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1

EB12 knock-out mice show greater loss of brain lipids followed by earlier attempts at remyelination in the cuprizone model of demyelination

100%
Klimaszewska-Lata J., Shimshek D. R., Szutowicz A., Rutkowska A.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr Suppl.1
INTRODUCTION: The EBI2 receptor is one of the key mediators of innate immune responses. In cooperation with its ligand, oxysterol 7α,25HC, EBI2 coordinates immune cell positioning in the secondary lymphoid tissue, enabling appropriate humoral and cellular immune responses. EBI2 is also expressed in the central nervous system (CNS), where it regulates inflammatory signalling and myelination. Importantly, EBI2 receptor’s altered expression and signalling have been linked to a range of diseases including multiple sclerosis. AIM(S): The aim of the study was to investigate the effects of EBI2 signalling on lipid parameters in the cuprizone model of demyelination. METHOD(S): 37-week-old EBI2 knock-out (KO) and wild‑type C57BL6J mice were fed a 0.2% cuprizone diet for 5 weeks. The animals were decapitated immediately after 5 weeks or after an additional 2 weeks of recovery period on normal diet. Here, we report greater loss of brain cholesterol and triglycerides in EBI2 KO mice after 5 weeks on the cuprizone diet, indicating EBI2 receptor involvement in CNS lipid maintenance under demyelinating conditions. RESULTS: However, two weeks after return to normal diet, when spontaneous remyelination is observed, the data showed higher cholesterol and triglycerides levels and a greater increase in lipase activity in the EBI2 KO mice. Other studies showed that a sharp increase in lipase activity is observed in an experimental autoimmune encephalomyelitis model around the time of symptom remission and in cerebellar slices between deand re‑myelination phases. CONCLUSIONS: Our data is, therefore, in line with these findings showing that earlier lipase activity in the EBI2 KO mice possibly leads to an earlier remyelination attempt, as observed by increased cholesterol and triglycerides levels. These results indicate functional involvement of EBI2 receptor in lipid homeostasis under pathophysiological conditions and thus warrant further investigations into the role of EBI2 in demyelinating diseases.
2

Relationships between acetyl-CoA level and function of fenotypically modified N9 murine microglial cells

100%
Klimaszewska-Lata J., Ronowska A., Bielarczyk H., Szutowicz A.
Acta Neurobiologiae Experimentalis
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2009
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tom 69
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nr 1
Neurodegenerative lesions in cholinergic encephalopathies include an excessive activation of microglia, which may aggravate this process. Infl amatory cytokines were reported to affect viability of cultured cholinergic cells, through the infl uence on their acetyl-CoA metabolism. The aim of this work was to investigate whether phenotypic modifi cations of N9 microglia by common neuron-differentiating stimuli can alter its energy metabolism, viability and biological activity in neurodegenerative conditions. In basal conditions lipopolysaccharide (LPS) slightly decreased PDH activity and acetyl-CoA content and activated NO synthesis (600%). The cyclic AMP alone (0.25 mM), caused 15% increase of nonviable cells at 300% rise in NO synthesis and 50 and 30% decreases in acetyl-CoA and ATP contents, respectively. In such conditions LPS resulted in further increase of NO accumulation and aggravated loss of cell viability and their acetyl-CoA content. In basic conditions retinoic acid (RA) alone did not alter viability and NO synthesizing capacity but increased acetyl-CoA and blunted cytotoxic potencies of cAMP and LPS to N9. RA-evoked restoration of N9 cell viability was accompanied by the increase in their acetyl-CoA content. These data indicate that activation of microglia depletes their acetyl-CoA, making them more vulnerable to cytotoxic insults. On the contrary, rescue of microglia by RA-signaling pathways is connected with restoration their acetylCoA pool. Supported by MNiSW projects P05A 11030 and NN401 2333 33 and AMG fund St-57.
3

Zinc as early neurotoxic signal in cholinergic SN56 neuroblastoma cells

76%
Dys A., Ronowska A., Gul-Hinc A. S., Klimaszewska-Lata J., Kocbuch K., Szutowicz A., Bielarczyk H.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
|
nr 1
Preferential loss of septal cholinergic neurons is a main cause of cognitive deficits in various encephalopathies. Zinc excess is one of multiple pathologic signals contributing to mechanisms of Alzheimer’s and other neurodegenerative diseases. We suggest that zinc may be involved in early excitotoxic phase of neuronal injury. In homogenates of SN56 cholinergic neuroblastoma cells, Zn caused instant inhibition of pyruvate dehydrogenase (PDH), aconitase, isocitrate dehydrogenase (IDH) and ketoglutarate dehydrogenase (KDH) activities with Ki values equal to 0.08, 0.008, 0.005 and 0.005 mM, respectively. Short term, 30 minute exposition to Zn caused a concentration dependent increase in mortality of cAMP/retinoic acid differentiated SN56 cholinergic cells (DC) that was two times higher than that of differentiated ones (NC). Zn also decreased cytoplasmic acetyl-CoA as well as ACh content and inhibited its release. Exposition of DC and NC to increasing concentrations of Zn yielded concave up non saturable accumulation plots that reached level of 60 nmol/mg protein at 0,15 mM extracellular concentration of a cation. In these conditions no change in whole cell Ca level was observed. However the level of intramitochondrial Ca was decreased by 30%, at 100 % increase of cytoplasmic Ca. Significant, direct correlation between Zn accumulation and cytoplasmic Ca concentration (r=0.97, p=0.028) and the inverse one with mitochondrial Ca (r=- 0.96, p=0.028) were found, respectively. On the other hand, 24 h cell exposition to 0,15 mM Zn increased its intracellular content from 1.4 to about 6 nmol/mg protein at simultaneous 40% decrease of whole cell Ca level. Zn caused no significant changes in the density of ZnT1 and ZnT4 transporter proteins in the cells. Presented data indicate the coexistence in SN56 cell plasma membranes low density - high-affinity and high density - low affinity Zn-transporting sites. Inhibition of mitochondrial Na-Ca exchanger by accumulated Zn might cause depletion of Ca in mitochondria. In addition chronic exposition to Zn apparently induced adaptative mechanisms eliminating excess of the metal from the cells. These changes may directly inhibit intramitochondrial acetyl-CoA synthesis and its transport to cytoplasmic compartment, yielding impairment of cell viability and suppression their transmitter functions. Supported by MWiSW NN401 0299 37, St57 and W-109 MUG projects.
4

Cytotoxic effects of zinc on cholinergic and astroglial cells

76%
Dys A., Ronowska A., Klimaszewska-Lata J., Gul-Hinc S., Bielarczyk H., Szutowicz A.
Acta Neurobiologiae Experimentalis
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2013
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tom 73
|
nr Suppl.1
Zinc excess in the synaptic cleft may be one of pathologic signals triggering chronic neurodegenerative events. The aim of this work was to find relationships between Zn accumulation and integrity of cholinergic and astroglial cells. Exposition of cAMP/RA-differentiated (DC) and nondifferentiated cells (NC) cholinergic SN56 neuroblastoma and astroglial C6 cells to Zn yielded its concentration dependent accumulation. It caused inhibition of pyruvate dehydrogenase, aconitase and ketoglutarate dehydrogenase activities. Zn accumulation caused concentration-dependent death of both neuronal and astroglial cells. After 24 h exposition of SN56 cells to 0.15 mM Zn their death rates were equal to 35 and 50% for NC and DC at cation levels equal to 4.0 and 5.5 nmol/mg protein, respectively. In the same conditions, the death rates of astroglial NC and DC were close to 1–2% only, at intracellular Zn levels of 1.6 and 2.1 nmol/ mg protein, respectively. Higher about 0.25 mM Zn levels were required to evoke death rates of astroglial cells, similar to those seen in neuronal cells. In such conditions Zn levels in astroglia were about 6.4 and 27.0 nmol/mg protein, respectively. Such differential sensitivity of astroglial and neuronal cholinergic NC and DC to Zn may be due to respective differences in densities of ZnT1 transporters in their plasma membranes. Supported by M.S&H.E. project IP2010035370 and GUMed fund ST57.
5

Cytotoxic effects of zinc on cholinergic SN56 neuroblastoma and C6 astrocytoma cells

76%
Dys A., Ronowska A., Gul-Hinc S., Klimaszewska-Lata J., Bizon-Zygmanska D., Szutowicz A., Bielarczyk H.
Acta Neurobiologiae Experimentalis
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2015
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tom 75
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nr Supl.
BACKGROUND AND AIMS: The aim of this work was to find relationships between Zn accumulation and integrity of cholinergic and astroglial cells. METHODS: Exposition of cAMP/RA-differentiated (DC) and nondifferentiated (NC) cells cholinergic SN56 neuroblastoma and astroglial C6 cells to Zn yielded its concentration dependent accumulation. The level of Zn was measured by fluorimetric method with TSQ. RESULTS: After 24 h exposition of SN56 cells to 0.15 mM Zn their death rates were equal to 35 and 50% for NC and DC at cation levels equal to 4.0 and 5.5 nmol/mg protein, respectively. In the same conditions, the death rates of astroglial cells were close to 1–2% only, at intracellular Zn levels of 1.6 and 2.1 nmol/mg protein, respectively. Higher, about 0.25 mM Zn levels were required to evoke death rates of astroglial cells, similar to those seen in neuronal cells. In such conditions Zn levels in astroglia were about 6.4 and 27.0 nmol/mg protein, respectively. In thisstudy we examined the effects of accumulation of Zn in cholinergic neurons and adjacent astrocytes on activity of enzymes involved in energy metabolism. It caused inhibition of PDHC, aconitase and IDH activities. The high susceptibility of cholinergic neurons and a relative high resistance of astrocytes induced by cytotoxic concentration of zinc. Higher levels of Zn may cause deeper inhibition of acetyl-CoAsynthesis and the flow rate of the TCAcycle, which leads to a decrease in ATP synthesis and cell damage. CONCLUSIONS: Chronic exposition to Zn apparently induced adaptative mechanisms eliminating excess of the metal from the cells. These changes may directly inhibit intramitochondrial acetyl-CoA synthesis and its transport to cytoplasmic compartment, yielding impairment of cell viability and suppression their transmitter functions. Chronic neurons are more susceptible to increase extracellular concentrations of zinc than astrocytes. Supported by MNiSW projects MN 01-0108/08/248 and MUG fund ST-57.
6

Disturbances in acetyl-CoA metabolism a key point in mechanisms of cholinergic degeneration

76%
Szutowicz A., Bielarczyk H., Ronoweska A., Gul-Hinc S., Klimaszewska-Lata J., Dys A., Zyk M.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
Acetyl-CoA synthesized from glucose-derived pyruvate by pyruvate dehydrogenase complex (PDHC) is a main substrate, for mitochondrial energy production and cytoplasmic synthetic pathways in all types of brain cells. Activities of mitochondrial PDHC, and several enzymes of acetyl-CoA metabolism, and ZnT1 transporter level in cholinergic septal SN56 cells were from 2 to 8 times higher than those in microglial (N9) or astroglial (C6) cells. Differentiated cholinergic SN56 cells were highly susceptible to various neurotoxic signals: Zn, amyloid-β or NO excess. They decreased their viability and acetyl-CoA/ATP contents, due to inhibition or inactivation of PDHC and other enzymes of energy metabolism. Such conditions suppressed synthesis of acetyl-CoA, Nacetyl-L-aspartate, acetylcholine as well as its quantal release. Significant correlations existed between mitochondrial acetyl-CoA levels and SN56 viability in those conditions. On the other hand, nondifferentiated SN56, microglial (N9) or astroglial (C6) cells were more resistant to same detrimental insults. SN56 cells were resistant to high concentrations of lipopolysaccharide (LPS). On the contrary, in N9 cells low concentrations of LPS caused several-fold activation of NO and IL-6 and TNF-α synthesis/release, along with inhibition of PDHC, KDHC and aconitase activities yielding depression of acetyl-CoA, ATP contents but relatively small losses in their viability. Also, Zn and NO caused relatively weak inhibition enzymes of energy metabolism in N9 and C6 cells. Lipoic acid and L-carnitine rescued cells by preventing inhibition some of those enzymes by neurotoxins and alleviating acetyl-CoA and ATP deficits. Presented data indicate that particular types of brain cells constitute compartments of different levels and rates of acetyl-CoA metabolism, variably influencing their functional properties and viability both under neurodegenerative and cytoprotective conditions. Supported by MN59, MN58, MN108, ST57 GUMed funds.
7

Thiamine pyrophosphate deficiency causes energy disturbances in astroglial C6 and microglial N9 cells

64%
Romowska A., Bizon-Zygmanska D., Gul-Hinc S., Dys A., Klimaszewska-Lata J., Bielarczyk H., Wolska A., Szutowicz A.
Acta Neurobiologiae Experimentalis
|
2013
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tom 73
|
nr Suppl.1
Inhibition of pyruvate (PDHC) and ketoglutarate (KDHC) dehydrogenase complexes induced by thiamine pyrophosphate deficits is known to cause disturbances of cholinergic transmission in the brain, yielding clinical symptoms of cognitive and motor deficits. However, particular alterations in distribution of acetyl-CoA, in the glial cells of thiamine pyrophosphate-deficient brain remain unknown. Therefore, the aim of our work was to find out how amprolium-induced thiamine pyrophosphate deficits (TD) affect distribution of acetyl-CA in the compartments of glial cells. As an experimental model we used astroglial C6 and microglial N9 cell line cultured in low thiamine medium. In such conditions microglial N9 cells displayed significantly greater loss of viability than the C6 ones. In both groups of the cells the activity of the key enzymes of energy/acetyl-CoA metabolism such as: PDHC, KDHC, aconitase was inhibited by amprolium-induced thiamine deficits. It explains why acetyl-CoA levels in the mitochondrial compartment were decreased in the cells. Supported by the Ministry of Research and Higher Education projects: IP 2011 046071, 01-0100/08 and St 57.
8

Regulatory effects of acetyl-CoA distribution in cellular compartments of healthy and diseased brain

64%
Szutowicz A., Ronowska A., Bielarczyk H., Gul-Hinc S., Klimaszewska-Lata J., Dys A., Zysk M., Jankowska-Kulawy A.
Acta Biochimica Polonica
|
2018
|
tom 65
|
nr S2
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