death in cortical primary neurons. Pifithrin-alpha, at a 10 µM final concentration, protected the neuronal cells from the apoptotic death. However, at concentrations of 0.1 and 1 mM, the p53 inhibitor decreased PC-12 cells' viability in a dose-dependent manner. In in vivo experiments we did not observe any neuroprotection by pifithrin-alpha in the CA1 hippocampal layer, which suggests that its effects strongly depend on the duration and type of an ischemic insult. Our data indicate that pifithrin-alpha affects neuronal cells in a dual manner. It has a protective effect at a low concentration, but becomes neurotoxic at higher concentrations.

5

Endogenous STIM2 and endogenous ORAI1 form a calcium-sensitive and thapsigargin-insensitive complex in cortical neurons

84%

Gruszczynska-Biegala J., Kuznicki J.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

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nr 1

ER calcium sensors (STIM1, STIM2) and calcium channel-ORAI1 interaction is crucial for store-operated calcium entry (SOCE) in non-excitable cells, but in neurons their localization and dynamics are not clear. We showed earlier that in neurons STIM1 is involved in thapsigargin induced SOCE, while STIM2 is active after EGTA-driven depletion of extracellular Ca2+ (Klejman et al. 2009, Gruszczynska-Biegala et al. 2011). To confirm that this is not due to the overexpression of exogenous proteins we used Proximity Ligation Assay to analyze activities of endogenous proteins. Cortical neurons were cultured in 2 mM CaCl2, 2 mM EGTA or 2 µM thapsigargin, fixed and incubated with primary antibodies anti-STIM2 and anti-ORAI1. The pairs of appropriate secondary antibodies with conjugated oligonucleotides were then added and Duolink II was performed to create the fluorescent products. We detected in situ the endogenous STIM2/ORAI1 complexes in somata and quantified in single neurons the number of hetero- and homo-complexes. The amount of hetero-complexes increased up to 10-fold in response to calcium depletion by EGTA. The number of STIM2/ORAI1 endogenous complexes correlated well with the number of overexpressed YFP-STIM2/ORAI1 complexes formed under the same conditions (Gruszczynska-Biegala et al. 2011). By co-immunoprecipitation we confirmed the in situ interaction between endogenous STIM2 and ORAI1 and that the interaction is increased after Ca2+ depletion in the medium. In conclusion, the present study provides a novel finding that endogenous STIM2 can physically interact and form hetero-complexes with endogenous ORAI1 in TG-insensitive manner, suggesting that the proteins are key molecules that underlie the regulation of basal calcium levels in neurons and constitutive calcium entry. This work was supported by funds from a Polish Ministerial grant (1900/B/P01/2010/39, JK) and from National Science Centre (2011/01/D/NZ3/02051, JGB)

6

Interactions between P300 and passive probe responses differ in different visual cortical areas

84%

Michalski A.

Acta Neurobiologiae Experimentalis

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2001

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tom 61

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nr 2

7

Carboxyl terminal fragment of beta-amyloid precursor protein: electrophysiological effects and cellular toxicity

84%

Fraser S. P., Bryan A. A., Diss J. K. J., Kim J. H., Kim S. H., Suh Y. H., Djamgoz M. B. A.

Cellular and Molecular Biology Letters

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1997

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tom 02

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nr 2

Alzheimer's disease (AD) is characterized by deposition of β-amyloid (Aβ) in areas of the brain. Aβ is a metabolic fragment of the β-amyloid precursor protein (βAPP). Genetic evidence has linked βAPP to AD, and there is increasing evidence that fragments from βAPP are neurotoxic. Aβ, the main research focus, has been shown to induce depolarizing ion channel activity. Involvement of other cleaved products from βAPP are less clear. We have investigated the 105 amino acid C-terminal peptide (CT105) (containing the full sequence Aβ), an alternative fragment linked with cellular toxicity. CT105 induced non-selective ionic currents in Xenopus oocytes (a model cell used in cell signalling studies) and was toxic to oocytes and mammalian cortical neurones. These results suggest possible involvement of CT105 in inducing the neural toxicity characteristic of AD.

8

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Effects of 17-beta estradiol and estriol on NMDA-induced toxicity and apoptosis in primary cultures of rat cortical neurons

84%

Kajta M., Budziszewska B., Marszal M., Lason W.

Journal of Physiology and Pharmacology

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2001

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tom 52

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nr 3

9

DOI, an agonist of 5-HT2A-2C serotonin receptor, alters the expression of cyclooxygenase-2 in the rat parietal cortex

84%

Mackowiak M., Chocyk A., Sanak M., Czyrak A., Fijal K., Wedzony K.

Journal of Physiology and Pharmacology

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2002

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tom 53

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nr 3

The hallucinogenic effect of DOI, serotonin 5-HT2A/2C receptor agonist, is known to be associated with the activation of cortical 5-HT2 receptors. However, the effect of DOI on excitability of cortical neurons and their subsequent function is still not quite understood. Previous immunohistochemical studies using Fos proteins expression as a marker of neuronal activity showed the involvement of arachidonic acid cascade, particularly cyclooxygenase metabolic pathway, in DOI-induced Fos proteins expression in the rat parietal cortex. DOI increases arachidonic acid release which is transformed itself via acceleration of cyclooxygenase metabolic pathway to biologically active metabolites, such as prostaglandins and tromboxanes. Since cyclooxygenase-2 (COX-2) expression correlates with neuronal activity, it was of interest to investigate whether DOI is capable of influencing the level of COX-2 protein and mRNA expression in the rat parietal cortex. It was observed that neurons which were positive for 5-HT2A receptors showed constitutive COX-2 immunoreactivity. It was found further, that COX-2 protein level was increased at 1h, and returned to the control level at 3 and 6 h after DOI (5 mg/kg) administration. In contrast, DOI decreased the COX-2 mRNA expression at all tested time points (1h, 3h and 6h after DOI treatment). The obtained results further support the suggestion that COX-2 activation and possibly arachidonic acid metabolites generated by COX-2 may be considered as important mediators of functional responses generated by activation of cortical 5-HT2A/2C receptors.

10

Oestrogen effects on kainate-induced toxicity in primary cultures of rat cortical neurons

67%

Kajta M., Lason W.

Acta Neurobiologiae Experimentalis

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2000

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tom 60

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nr 3

11

L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol stimulates ganglioside biosynthesis, neurite outgrowth and synapse formation in cultured cortical neurons, and ameliorates memory deficits in ischemic rats

67%

Inokuchi J., Kuroda Y., Kosaka S., Fujiwara M.

Acta Biochimica Polonica

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1998

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tom 45

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nr 2

To address the role of brain gangliosides in synaptic plasticity, the synthetic ceramide analog, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) was used to manipulate the biosynthesis of gangliosides in cultured cortical neurons. Spontaneous synchronized oscillatory activity of intracellular Ca2+ between the neurons, which represents synapse formation, was suppressed by the depletion of endogenous gangliosides by D-threo-PDMP, an inhibitor of glucosylceramide synthase. The decreased functional synapse formation was normalized by supplementation of GQ1b but not by the other gangliosides, suggesting that de novo synthesis of ganglioside GQ1b is essential for the synaptic activity (Mizutani A. et al., Biochem. Biophys. Res. Commun. 222, 494-498, 1996). On the other hand, the enantiomer of the inhibitor, L-threo-PDMP, could elevate cellular levels of glycosphingolipids including gangliosides. This paper presents our recent findings on the neurotrophic actions of L-threo-PDMP in vitro and in vivo. We found that L-PDMP could up-regulate neurite outgrowth, functional synapse formation and ganglioside biosynthesis through activating GM3, GD3 and GQ1b synthases. Simultaneously, the activity of p42 mitogen-activated protein kinase was also facilitated by L-PDMP. To evaluate the efficacy of this drug on long term memory, rats were trained for 2 weeks using an 8-arm radial maze task, and then forebrain ischemia was induced by 4-vessel occlusion (for 10 min × 2 with a 60 min interval). Repeated treatment of L-threo-PDMP (40 mg/kg, i.p. for 6 days, twice a day) starting 24 h after the ischemia, improved the deficit of the well-learned spatial memory, demonstrating the potential therapeutic use of the ceramide analog for treatment of neurodegenerative disorders.

12

Monoamine modulation of the synaptic inhibition in the hippocampus

67%

Bijak M.

Acta Neurobiologiae Experimentalis

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1996

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tom 56

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nr 1

13

Brain injury: prolonged induction of transcription factors

51%

Pennypacker K. R., Kassed C. A., Eidizadeh S., O'Callaghan J. P.

Acta Neurobiologiae Experimentalis

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2000

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tom 60

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nr 4

A specific temporal order of events at the cellular and molecular level occurs in response to injury to the brain. Injury-compromised neurons degenerate while surviving neurons undergo neuritogenesis and synaptogenesis to establish neuronal connectivity destroyed in the injury. Several genes, such as those coding cytoskeletal proteins and growth factors, have been shown to be regulated by AP-1 and NF-kB transcription factors, two of the most studied DNA binding regulatory proteins. Our laboratory has discovered that Fos-related antigen-2 from AP-1 transcription factor family and NF-kB p65 and p50 subunits are induced long-term (days to months) in the brain after neurotoxic, excitotoxic or ischemic insult. Fos-related antigen-2 is induced in neurons in several models of injury and its elevated expression lasts days to months, corresponding to the severity. The time-course of FRA-2 induction is abbreviated with less severe insult (terminal damage) relative to the cell death, but the induction occurs during the period of regeneration and repair in both models. NF-kB p65 is basally expressed in hippocampal and cortical neurons, but is elevated in reactive astrocytes in hippocampus and entorhinal cortex starting at two days and lasting at least two weeks after kainate treatment. Neurons of the hippocampus surviving ischemic or neurotoxic injury increase expression of NF-kB p50 for at least a week after injury, suggesting a function for p50 in neuronal survival and/or repair. The extended expression of these transcription factors implies a role in the activation of genes related to repair and regeneration, such as growth factors and synaptic proteins, after injury to the CNS.

Ograniczanie wyników

Effects of estrone on quisqualate-induced toxicity in primary cultures of rat cortical neurons

Inhibition of c-JUN-JNK and MLK pathway activation blocks DNA damage-induced death in embryonic cortical neurons

Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons

Effects of p53 inhibitor on survival and death of cells subjected to oxidative stress

Endogenous STIM2 and endogenous ORAI1 form a calcium-sensitive and thapsigargin-insensitive complex in cortical neurons

Interactions between P300 and passive probe responses differ in different visual cortical areas

Carboxyl terminal fragment of beta-amyloid precursor protein: electrophysiological effects and cellular toxicity

Effects of 17-beta estradiol and estriol on NMDA-induced toxicity and apoptosis in primary cultures of rat cortical neurons

DOI, an agonist of 5-HT2A-2C serotonin receptor, alters the expression of cyclooxygenase-2 in the rat parietal cortex

Oestrogen effects on kainate-induced toxicity in primary cultures of rat cortical neurons

L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol stimulates ganglioside biosynthesis, neurite outgrowth and synapse formation in cultured cortical neurons, and ameliorates memory deficits in ischemic rats

Monoamine modulation of the synaptic inhibition in the hippocampus

Brain injury: prolonged induction of transcription factors