Ebselen alters cellular oxidative status and induces endoplasmic reticulum stress in rat hippocampal astrocytes.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is an organoselenium radical scavenger compound, which has strong antioxidant and anti-inflammatory effects. Because of its properties, it may be protective against injury to the nervous tissue. However, evidence suggests that its glutathione peroxidase activity could underlie certain deleterious actions on cell physiology. In this study we have analyzed the effect of ebselen on rat hippocampal astrocytes in culture. Cellular oxidative status, cytosolic free-Ca(2+) concentration ([Ca(2+)]c), setting of endoplasmic reticulum stress and phosphorylation of glial fibrillary acidic protein and major mitogen-activated protein kinases were analyzed. Our results show that ebselen induced a concentration-dependent increase in the generation of reactive oxygen species in the mitochondria. We observed a concentration-dependent increase in global cysteine oxidation and in the level of malondialdehyde in the presence of ebselen. We also detected increases in catalase, glutathione S-transferase and glutathione reductase activity. Ebselen also evoked a concentration-dependent increase in [Ca(2+)]c. Moreover, we observed a concentration-dependent increase in the phosphorylation of the unfolded protein response markers, eukaryotic translation initiation factor 2α and X-box binding protein 1. Finally, ebselen also induced an increase in the phosphorylation of glial fibrillary acidic protein, SAPK/JNK, p38 MAPK and p44/42 MAPK. Our results provide strong evidence that implicate endoplasmic reticulum stress and activation of crucial mitogen-activated protein kinases in an oxidative damage of cells in the presence of ebselen. The compound thus might exert deleterious actions on astrocyte physiology that could compromise their function.
Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003 Caceres, Spain.
Patricia
P
Santofimia-Castaño
Servicio de Inmunologia, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), E-28006 Madrid, Spain.
Alicia
A
Izquierdo-Alvarez
Toxicology Unit, Veterinary School (UEx), 10003 Caceres, Spain.
Irene
I
de la Casa-Resino
Servicio de Inmunologia, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), E-28006 Madrid, Spain.
Antonio
A
Martinez-Ruiz
Toxicology Unit, Veterinary School (UEx), 10003 Caceres, Spain.
Marcos
M
Perez-Lopez
Neurology Unit, San Pedro de Alcantara Hospital, 10003 Caceres, Spain.
Juan C
JC
Portilla
Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003 Caceres, Spain.
Gines M
GM
Salido
Department of Physiology (Cell Physiology Research Group), University of Extremadura, 10003 Caceres, Spain. Electronic address: agmateos@unex.es.
Antonio
A
Gonzalez
D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D001393:Azoles / Q000008:administration & dosage / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D054833:Isoindoles; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D001393:Azoles; D005904:Glial Fibrillary Acidic Protein; D054833:Isoindoles; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C042986:ebselen; D008315:Malondialdehyde; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D003545:Cysteine; D002118:Calcium
Astrocytes; Cysteine oxydation; Ebselen; Endoplasmic reticulum stress; Hippocampus