title: Preconditioning-induced protection against cyanide-induced neurotoxicity is mediated by preserving mitochondrial function.
abstract: The central nervous system is one of the main target organs in cyanide toxicity. In this study, primary cultures of chick embryonic neurons were used to characterize sodium cyanide (NaCN)-induced cell death and to investigate the mechanism of NaCN-mediated preconditioning. After treatment of the cells with 1mM NaCN for 1h followed by a NaCN-free incubation period of 23 h, we observed features of apoptosis such as a reduction in nuclear size, chromatin condensation and nuclear fragmentation as evaluated by nuclear staining with Hoechst 33258 and electron microscopy. In addition, NaCN-induced neurotoxicity was reduced by the protein synthesis inhibitor cycloheximide (CHX) suggesting an active type of cell death. Most of the neurons with condensed chromatin and a shrunken nuclei also showed membrane damage at a late stage. Mitochondrial membrane potential as well as the protein levels of Bcl-2 and Bcl-x(L) decreased 15-60 min and 1-3 h after the exposure to NaCN (1mM, 1h), respectively. Preconditioning caused by incubating chick neurons with 100 microM NaCN for 30 min followed by a NaCN-free interval of 24h significantly protected the neurons against subsequent NaCN (1mM, 1h)-induced damage. Preconditioning prevented NaCN-induced decrease in the mitochondrial membrane potential as well as in the protein levels of Bcl-2 and Bcl-x(L) suggesting that preconditioning-induced neuroprotection is mediated by preserving mitochondrial function.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Fachbereich Pharmazie der Philipps-Universität Marburg, Ketzerbach 63, D-35032 Marburg, Germany.
authors.forename: Mads Skak
authors.initials: MS
authors.lastname: Jensen
authors.forename: Barbara
authors.initials: B
authors.lastname: Ahlemeyer
authors.forename: Alexander
authors.initials: A
authors.lastname: Ravati
authors.forename: Pratima
authors.initials: P
authors.lastname: Thakur
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Mennel
authors.forename: Josef
authors.initials: J
authors.lastname: Krieglstein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002642:Chick Embryo; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012966:Sodium Cyanide / Q000494:pharmacology / Q000633:toxicity*; D013687:Telencephalon / Q000166:cytology / Q000196:embryology; D051020:bcl-X Protein
chemical_list: D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003513:Cycloheximide; D003576:Electron Transport Complex IV; D012966:Sodium Cyanide