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1

Human neuroblastoma SH-SY5Y cells-in vitro model to study neurodegeneration and neuroprotection in relation to Parkinson’s disease

100%
Jantas D.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
Human neuroblastoma SH-SY5Y cells are widely used in neurotoxicity and neuroprotection research. Since this cell line, derived from peripheral nervous system, possesses a dopaminergic phenotype and is sensitive to dopaminergic specific toxins (e.g. MPP(+), 6-OHDA), it has been extensively utilized not only to study Parkinson’s disease (PD) pathology but also to test new putative neuroprotective agents. During the presentation the advantages and limitations associated with the use of this cellular model for the study of PD will be presented with discussion on its translational potential. Finally, data from the study performed in SH-SY5Y cells aimed to assess the neuroprotective potential of metabotropic glutamate receptors group II and III (mGluR II/III) activators will be demonstrated. There are many experimental evidences demonstrating the importance of normalizing glutamatergic and GABAergic pathways in the basal ganglia circuitry, using for example agonists of mGluR II and III. With the emergence of new mGluR III specific agents, there is a need for efficient cellular screening platform to assess both neuroprotective effects and mechanisms of action.
2

Tyreoliberyna [TRH] - neuropeptyd regulujacy homeostaze w osrodkowym ukladzie nerwowym

100%
Jantas D.
Postępy Biologii Komórki
|
2009
|
tom 36
|
nr 3
483-496
3

Dysfunkcje mitochondriów w chorobach neurodegeneracyjnych: potencjalny punkt uchwytu dla leków neuroprotekcyjnych

63%
Greda A., Jantas D.
Postępy Biologii Komórki
|
2012
|
tom 39
|
nr 3
4

Effects of doxorubicin on undifferentiated and retinoic acid (RA)-treated neuroblastoma SH-SYSY cells

63%
Jantas D., Lason W.
Acta Neurobiologiae Experimentalis
|
2006
|
tom 66
|
nr 4
5

The evaluation of the role of mGluR7 in neuronal apoptotic processes by usage of AMN082, a selective mGluR7 agonist and mGluR7 knockout-derived cells

51%
Jantas D., Lech T., Pilc A., Lason W.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
Increasing body of evidence suggests a neuroprotective potential of metabotropic glutamatergic receptor group III (mGluR III) stimulation, however the role of particular subtypes of these receptors (mGluR4, mGluR7, mGluR8) in apoptotic processes is not fully recognized. Of special interest is the study on the role of mGluR7 which is widely expressed throughout the brain and recently developed selective positive allosteric modulator of this receptor, AMN082 (N,N=-dibenzhydrylethane-1,2-diamine dihydrochloride) enables investigation the biological role of mGluR7. In the present study, firstly we evaluated the possible neuroprotective effects of AMN082 (0.001–1 µM) on neurotoxicity induced by various apoptotic [stimuli staurosporine (St), doxorubicin (Dox) and low potassium (LP)] in 7 DIV cerebellar granule cells (CGC). The data showed that AMN082 (0.1–1 µM) partially attenuated the cell death induced by St and LP, but not by Dox. Next, we investigated the role of mGluR7 in neuronal cell death by testing the vulnerability of CGC from wild and mGluR7KO animals to toxic action of St, Dox and LP. No differences between groups under basal conditions have been found. However, after primary deprivation of CGC cells from potassium in culture medium and secondary application of proapoptotic stimuli we observed the higher vulnerability of mGluR7KO CGC to cell damaging effect of St and Dox but not LP. Further experiments performed on cortical glia cells demonstrated higher toxic action of St and Dox in mGluR7KO cells when compared to wild type one. Additionally, in mGluR7KO glia cells we found higher basal and stimulated by St or Dox caspase-3 activity when compared to wild type one. The obtained data suggest that specific stimulation of mGluR7 by AMN082 could be protective against staurosporine and low-potassium induced neuronal ell death. Moreover, the presence of mGluR7 could be particularly important for survival of glia cells under harmful conditions. The study was supported by statutory funds for Institute of Pharmacology PAS and grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
6
Content available remote

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

51%
Leskiewicz M., Jantas D., Budziszewska B., Lason W.
Journal of Physiology and Pharmacology
|
2008
|
tom 59
|
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.
7

Agonists of mGluRs II/III attenuate the staurosporine-induced toxicity in human neuroblastoma SH-SY5Y cells

51%
Jantas D., Laskiewicz M., Pilc A., Lason W.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Agonists of metabotropic glutamate receptors group II and III (mGluRs II/III) show neuroprotective effects in in vitro and in vivo models of excitotoxicity. However, their influence on neuronal apoptosis remains unknown. In this study the effect of agonists of mGluRs II/III on staurosporine (St)-evoked LDH release was estimated in undifferentiated (UN-) and retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells. It has been found that LY354740 (0.01-100 microM) and ACTP-I (0.01-100 microM), a nonspecific agonists of mGluRs group II and III, respectively when given alone had no effect on cell proliferation and cell viability. However, both of these compounds partially decreased the St-induced cell death in UN- and RA-SHSY5Y. The selective agonist of mGluR7, AMN082 in low concentrations (0.001-1 microM) had no effect on cell proliferation/viability and tended to attenuate the Stinduced toxicity only in UN-SHSY5Y. On the other hand, AMN082 in higher concentrations (>10 microM) had the cell damaging effect in both UN- and RA- SHSY5Y cells. This study indicates that agonists of mGluRs II/III have potential to attenuate cell death evoked by staurosporine - a well recognized inducer of apoptosis. Acknowledgment: The study was supported by grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
8

The influence of LY354740 - an agonist of group-II metabotropic glutamate receptors (mGLuR II) on neuronal apoptosis in primary neurons

51%
Jantas D., Greda A., Pilc A., Lason W.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
A number of studies have shown neuroprotective effects of agonists of group-II metabotropic glutamate receptors (mGluR II) in various experimental models of excitotoxicity. However, an influence of these compounds on neuronal apoptosis is less recognized. We tested the effect of nonspecific agonist of mGluR II, LY354740 ((+)-2-aminobicyclo[3.1.0]hexane-2,6dicarboxylate) on staurosporine and doxorubicin evoked cell death in primary pure neuronal and neuronal-glial cortical cells, as well in cerebellar granule cells (CGC). We found that LY354740 (0.01-10 microM) was protective against staurosporine-evoked cell death in both, pure cortical neurons and CGC with higher efficacy in 12 DIV in comparison with the 7 DIV ones. Moreover, the neuroprotective effect of LY354470 in neuronal-glial cells did not differ from that found in pure neurons. The protective effect of mGluR II agonist was not connected with attenuation the St-induced caspase-3 activity and DNA fragmentation, but this agent decreased the St-evoked necrotic cell death as measured by propidium ioide staining. LY354470 had no influence on doxorubicin-evoked cell death, but attenuated the glutamate-mediated neuronal cell damage. Our data suggest that neuroprotective effects of the mGluR II ligand are stimuli- and development-dependent and are rather connected with attenuation of necrotic-, than the apoptotic cell death. The study was supported by grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
9

The protective effect of TRH and its analogues on staurosporine-but not doxorubicin-induced apoptosis in primary cortical neurons

51%
Jantas D., Jaworska-Feil L., Lipkowski A. W., Lason W.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 1
In the present study we investigated the infl uence of thyrotropinreleasing hormone (TRH, pGlu-His-Pro-NH2) and its more stable analogues: CG-3703 (Montirelin), RGH-2202 (L-6-keto-piperidine-2carbonyl-L-leucyl-L-prolinamide) and Z-TRH (Z-pGlutamyl-Histydyl-Proline) on neuronal apoptosis evoked by staurosporine ñ or doxorubicin, agents activating mitochondrial or extracellular (FAS) apoptotic cell death, respectively. We showed that TRH (0.001ñ10 μM) in U-shape concentration dependent way (effective concentrations: 0.01 and 0.1 μM) partially attenuated the staurosporine (0.5 μM) ñ but not doxorubicin (0.5 μM)-evoked cell damage in mouse 7 DIV cortical neurons only when added 24 h before toxin administration. The TRH analogues (MON, RGH, Z-TRH) were also effective in lower concentration (0.001 μM) than TRH in attenuation of the staurosporine-induced LDH release. Moreover, that benefi cial effect of TRH and its analogues was not accompanied with its infl uence on caspase-3 activity, though the attenuation of number of apoptotic cells was observed in Hoechstís staining. Furthermore, we found that neither PI3-K (wortmannin 10 μM, LY294002 1 μM) nor MAPK/ERK1/2 (PD098059 1 uM and U0126 1 μM) inhibitors were able to abolish protection served by TRH and MON. There was no protection observed when peptides were added concomitantly with staurosporine and doxorubicin. The obtained data showed ameliorating effect of pretreatment with low concentrations of TRH and its analogues on neuronal cell death mediated by agent activating mitochondrial pathway of apoptosis. That effect seems to be caspase-3-independent and does not engage the PI3-K/ Akt and MAPK/ERK1/2 cellular prosurvival pathways. Supported by grant No. 2PO5A15530 from the Ministry of Education and Science (Warsaw, Poland)
10

The group III metabotropic glutamate receptor agonists attenuate neuronal cell death in primary cortical cultures exposed to oxygen-glucose deprivation

51%
Domin H., Jantas D., Smialowska M.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr 1
Oxygen-glucose deprivation (OGD) induces excitotoxic cell death mediated primarily by excessive release of glutamate. A growing body of evidence suggests that metabotropic glutamate (mGlu) receptors can modulate glutamatergic transmission, so these receptors are regarded as potential targets for neuroprotective drugs. Group III mGluRs (mGlu4, mGlu6, mGlu7 and mGlu8) agonists are known to reduce glutamatergic neurotransmission by inhibiting glutamate release. Therefore in the present study we tried to find out whether the agonist of group III mGluR (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-1) and the first selective allosteric mGlu7 receptor agonist, N,N’-bis (diphenylmethyl)-1,2- ethanediamine (AMN082) have neuroprotective potential in primary neuronal cortical cultures exposed to oxygen-glucose deprivation, as an in vitro ischemic injury paradigm. In order to evoke toxic effects cortical cultures were exposed to OGD for 1 - 5 h. ACPT-1, at concentrations of 1, 10, 100 and 200 µM, or AMN082, at concentrations of 0.01, 0.1, 0.5 and 1 µM, were applied in two ways: twice, just before the start of OGD and immediately after OGD or once, immediately after OGD. Neurotoxicity was measured by lactate dehydrogenase (LDH) efflux from the damaged cells into the culture media 24 h after the end of OGD. It was found that a double application of ACPT-1 or AMN082 significantly attenuated the LDH release by 20-30% and 30-43%, respectively. A particularly important finding is that AMN082, given once after the end of OGD also significantly decreased ischemic-induced LDH release by 30%. These data were confirmed by immunohistochemical staining for the presence of characteristic neuronal protein MAP-2. In conclusion, the above results indicate that group III mGlu receptor agonists may have neuroprotective potential and may play a potential therapeutic role in neurodegenerative disorders. The study was supported by Grant No N N401 091037 from the MSHE, Poland.
11

An involvement MAPK/ERK1/2 pathway in mechanism of lactacystin-induced cell damage in primary cortical neurons

45%
Jantas D., Konieczny J., Lenda T., Lason W., Lorenc-Koci E.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 3
Proteasome dysfunction is involved in pathomechanism of several neurodegenerative diseases where an accumulation of aberrant proteins occurs (e.g. Parkinson’s disease, Alzheimer’s disease). Lactacystin (LC) has been used for induction of proteasome inhibition-dependent neuronal cell death for several years but mechanism of its toxic action on neurons is still poorly understood. In the present study we showed time- and concentration-dependent toxic action of lactacystin (0.25–50 μM) in mouse cortical neurons. Although, lactacystin induced caspase-3 activation, its toxic action was not attenuated by caspase-3 inhibitor AcDEVD-CHO. We demonstrated that inhibitors of MAPK/ERK1/2 cellular signaling (U0126 and PD98052) were protective against LC-evoked cell death as confi rmed by LDH and MTT reduction assays. Moreover, these data were verifi ed by Western Blot analysis, where we observed the increase in ERK1/2 activity after LC treatment and this effect was inhibited by U0126. The obtained data point to engagement of activation of MAPK/ERK1/2 in toxic action of lactacystin and give a rationale for using agents which inhibit this intracellular pathway in treatment of neurodegenerative diseases connected with proteasome dysfunction. Supported by Polish MNSW Scientifi c Network Fund no 26/E-40/BWSN-0023/2008.
12

New evidence for a role of mGluR7 in astrocyte survival: Possible implications for neuroprotection

45%
Jantas D., Lech T., Golda S., Pilc A., Lason W.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: A specific activation of metabotropic glutamatergic receptor subtype 7 (mGluR7) by its allosteric agonist AMN082 has been shown to protect neuronal cells against various detrimental factors. It is well established that some of subtypes of mGluRs (e.g., mGluR5 or mGluR3) engage glia cells to more efficiently protect neurons against various harmful stimuli. AIM(S): We aimed to study the role of mGluR7 in glia and neuronal cell survival. METHOD(S): We used primary cortical glia cell cultures and cerebellar granule neurons (CGNs)from mGluR7+/+ and mGluR7-/- C57Bl/6J mice which were exposed to various cell damaging factors (staurosporine (St), doxorubicin (Dox)and low potassium (LP)). MTT reduction, LDH release and caspase-3 activity biochemical assays were used for assessment of cell damage. The mRNA expression level of various subtypes of mGluRs was measured by qPCR. RESULTS: We showed the expression of mGluR7 in glia cell cultures and demonstrated the higher toxicity of St and Dox in mGluR7-/- glia cells when compared to wild type one. Moreover, we found a partial protection mediated by AMN082 against St and Dox in mGluR7+/+ glia cells. However, we did not find any differences in vulnerability of CGNs derived from mGluR7+/+ and mGluR7-/- animals to the cell damaging action of LP, St or Dox under standard treatment. Intriguingly, when we primed both types of CGNs by culturing them overnight in LP medium, we found significant higher toxic action of St and Dox in mGluR7‑/‑ CGNs. Finally, we confirmed neuroprotective properties of AMN082 in CGNs and showed that this effect is stimuli‑ and development-dependent. CONCLUSIONS: Our data obtained in isolated glia and neuronal cellular models showed a protective potential of mGluR7‑specific agonist AMN082 and pro‑survival role of mGluR7 in glia cells which together with its already known direct role on neuronal cells could suggest its higher efficacy under in vivo conditions. FINANCIAL SUPPORT: The study was supported by statutory funds for Institute of Pharmacology PAS and grant No NN405611638 from the Ministry of Science and Higher Education, Warsaw, Poland.
13

Pretreatment is not mandatory for neuroprotection with 1alpha,25-dihydroxyvitamin D3 in perinatal hypoxic-ischemic rat brain damage in vivo and in excitotoxic injury of primary neuronal cell cultures

33%
Makarewicz D., Kajta M., Zieminska E., Jantas D., Domin H., Lason W., Kutner A., Lazarewicz J. W.
Acta Neurobiologiae Experimentalis
|
2009
|
tom 69
|
nr 1
Previous in vivo and in vitro studies demonstrated neuroprotective potential of pretreatment with 1α, 25-dihydroxyvitamin D3 (calcitriol). The aim of present study was to determine effectiveness of calcitriol administered in vivo after brain ischemic episode in the rat model of perinatal asphyxia, or co-applied with some delay during 24 h exposure to glutamate of the mice hippocampal, cortical and cerebellar neuronal cultures at 7th and 12th day in vitro. In some experiments calcitriol was given after acute exposure to glutamate of the rat cerebellar neurons. Our results demonstrated, that in the 7 day old rat pups submitted to hypoxia ñ ischemia acute application of calcitriol in one dose of 2 μg/kg 30 min after termination of the insult or sub-chronic, 7-day post-treatment with calcitriol effectively diminished brain damage. The rate of such accomplished neuroprotection exceeded that achieved by hypoxic preconditioning, used as the reference neuroprotective method. Moreover the results of our in vitro experiments revealed the ability of calcitriol to reduce excitotoxicity in a way dependent on origin of neuronal cells, stage of their development and duration of excitotoxic insult. Calcitriol was neuroprotective when it was applied together with glutamate or even with up to 6 h delay during 24-h excitotoxic challenge to the hippocampal and neocortical, but not cerebellar neuronal cultures. In addition calcitriol inhibited glutamate-induced caspase-3 activity in hippocampal cultures. We ascribe these protective effects of calcitriol to a rapid, possibly non-genomic modulation by this compound of the mechanisms that are instrumental in its direct neuroprotective action. The study was supported by Polish MNSW Scientifi c Network Fund no 26/E-40/SN-0023/2007
14
Content available remote

The decrease in JNK- and p38-MAP kinase activity is accompanied by the enhancement of PP2A phosphatase level in the brain of prenatally stressed rats

33%
Budziszewska B., Szymanska M., Leskiewicz M., Basta-Kaim A., Jaworska-Feil L., Kubera M., Jantas D., Lason W.
Journal of Physiology and Pharmacology
|
2010
|
tom 61
|
nr 2
Our previous study suggests that in prenatal stress model of depression glucocorticoid receptor (GR) function in adult rats is enhanced. However, the long-term consequences of stress, a causal factor in depression, on intracellular elements involved into the regulation of GR function is poorly examined. Mitogen-activated protein kinases (MAPKs), activity of which is disturbed in depression, are important regulators of GR action, so they can mediate the effect of stress on GR function. Therefore, the aim of the present study was to investigate the levels of active phosphorylated forms of extracellular signal-regulated kinases (ERK), Jun N-terminal kinases (JNK) and the p38 kinase in the hippocampus and frontal cortex in rats subjected to prenatal stress. The concentration of MAP kinase phosphatase (MKP-1, MKP-2) and protein phosphatase-2A (PP2A), which dephosphorylate all forms of MAP kinases, were also determined. During verification of the applied model of depression, we found that prenatally stressed rats displayed high level of immobility in the Porsolt test and that the administration of imipramine, fluoxetine, mirtazapine and tianeptine for 21 days normalized this parameter. Western blot study revealed that rats subjected to prenatal stress had decreased levels of p-JNK1 and p-JNK2 in the hippocampus and p-p38 in the frontal cortex, but the concentrations of p-ERK1 and p-ERK2 were not changed. Chronic treatment with imipramine inhibited the stress-induced decrease in p-JNK1/2, while imipramine, fluoxetine and mirtazapine blocked changes in p-p38. PP2A phosphatase level was higher in the hippocampus and frontal cortex in prenatally stressed animals than in control rats. Chronic treatment with antidepressant drugs attenuated the stress-induced increase in the level of this phosphatase, but had no effect on its concentration in control animals. There was no significant difference in MKP-1 and in MKP-2 levels in both brain structures between control and prenatally stressed rats. The obtained results showed that prenatal stress decreased the levels of active form of JNK and p38, but enhanced PP2A phosphatase expression and most of these changes were reversed by antidepressant drugs. Since p-JNK and p-p38 are known to inhibit GR function their lowered levels may enhance glucocorticoid action. Furthermore, the increased PP2A concentration may intensify GR action not only by inhibition of JNK and p38 phosphorylation, but also by a direct influence on the process of GR translocation.
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