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Prevention of oxytosis-induced c-Raf down-regulation by (arylthio)cyclopentenone prostaglandins is neuroprotective
- Source :
- Toxicology. 390:83-87
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Prolonged exposure to high concentrations of glutamate leads to cell type specific glutathione depletion and resulting oxidative stress, known as oxytosis. As a result of glutathione depletion, accumulation of reactive oxygen species and Ca2+ influx are increased; however, the specific target of oxytosis has yet to be identified. In the present study, we focused on the effect of glutamate-induced oxidative stress on the extracellular-regulated protein kinase (ERK) pathway using the murine hippocampal HT22 cell line. Although the contribution of the ERK pathway to glutamate-induced oxytosis in HT22 cells is controversial, Western blot analysis revealed that glutamate caused down-regulation of mitogen-activated protein kinase kinase kinase (c-Raf) and a resulting decrease in the phosphorylation of c-Raf, as well as of mitogen-activated protein kinase kinase1/2 (MEK1/2) and ERK1/2, downstream components of the c-Raf/MEK/ERK pathway. Furthermore, neuroprotective (arylthio)cyclopentenone prostaglandins prevented glutamate-induced c-Raf down-regulation and consequently maintained the basal activity of c-Raf and its downstream signaling components. A pull-down assay using biotin-labeled cyclopentenone prostaglandins revealed that they preferentially bound to c-Raf relative to other signaling molecules of the ERK pathway, including Ras, MEK1/2, and ERK. These results suggest that neuroprotective (arylthio)cyclopentenone prostaglandins directly bind to c-Raf protein and protect cells from down-regulation of the c-Raf protein itself, resulting in neuroprotection against oxidative stress.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cell signaling
Cell Survival
Down-Regulation
Glutamic Acid
Cyclopentanes
Biology
Toxicology
Hippocampus
Neuroprotection
Antioxidants
Cell Line
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Animals
ASK1
c-Raf
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Protein kinase A
Cyclopentenone prostaglandins
Neurons
Dose-Response Relationship, Drug
Kinase
MAP Kinase Kinase Kinases
Glutathione
Molecular biology
Proto-Oncogene Proteins c-raf
Oxidative Stress
Neuroprotective Agents
030104 developmental biology
chemistry
Cytoprotection
Prostaglandins
Neurotoxicity Syndromes
030217 neurology & neurosurgery
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 0300483X
- Volume :
- 390
- Database :
- OpenAIRE
- Journal :
- Toxicology
- Accession number :
- edsair.doi.dedup.....8a8ebf4db33f8f7903724069aa05b791