The effects of ebselen on cisplatin and diethyldithiocarbamate (DDC) cytotoxicity in rat hippocampal astrocytes.
Ebselen is a seleno-organic compound with documented cytoprotective properties. Little work has been done, however, demonstrating ebselen's cytoprotective properties in neural cell lines. In order to examine the effects of this compound and its mechanism of action, astrocytes were exposed to two known neurotoxicants, cisplatin and diethyldithiocarbamate (DDC). Cells were pretreated with 30 microM ebselen and subsequently treated with either 150 microM DDC for 1 h or 250 and 500 microM cisplatin for 24 h. Results indicate significant increases in viability in cells pretreated with ebselen and exposed to cisplatin. Ebselen pretreatment did not significantly increase viability in cells exposed to DDC. Light and scanning electron microscopy studies confirm the viability studies. Gross morphological damage was seen in cells treated with cisplatin, however, cells pretreated with ebselen and then exposed to cisplatin, appeared similar to controls. No differences were noted in cells pretreated with ebselen and then exposed to DDC or cells treated with DDC alone. In order to examine the mechanism of protection of this compound, glutathione status was examined. Results show that ebselen does not significantly increase reduced or oxidized glutathione (GSH, GSSG). All cell groups treated with cisplatin showed an increase in GSH levels. Ebselen showed protection in glutathione depleted cells at the 250 microM cisplatin dose. DDC treatment showed no significant increase in either reduced or oxidized glutathione. We conclude that ebselen significantly protects against cisplatin, but not DDC toxicity. We further conclude that this protection is not related to changes in glutathione status in the rat hippocampal cell line as has been reported in other cell types.
Hardej
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College of Pharmacy and Allied Health Professions, St. John's University, Toxicology Program, 8000 Utopia Parkway, Jamaica, NY 11439, USA.
Trombetta
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D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology*; D001393:Azoles / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000633:toxicity*; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004050:Ditiocarb / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D054833:Isoindoles; D008855:Microscopy, Electron, Scanning; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts; D013844:Thiazoles
D000970:Antineoplastic Agents; D001393:Azoles; D002614:Chelating Agents; D054833:Isoindoles; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; C042986:ebselen; D004050:Ditiocarb; C022616:thiazolyl blue; D005978:Glutathione; D002945:Cisplatin