Wyniki wyszukiwania

1

The Alzheimer's ABeta peptide evoked oxidative and metabolic stress in rat hippocampal and cortical neurons

100%

Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2001

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tom 61

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nr 3

2

Alteration of sphingolipid biostat in experimental model of oxidative stress evoked by 1-methyl-4-phenylpyridinium (MPPplus)

63%

Pyszko J., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

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nr 1

Bioactive sphingolipids are important molecules that control wide spectrum of neuronal processes including neurotransmission, synaptic function, cells proliferation and death. Sphingosine kinases (SK1/2) are conserved enzymes that phosphorylate sphingosine to sphingosine-1-phosphate (S1P), which acts as a primary and secondary messenger. S1P binds to 5 receptors and plays essential role in neural signal transduction under physiological and various pathological conditions. Although growing evidence suggests important role of SK1/2 and S1P in neurodegenerative disorders including ischemia, inflammation and Alzheimer’s Disease, till now disturbances of sphingolipids homeostasis in Parkinson’s Disease (PD) remain unknown. Our study try to explain the role of SK1/2 and S1P in molecular mechanism of cell survival and death in model of oxidative stress evoked by neurotoxin 1-methyl-4-phenylpyridinium (MPP+), compound widely used in experimental model of PD. Our data presented that MPP+, comparable to SK inhibition evoked death of human neuroblastoma cells SH-SY5Y in time and concentration dependent manner. These changes are accompanied by increased free radicals concentration in these cells. Reduced level of SK1 protein was detected in SH-SY5Y cells after 24h exposure to MPP+ comparing to control. Moreover S1P pretreatment enhanced survival of these cells and protein level of SK1 comparing to MPP+ treated cells. Our data indicated that MPP+ evoked neuronal death is mediated by SK1/2 inhibition and altered sphingolipids signaling. These molecular events lead to caspase dependent apoptotic cells death and poly(ADP-ribose) polymerase-1 (PARP-1) degradation. All above results presented the alteration of sphingolipid biostat in experimental model of PD and suggested that S1P can offer novel, protective strategy.Supported by NCN Grant 5870/B/PO1/2011/40

3

Cyclic GMP metabolism and its role in brain physiology

63%

Domek-Lopacinska K., Strosznajder J. B.

Journal of Physiology and Pharmacology. Supplement

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2005

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tom 56

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nr 2

15-34

Cyclic GMP (cGMP) is synthesized by guanylyl cyclase (GC) in response to nitric oxide (NO) and carbon monoxide (CO) or natiuretic peptides (NPs); atrial, brain and C-type (ANP, BNP and CNP). cGMP is degraded by several cGMP-specific phosphodiesterases (PDEs). Guanylate cyclases (GC) are differentiated into: membrane-bound/particulate (pGC) and cytosolic/soluble (sGC). In recent years evidence has accumulated that NO is the main activator of sGC and NO/cGMP plays important role in glutaminergic, cholinergic and dopaminergic signaling pathways. cGMP in the nervous system is involved in long term potentiation and depression (LTP, LTD) suggesting its participation in learning and memory mechanism. cGMP regulates calcium homeostasis and phototransduction. Its level is regulated by PDEs and their specific inhibitors protect cGMP level in cells and are very important from clinical point of view.

4

Effect of myloid Beta peptides on DNA degradation

51%

Zambrzycka A., Czapski G., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2001

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tom 61

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nr 3

5

The role of nitric oxide in maturation of the cholinergic system in rat brain

51%

Domek-Lopacinska K., Kaminska M., Kopczuk D., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2005

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tom 65

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nr 3

6

Role of lipoxygenases and poly(ADP-ribose) polymerase in amyloid beta cytotoxicity

51%

Cieslik M., Strosznajder J. B., Gajkowska B., Strosznajder R. P.

Acta Neurobiologiae Experimentalis

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2011

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tom 71

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nr 1

The roles of 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the molecular processes evoked by amyloid β (Aβ) toxicity were investigated in PC12 cells that express either wild-type (APPwt) or double Swedish mutation (APPsw) forms of human Aβ precursor protein. Different levels of Aβ secretion characterize these cells. The results demonstrated a relationship between the Aβ levels and LOX protein expression and activity. High Aβ concentration in APPsw cells correlated with a significant increase in free radicals and LOX activation, which leads to translocation of p65/NF-κB into the nucleus. An increase in AIF expression in mitochondria was observed concurrently with inhibition of PARP-1 activity in the nuclear fraction of APPsw cells. AIF accumulation in mitochondria may be involved in adaptive/protective processes. However, inhibition of PARP-1 may be responsible for the disturbances in transcription and DNA repair as well as the degeneration of APP cells. Under conditions of increased nitrosative stress, evoked by the nitric oxide donor, sodium nitroprusside (SNP, 0.5 mM), 70-80 % of all cells types died after 24 h, significantly more in APPsw cells. There was no further significant change in mitochondrial AIF level and PARP-1 activity compared to corresponding nontreated with SNP cells. Only one exception was observed in PC12 control, where SNP significantly inhibits PARP-1 activity. Moreover, SNP significantly activated gene expression for 12/15-LOX in all types of investigated cells. Inhibitors of all LOX isoforms and specific inhibitor of 12-LOX enhanced the survival of cells that were subjected to SNP. We conclude that the LOX pathways may play a role in Aβ toxicity and in nitrosative-stress-induced cell death and that inhibition of these pathways offers novel protective strategies. Supported by MS&HE grant NN40113938 and MRC statutory theme No 7.

7

Inhibition of 12-lipoxygenase protects against amyloid beta peptides-evoked toxicity, memory impairment and alteration of locomotor activity

51%

Czapski G. A., Cakala M., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2009

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tom 69

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nr 1

The pro-infl ammatory enzyme 12/15-lipoxygenase (12/15-LOX) is upregulated in Alzheimerís disease (AD), but the role of the enzyme in a amyloid beta (AB)-evoked toxicity is not fully understood. Its pro-oxidative activity may contribute to the pathophysiology of AD. The aim of this study was to analyze the expression and activity of 12-LOX in animal model of AD. The role of 12-LOX in AB42-evoked memory impairment and locomotory activity and the effect of systemic infl ammation on AB-dependent alterations were also studied. Then the relationship between AB concentration and 12-LOX was examined using PC12 cells transfected with human wild-type and mutant AB precursor protein (APP) gene. Twelve-month-old C57Bl6 mice were injected with AB42 (1 nmol, icv) alone or simultaneously with lipopolysaccharide (LPS; 1 mg/kg, ip). Some mice received 12-LOX inhibitor, beicalein (10 mg/kg, ip). Our results indicated that AB signifi cantly increased 12-LOX expression and activity in hippocampus. Beicalein effectively prevented AB-induced 12-LOX activation and protected mice against memory defi cit and locomotory disturbances. In vitro studies demonstrated the signifi cant relationship between AB level and 12-LOX expression, oxidative stress and NF-κB activation. Beicalein protected PC12 cells against NF-κB nuclear translocation. Our data indicated that 12-LOX is involved in AB toxicity. Beicalein protected mice against memory defi cit and locomotory disturbances, suggesting that 12/15-LOX inhibitors may provide new therapeutic opportunities in treatment of AD. Supported by MS&HE scientifi c network 28/E-32/SN-0053/2007

8

alpha-Synuclein stimulates nitric oxide synthase (NOS) by activation of NMDA receptor

51%

Adamczyk A., Czapski G. A., Kazmierczak A., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2006

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tom 66

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nr 4

9

The role of Cdk5/p35 and cPLA2/LOX in neuroinflammation and neurodegeneration

51%

Czapski G. A., Cakala M., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

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nr Suppl.1

Cyclin dependent kinase 5 (Cdk5) is implicated in the pathomechanism of Alzheimer’s disease (AD), as a kinase responsible for hyperphosphorylation of tau protein and aberrant metabolism of Amyloid β (Aβ) precursor protein. The previous data indicated the involvement of Cdk5 in regulation of cytosolic phospholipase A2 (cPLA2) gene, but its precise function is not fully understood. In our studies, we analyzed in animal AD model the role of Cdk5 in neuroinflammation and in regulation of cPLA2/lipoxygenase (LOX) pathway. Our data indicated an increase in gene expression for cPLA2, 5-LOX and 12/15-LOX in the hippocampus during the systemic inflammation. In parallel, we observed an increase in expression of the Cdk5 activating protein – Cdk5r1 (p35), suggesting the enhancement of Cdk5 activity and its possible role, as the regulatory factor. Using mouse AD model we demonstrated enhancement of 12-LOX expression and activity and cognitive impairment, which was prevented by 12-LOX inhibitor. Our results demonstrated the important role of inflammatory reaction in cognitive impairment. The relationship between Cdk5 and cPLA2/ LOX during neuroinflammation may have a significant implication for the pathomechanism of AD, and presents Cdk5/p35 as the promising target for improvement of AD therapy. This study was funded by grant from The National Science Centre 2011/03/B/NZ3/04549.

10

Sphingosine-1-phosphate and its receptors signaling in neurodegeneration/neuroprotection

51%

Strosznajder J. B., Motyl J., Czubowicz K., Strosznajder R.

Acta Neurobiologiae Experimentalis

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2015

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tom 75

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nr Supl.

Sphingosine -1-phosphate (S1P) is synthesized by sphingosine kinases (SphK1/2E.C. 2.7.1.91) and exerts its function as intracellular messenger or acts in an autocrine or paracrine fashion through specific G protein operated receptors (S1P1-S1P5). Depending on SphK type and its localization S1P may influence different cell functions. S1P synthesized by SphK1 is involved in cell survival while produced by SphK2 may activate death signaling. S1P is degraded by phosphohydrolyses and irreversibly by S1P lyase (SPL, E.C.4.1.2.27) which appears to be very important in sphingolipid homeostasis. The alterations of sphingolipid rheostat is suggested to be crucial in pathogenesis/pathomechanism of neurodegenerative disorders. In our study we have evaluated the SphKs and SPL expression/activity as well as the role of S1P in different types of oxidative stress involved in neurodegenerative disorders. Moreover, the implications of SphK/S1P in the cell models of Alzheimer’s disease induced by amyloid peptides (AB) and alfa synuclein (ASN) were determined. Oxidative stress alters SphKs and SPL expression, activity and cells viability. In AD model significant decrease of SphK expression and activity/lower S1P synthesis leads to series of the following consecutive events: oxidative stress, down regulation of antiapoptotic protein Bcl-2, up-regulation of pro-apoptotic BAX and HrK and finally to cell’s death. Exogenous S1P and the agonist(s) of S1P1 or S1P3 receptors exert cytoprotective effects which are mediated by PI3/ Akt signaling pathway and by regulation of Bcl2 proteins. Summarizing, our data suggest that S1P, its receptor(s) agonists and inhibitors of SPL should be considered in therapy of neurodegenerative disorders. Supported by NCN grant 5870/P01/2011/40

11

NAC peptide evoked oxidative stress leads to p53 mediated apoptosis

51%

Kazmierczak A., Czapski G. A., Adamczyk A., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2011

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tom 71

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nr 1

The non-Aβ component of Alzheimer’s disease (AD) amyloid (NAC) is a highly amyloidogenic peptide consisting of 35 amino acids which was first identified associated with senile plaques in AD brain. It is a fragment of the presynaptic protein alpha-synuclein and, as such, it is implicated in the etiologies of both Alzheimer’s and Parkinson’s (PD) disease. However the molecular mechanisms of NAC toxicity is not fully understood. Our present study focused on the role of oxidative stress mediated p53 pathway in apoptotic cell death evoked by NAC peptide. Here we found that exposure of PC12 cells to exogenous NAC peptide (10 µM) enhanced free radical generation, induced mitochondria dysfunction and cell death. We also observed free radicals-dependent enhancement of Tp53 gene expression after NAC treatment. The inhibition of p53 by pifithrin significantly protected PC12 cells against NAC peptide - evoked mitochondria failure and death. In addition, exposure to NAC peptide resulted in the higher expression of cyclin-dependent kinase 5 (Cdk5), one of the enzymes responsible for p53 phosphorylation and activation. Concomitantly, we observed the increase of expression of Cdk5r1 and Cdk5r2 genes, coding p35 and p39 peptides, that are essential co-factors in regulation of Cdk5 activity. Moreover, the specific Cdk5 inhibitor (BML-259, 10µM) protected large population of cells against NAC-evoked cell death. Our findings indicate that NAC peptide exerts its toxic effect by activation of p53/Cdk5 - dependent apoptotic signaling pathway. This study was supported by MSHE Grant NN 401024236 and statutory theme no 7.

12

Inhibitory effect of alpha-synuclein and non-amyloid beta component of Alzheimer's disease amyloid on dopamine transporter function in rat striatal synaptosoines:relationship to oxidative stress

51%

Adamczyk A., Kazmierczak A., Cakala M., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2005

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tom 65

|

nr 3

13

Inhibitors of poly(ADP-ribose) polymerase protect hippocampal neurons against genotoxic stress via PI-3K/AKT regulated pathway and by suppression of AIF translocation

51%

Cieslik M., Jacewicz M., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2009

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tom 69

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nr 1

Poly(ADP-ribose)polymerase (PARP-1) plays a key role in DNA repair but its over activation has been proposed to be important in pathogenesis of brain ischemia and in neurodegenerative diseases. PARP catalyzes the conversion of bNAD+ to polymers of poly(ADP-ribose) (PAR) and is fully responsible for producing of PAR polymers during genotoxic stress. The last data indicated that PAR act at the mitochondria to induce cell death through stimulation of apoptosis inducing factor (AIF) release. However, the role of PAR in cell death seems to be complex and not fully elucidated. To better understand the role and relationship between AIF and PARP/PAR in death signaling the hippocampal neuronal (HT22) cells in culture were subjected to different concentration of DNA alkylating agent, 1-methyl-3-nitro-1-nitrosoguanidine (MNNG). The immunochemical and spectrophotometrical methods were applied. Consequently, HT22 cells treated with MNNG at 50ñ 500 mM demonstrated concentration dependent mitochondria failure and death. 24 h after 500 mM MNNG treatment only 15% of cells survive. PARP-1 inhibitors: 3-aminobenzamide (3AB) and PJ34 at 5 mM and 20 mM, respectively, protect most of the cells against MNNG induced death signaling. At lethal MNNG concentration PARP/PAR dependent AIF translocation from mitochondria is observed and the caspase independent death signaling is activated. Concomitantly PARP inhibitors affect the endogenous pathway regulated by PI-3K/AKT PKB/GSK-3 and infl uence the level of GSK-3β active form phosphorylated on Tyrosine 216. Summarizing our data indicated that inhibitors of PARP have positive effect on neuroprotective pathway regulated by PI-3K/AKT and on mitochondria function. Supported by Scientifi c Network of MS&HE No 28/E-32/SN0053/2007

14

alpha-Synuclein and its neurotoxic fragment induce apoptotic pathway in PC 12 cells with diferent amyloid beta load

51%

Kazmierczak A., Adamczyk A., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2006

|

tom 66

|

nr 4

15

Inflammation related apoptosis can be prevented by inhibition of nitric oxide synthesis

51%

Czapski G. A., Cakala M., Gajkowska B., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2005

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tom 65

|

nr 3

16

The role of cyclooxygenases and lipooxygenases in mechanism of amyloid beta toxicity

51%

Cakala M., Jesko H., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2006

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tom 66

|

nr 4

17

Sphingosine kinase and glycogen synthase kinase-3Beta in molecular mechanism of Alzheimer’s amyloid Beta toxicity

51%

Czapski G. A., Gassowska M., Wilkaniec A., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2013

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tom 73

|

nr Suppl.1

Alterations of phosphorylation-dephosphorylation processes play a crucial role in the pathomechanism of Alzheimer’s disease (AD). They affect signaling cascades and lead to hyperphosphorylation of tau protein. Glycogen synthase kinase 3β (Gsk-3β) is the main tau-kinase; however, little is known about the role of sphingolipid pathway in its regulation. Alteration of sphingolipid biostat may be an early event in etiopathology of AD. The question arises, if the sphingosine kinase (Sphk), a key enzyme in sphingolipid pathway, regulates Gsk-3β? We analyzed acute effects of exogenous amyloid β (Aβ) oligomers in PC12 cells, and prolonged exposition to endogenous Aβ in PC12 cells stably expressing human Swedish mutant APPsw gene. Our data indicated that in cells subjected to exogenous Aβ expression of Sphk1 and phosphorylation of Gsk-3β at Ser9 were enhanced, what could be considered as a component of protective mechanism. However, prolonged liberation of Aβ in APPsw cells evoked inhibition of Sphk1 expression, activation of Gsk-3β and death of significant population of cells. Consequently, an inhibitor of Sphk1 also reduced cell viability. Our data suggest the existence of specific relationship between Sphk1 and Gsk-3β and indicate their role in alteration of cell function and survival. The study was supported by MSHE Grant N401 587040.

18

Udzial alfa-synukleiny w funkcji ukladu dopaminergicznego

51%

Kazmierczak A., Adamczyk A., Strosznajder J. B.

Postępy Biologii Komórki

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2007

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tom 34

|

nr 2

377-390

19

Alfa-synukleina w fizjologii i patologii mozgu

51%

Solecka J., Adamczyk A., Strosznajder J. B.

Postępy Biologii Komórki

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2005

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tom 32

|

nr 2

343-357

20

Expression of poly(ADP-ribose) polymerases in hippocampus during systemic inflammatory response. The role of PARP-1 protein interactions in cognition

51%

Czapski G., Adamczyk A., Strosznajder R. P., Strosznajder J. B.

Acta Neurobiologiae Experimentalis

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2011

|

tom 71

|

nr 1

Poly(ADP-ribosyl)ation is covalent modification of proteins responsible for the alterations of their function. This process is catalyzed by poly(ADP-ribose)polymerases (PARP) family, consisted of 18 isoforms. Among target proteins, there are many DNA-related proteins and PARP-1 itself. In the brain, PARP-1 is responsible for more than 90% of poly(ADP-ribosyl)ation. PARP-1 plays a significant role in regulation of several transcription factors including NF-kB and p53. Our previous data indicated an important impact of PARP-1 in brain ischemia and in systemic inflammatory response (SIR). In this study we have analyzed the expression of PARP family genes in hippocampus of mice subjected to lipopolysaccharide (LPS)- evoked SIR. Moreover, the effect of SIR on PARP-1/PAR protein interaction and on memory function was evaluated. Mice C57BL6 were injected i.p. with LPS (1 mg/kg b.w.) alone or together with PARP inhibitors 3-aminobenzamide (30 mg/kg b.w.). The studies were carried out by using immunochemistry, microarray, real-time RT-PCR, and behavioral analysis. Our data indicated the small effect of SIR on PARP-1 gene expression level, however, expression of genes for PARP-3, -9, -12 and -14 was significantly increased 12 h after LPS administration. The level of PAR in hippocampus was elevated during SIR indicating activation of protein poly(ADP-ribosyl)ation. Moreover, further analysis of LPS-affected genes indicated that among 83 proteins known for their direct interaction with PARP-1, genes for 21 are present in SIR-related interactome, along with several genes for transcription factors and proteins involved in signal transduction. The enhancement of gene expression in hippocampus for several members of PARP family during SIR may be responsible for the alteration of PARPs function, higher level of PAR formation and for the modification of PARP/PAR protein interaction, transcription, cell signaling and memory. Our data indicated that SIR significantly decreases object recognition but has small effect on spatial memory. PARP-1 inhibitor protects against SIR induced molecular alteration in hippocampus and against SIR-evoked cognition impairment. Moreover, PARP-1 inhibitors significantly enhanced spatial memory in LPS treated mice. Our results indicate that inhibition of PARP-1 is a promising protective strategy during overactivation of inflammatory reaction. The role of other PARP family members in SIR is a target of our future investigation.

Ograniczanie wyników

The Alzheimer's ABeta peptide evoked oxidative and metabolic stress in rat hippocampal and cortical neurons

Alteration of sphingolipid biostat in experimental model of oxidative stress evoked by 1-methyl-4-phenylpyridinium (MPPplus)

Cyclic GMP metabolism and its role in brain physiology

Effect of myloid Beta peptides on DNA degradation

The role of nitric oxide in maturation of the cholinergic system in rat brain

Role of lipoxygenases and poly(ADP-ribose) polymerase in amyloid beta cytotoxicity

Inhibition of 12-lipoxygenase protects against amyloid beta peptides-evoked toxicity, memory impairment and alteration of locomotor activity

alpha-Synuclein stimulates nitric oxide synthase (NOS) by activation of NMDA receptor

The role of Cdk5/p35 and cPLA2/LOX in neuroinflammation and neurodegeneration

Sphingosine-1-phosphate and its receptors signaling in neurodegeneration/neuroprotection

NAC peptide evoked oxidative stress leads to p53 mediated apoptosis

Inhibitory effect of alpha-synuclein and non-amyloid beta component of Alzheimer's disease amyloid on dopamine transporter function in rat striatal synaptosoines:relationship to oxidative stress

Inhibitors of poly(ADP-ribose) polymerase protect hippocampal neurons against genotoxic stress via PI-3K/AKT regulated pathway and by suppression of AIF translocation

alpha-Synuclein and its neurotoxic fragment induce apoptotic pathway in PC 12 cells with diferent amyloid beta load

Inflammation related apoptosis can be prevented by inhibition of nitric oxide synthesis

The role of cyclooxygenases and lipooxygenases in mechanism of amyloid beta toxicity

Sphingosine kinase and glycogen synthase kinase-3Beta in molecular mechanism of Alzheimer’s amyloid Beta toxicity

Udzial alfa-synukleiny w funkcji ukladu dopaminergicznego

Alfa-synukleina w fizjologii i patologii mozgu

Expression of poly(ADP-ribose) polymerases in hippocampus during systemic inflammatory response. The role of PARP-1 protein interactions in cognition