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

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Jantas D. , Laskiewicz M. , Pilc A. , Lason W.

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nr 1

EN

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.

2

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

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Domin H. , Jantas D. , Smialowska M.

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nr 1

EN

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.

3

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

63%

Budziszewska B. , Szymanska M. , Leskiewicz M. , Basta-Kaim A. , Jaworska-Feil L. , Kubera M. , Jantas D. , Lason W.

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nr 2

EN

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.