title: Cytoplasmic vacuolation in cultured rat astrocytes induced by an organophosphorus agent requires extracellular signal-regulated kinase activation.
abstract: There are various toxic chemicals that cause cell death. However, in certain cases deleterious agents elicit various cellular responses prior to cell death. To determine the cellular mechanisms by which such cellular responses are induced is important, but sufficient attention has not been paid to this issue to date. In this study, we showed the characteristic effects of an organophosphorus (OP) agent, bis(pinacolyl methyl)phosphonate (BPMP), which we synthesized for the study of OP nerve agents, on cultured rat astrocytes. Morphologically, BPMP induced cytoplasmic vacuolation and stellation in the rat astrocytes. Cytoplasmic vacuolation is a cell pathological change observed, for example, in vacuolar degeneration, and stellation has been reported in astrocytic reactions against various stimuli. By pretreatment with cycloheximide, a protein synthesis inhibitor, stellation was inhibited, although vacuolation was not. Cell staining with a mitochondrion-selective dye indicated that the vacuolation probably occurs in the mitochondria that are swollen and vacuolatred in the center. Interestingly, the extracellular signal-regulated kinase (ERK) cascade inhibitor inhibited vacuolation and, to some extent, stellation. These results suggest that the ERK signaling cascade is important for the induction of mitochondrial vacuolation. We expect that a detailed study of these astrocytic reactions will provide us new perspectives regarding the variation and pathological significance of cell morphological changes, such as vacuolar degeneration, and also the mechanisms underlying various neurological disorders.
authors.affiliation: Department of Forensic Medical Science, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan. iisobe@med.nagoya-cu.ac.jp
authors.forename: Ichiro
authors.initials: I
authors.lastname: Isobe
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Maeno
authors.forename: Masataka
authors.initials: M
authors.lastname: Nagao
authors.forename: Mineo
authors.initials: M
authors.lastname: Iwasa
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Koyama
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Seko-Nakamura
authors.forename: Jun
authors.initials: J
authors.lastname: Monma-Ohtaki
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008933:Mitochondrial Swelling / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014617:Vacuoles / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
chemical_list: D009943:Organophosphorus Compounds; D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; D020928:Mitogen-Activated Protein Kinases