Thiol oxidation and altered NR2B/NMDA receptor functions in in vitro and in vivo pilocarpine models: Implications for epileptogenesis
| Autor: | Laura M. Montero, Roberto Di Maio, J. Timothy Greenamyre, Pier G. Mastroberardino, Xiaoping Hu |
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| Přispěvatelé: | Molecular Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Programmed cell death MAP Kinase Signaling System Apoptosis Pharmacology Hippocampal formation medicine.disease_cause Hippocampus Receptors N-Methyl-D-Aspartate Epileptogenesis lcsh:RC321-571 Rats Sprague-Dawley chemistry.chemical_compound Piperidines medicine Ifenprodil Animals Sulfhydryl Compounds lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Neuronal excitability Cells Cultured NMDA receptor subunits expression Neurons ERK signaling Oxidative stress Hippocampal sclerosis Chemistry Pilocarpine medicine.disease Acetylcysteine Disease Models Animal Neuroprotective Agents Epilepsy Temporal Lobe nervous system Neurology NMDA receptor Dizocilpine Maleate Excitatory Amino Acid Antagonists Oxidation-Reduction Neuroscience medicine.drug |
| Zdroj: | Neurobiology of Disease, Vol 49, Iss, Pp 87-98 (2013) Neurobiology of Disease, 49, 87-98. Academic Press |
| ISSN: | 0969-9961 |
| Popis: | Hippocampal sclerosis, the main pathological sign of chronic temporal lobe epilepsy (TLE), is associated with oxidative injury, altered N-methyl D-aspartate receptor (NMDAR) stoichiometry, and loss of hippocampal neurons. However, the mechanisms that drive the chronic progression of TIE remain elusive. Our previous studies have shown that NADPH oxidase activation and ERK 1/2 phosphorylation are required for the up-regulation of the predominantly pre-synaptic NR2B subunit auto-receptor in both in vitro and in vivo pilocarpine (PILO) models of Tu. To provide further understanding of the cellular responses during the early-stages of hyper excitability, we investigated the role of oxidative damage and altered NR2B functions. In rat primary hippocampal cultures, we found that N-acetylcysteine (NAC) prevented PILO-mediated thiol oxidation, apoptosis, cell death and NR2B subunit over-expression. Interestingly, NAC did not block thiol oxidation when added to the neurons 6 h after the PILO exposure, suggesting that disulfide formation could rapidly become an irreversible phenomenon. Moreover, NAC pre-treatment did not prevent PILO-induced NR2A subunit over-expression, a critical event in hippocampal sclerosis. Pre-treatment with the highly specific NR2B subunit inhibitor, ifenprodil, partially decreased PILO-mediated thiol oxidation and was not effective in preventing apoptosis and cell death. However, if acutely administered 48 h after PILO exposure. ifenprodil blocked glutamate-induced aberrant calcium influx, suggesting the crucial role of NR2B over-expression in triggering neuronal hyper-excitability. Furthermore, ifenprodil treatment was able to prevent NR2A subunit over-expression by means of ERK1/2 phosphorylation. Our findings indicate oxidative stress and NR2B/NMDA signaling as promising therapeutic targets for co-treatments aimed to prevent chronic epilepsy following the seizure onset. (c) 2012 Elsevier Inc. All rights reserved. |
| Databáze: | OpenAIRE |
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