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1

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

100%
Czapski G. A., Cakala M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
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
2

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

100%
Czapski G. A., Cakala M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
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.
3

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

100%
Adamczyk A., Kazmierczak A., Cakala M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
4

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

100%
Czapski G. A., Cakala M., Gajkowska B., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2005
|
tom 65
|
nr 3
5

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

100%
Cakala M., Jesko H., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2006
|
tom 66
|
nr 4
6

Molecular mechanism of PC12 cell death evoked by sodium nitroprusside, a nitric oxide donor

88%
Pytlowany M., Strosznajder J. B., Jesko H., Cakala M., Strosznajder R. P.
Acta Biochimica Polonica
|
2008
|
tom 55
|
nr 2
339-347
Nitric oxide (NO) is a potent extracellular and intracellular physiological messenger. However, NO liberated in excessive amounts can be involved in macromolecular and mitochondrial damage in brain aging and in neurodegenerative disorders. The molecular mechanism of its neurotoxic action is not fully understood. Our previous data indicated involvement of NO in the release of arachidonic acid (AA), a substrate for cyclo- and lipoxygenases (COX and LOX, respectively). In this study we investigated biochemical processes leading to cell death evoked by an NO donor, sodium nitroprusside (SNP). We found that SNP decreased viability of pheochromocytoma (PC12) cells in a concentration- and time-dependent manner. SNP at 0.1 mM caused a significant increase of apoptosis-inducing factor (AIF) protein level in mitochondria. Under these conditions 80% of PC12 cells survived. The enhancement of mitochondrial AIF level might protect most of PC12 cells against death. However, NO released from 0.5 mM SNP induced massive cell death but had no effect on protein level and localization of AIF and cytochrome c. Caspase-3 activity and poly(ADP-ribose) polymerase-1 (PARP-1) protein levels were not changed. However, PARP activity significantly decreased in a time-dependent manner. Inhibition of both COX isoforms and of 12/15-LOX significantly lowered the SNP-evoked cell death. We conclude that AIF, cytochrome cand caspase-3 are not responsible for the NO-mediated cell death evoked by SNP. The data demonstrate that NO liberated in excess decreases PARP-1 activity. Our results indicate that COX(s) and LOX(s) are involved in PC12 cell death evoked by NO released from its donor, SNP.
7

Mitochondrial and nuclear targets of amyloid wita-evoked oxidative stress

88%
Jesko H., Strosznajder J., Cieslik M., Cakala M., Strosznajder R.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
Amyloid β (Aβ) is responsible for mitochondrial failure and biochemical alterations linked to Alzheimer`s disease (AD). To better understand mechanisms of Aβ toxicity we investigated its mitochondrial and nuclear targets, apoptosis-inducing factor (AIF) and Poly(ADP-ribose) polymerase-1 (PARP-1) in PC12 cells transfected with wild type (APPwt) or double Swedish-mutated human Amyloid Precursor Protein gene (APPsw) characterized by different Aβ concentrations. We found close relationship between Aβ level and cyclooxygenase (COX)- and lipoxygenase (LOX)-related free radical formation leading to p65/NF-κB nuclear translocation. COX and LOX inhibitors protected APPsw cells against p65 translocation. Aβ-evoked oxidative stress enhanced mitochondrial AIF level and inhibited PARP-1 in APPsw cells. Nitrosative stress evoked by 0.5 mM sodium nitroprusside (SNP) had no further effect on Aβ-altered PARP-1 activity and mitochondrial AIF level in APPsw cells. However, SNP evoked death of 70–80% of all cell types after 24 h. COX and LOX inhibitors had ameliorating effect in these conditions. Our data indicated that double Swedish mutation in APP signifi cantly increased cell vulnerability to oxidative stress. Enhanced mitochondrial AIF level and PARP-1 inhibition might be responsible for cell survival under oxidative stress evoked by accumulating Aβ in APPsw cells. COX and LOX inhibitors protected the cells against death caused by simultaneous Aβ toxicity and nitrosative stress.
8

Amyloid beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells

64%
Chalimoniuk M., Stolecka A., Cakala M., Hauptmann S., Schulz K., Lipka U., Leuner K., Eckert A., Muller W. E., Strosznajder J. B.
Acta Biochimica Polonica
|
2007
|
tom 54
|
nr 3
Cytosolic phospholipase A2 (cPLA2) preferentially liberates arachidonic acid (AA), which is known to be elevated in Alzheimer's disease (AD). The aim of this study was to investigate the possible relationship between enhanced nitric oxide (NO) generation observed in AD and cPLA2 protein level, phosphorylation, and AA release in rat pheochromocytoma cell lines (PC12) differing in amyloid beta secretion. PC12 control cells, PC12 cells bearing the Swedish double mutation in amyloid beta precursor protein (APPsw), and PC12 cells transfected with human APP (APPwt) were used. The transfected APPwt and APPsw PC12 cells showed an about 2.8- and 4.8-fold increase of amyloid β (Aβ) secretion comparing to control PC12 cells. An increase of NO synthase activity, cGMP and free radical levels in APPsw and APPwt PC12 cells was observed. cPLA2 protein level was higher in APPsw and APPwt PC12 cells comparing to PC12 cells. Moreover, phosphorylated cPLA2 protein level and [3H]AA release were also higher in APP-transfected PC12 cells than in the control PC12 cells. An NO donor, sodium nitroprusside, stimulated [3H]AA release from prelabeled cells. The highest NO-induced AA release was observed in control PC12 cells, the effect in the other cell lines being statistically insignificant. Inhibition of cPLA2 by AACOCF3 significantly decreased the AA release. Inhibitors of nNOS and γ-secretase reduced AA release in APPsw and APPwt PC12 cells. The basal cytosolic [Ca2+]i and mitochondrial Ca2+ concentration was not changed in all investigated cell lines. Stimulation with thapsigargin increased the cytosolic and mitochondrial Ca2+ level, activated NOS and stimulated AA release in APP-transfected PC12 cells. These results indicate that Aβ peptides enhance the protein level and phosphorylation of cPLA2 and AA release by the NO signaling pathway.
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