Biomedical subjects

Agnes Simonyi

Publications and source records attributed to Agnes Simonyi.

21 records · Page 2Linked to original sources

PubMed2002

Role of PKC and MAPK in cytosolic PLA2 phosphorylation and arachadonic acid release in primary murine astrocytes.

Although Group IV cytosolic phospholipase A2 (cPLA2) in astrocytes has been implicated in a number of neurodegenerative diseases, mechanisms leading to its activation and release of arachidonic acid (AA) have not been clearly elucidated. In primary murine astrocytes, phorbol myristate acetate (PMA) and ATP stimulated phosphorylation of ERK1/2 and cPLA2 as well as evoked AA release. However, complete inhibition of phospho-ERK by U0126, an inhibitor of mitogen-activated protein kinase kinase (MEK), did not completely inhibit PMA-stimulated cPLA2 and AA release. Epidermal growth factor (EGF) also stimulated phosphorylation of ERK1/2 and cPLA2[largely through a protein kinase C (PKC)-independent pathway], but EGF did not evoke AA release. These results suggest that phosphorylation of cPLA2 due to phospho-ERK is not sufficient to evoke AA release. However, complete inhibition of ATP-induced cPLA2 phosphorylation and AA release was observed when astrocytes were treated with GF109203x, a general PKC inhibitor, together with U0126, indicating the important role for both PKC and ERK in mediating the ATP-induced AA response. There is evidence that PMA and ATP stimulated AA release through different PKC isoforms in astrocytes. In agreement with the sensitivity of PMA-induced responses to PKC down-regulation, prolonged treatment with PMA resulted in down-regulation of PKCalpha and epsilon in these cells. Furthermore, PMA but not ATP stimulated rapid translocation of PKCalpha from cytosol to membranes. Together, our results provided evidence for an important role of PKC in mediating cPLA2 phosphorylation and AA release in astrocytes through both ERK1/2-dependent and ERK1/2-independent pathways.

Adenosine Triphosphate↗

PubMed2002

Grape polyphenols inhibit chronic ethanol-induced COX-2 mRNA expression in rat brain.

BACKGROUND: Chronic ethanol has been shown to increase oxidative stress leading to neurodegenerative changes in the brain. Oxidative stress may up-regulate extracellular signal regulated kinases (ERK1/2) and, subsequently, the arachidonic acid cascade mediated by phospholipase A2 (PLA2) and cyclooxygenase (COX-2). Our earlier study showed that grape polyphenols (GP) could ameliorate oxidative damage to synaptic membrane proteins due to chronic ethanol treatment. This study was aimed at examining the effects of GP on mRNA expression of ERK1/2, cytosolic PLA2 (cPLA2), and COX-2 in different brain regions after chronic ethanol treatment. METHODS: Male Sprague-Dawley rats were fed a Lieber-DeCarli liquid diet with ethanol or isocaloric amount of maltose, with or without GP for 2 months. In situ hybridization was carried out using coronal brain sections through the hippocampus. RESULTS: Quantitative in situ hybridization showed no changes in ERK1 and cPLA2 mRNA levels in cortical areas and hippocampus after ethanol and/or GP administration. However, a decrease in ERK2 and an increase in COX-2 mRNA level was found in the hippocampus of ethanol-treated animals. GP completely inhibited the increase in COX-2 due to ethanol treatment. CONCLUSION: Increase in COX-2 expression may be an underlying mechanism for the increase in oxidative stress induced by chronic ethanol administration. Dietary supplementation of GP may have a beneficial role in inhibiting certain alcohol effects.

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PubMedDate not supplied

The role of metabotropic glutamate receptor 5 in learning and memory processes.

Metabotropic glutamate receptor 5 (mGluR5), a subtype in the group I mGluRs, couples to phospholipase C through Gq protein. Stimulation of mGluR5 leads to the release of calcium from intracellular stores and protein kinase C activation. In addition, links to different ion channels and other signaling mechanisms have also been revealed. MGluR5s are mainly localized postsynaptically on the periphery of synap-ses. MGluR5s have been implicated in synaptic plasticity and learning and memory. The development of the highly potent and selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has facilitated the understanding of the roles of mGluR5s in the central nervous system. Both in vitro and in vivo studies have demonstrated that the activation of mGluR5s is necessary for some forms of long-term potentiation and long-term depression in different brain regions. Investigations of the effects of MPEP in various behavioral paradigms have concluded that mGluR5s play a critical role in aversive learning tasks and in hippocampal-dependent spatial learning. However, MPEP has proved ineffective in certain other learning tasks. MGluR5 knockout mice have shown impairments in water maze and radial arm maze performance as well as in contextual fear conditioning, but not in cue conditioning. This review summarizes recent advances reported on mGluR5 function in synaptic plasticity, learning and memory. The current development of positive and negative allosteric modulators of mGluR5 will provide new pharmacological tools to enhance our knowledge of these receptors in physiological and pathophysiological processes and will further facilitate new investigations on mGluR5 as a therapeutic target for a range of neurological and psychological disorders.

Animals↗