Prevention of methylmercury-induced mitochondrial depolarization, glutathione depletion and cell death by 15-deoxy-delta-12,14-prostaglandin J(2).
Methylmercury (MeHg) is an environmental toxin that causes severe neurological complications in humans and experimental animals. In addition to neurons, glia in the central nervous system are very susceptible to MeHg toxicity. Pretreatment of glia with the prostaglandin derivative, 15-deoxy-delta-12,14-prostaglandin J(2) (15d-PGJ(2)), caused a significant protection against MeHg cytotoxicity. Results with the C6 glioma cells demonstrated that the protection was dependent on the duration of pretreatment, suggesting that time was required for the up-regulation of cellular defenses. Subsequent experiments indicated that 15d-PGJ(2) prevented MeHg induced mitochondrial depolarization. Similar protection against MeHg cytotoxicity was observed in primary cultures of mouse glia. Analysis of cellular glutathione (GSH) levels indicated that 15d-PGJ(2) caused an up-regulation of GSH and prevented MeHg-induced GSH depletion. Buthionine sulfoximine (BSO), a GSH synthesis inhibitor, completely inhibited the GSH induction by 15d-PGJ(2). However, BSO did not prevent the stabilization of mitochondrial potential and only partially prevented the protection caused by 15d-PGJ(2). While induction of heme oxygenase-1 was implicated in the cytoprotection by 15d-PGJ(2) under some experimental conditions, additional experiments indicated that this enzyme was not involved in the cytoprotection observed in this system. Together, these results suggested that while up-regulation of GSH by 15d-PGJ(2) might help cells to defend against MeHg toxicity, there may be other yet unidentified mechanism(s) initiated by 15d-PGJ(2) treatment that contributed to its protection against MeHg cytotoxicity.
Chang
Jason Y
JY
Department of Neurobiology & Developmental Sciences, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. changjasony@uams.edu
Tsai
Pao-Feng
PF
D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002232:Carbocyanines / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D001562:Benzimidazoles; D002232:Carbocyanines; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008767:Methylmercury Compounds; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D019328:Buthionine Sulfoximine; D005978:Glutathione
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