title: Cyanide-induced apoptosis involves oxidative-stress-activated NF-kappaB in cortical neurons.
abstract: The central nervous system is one of the main target organs in cyanide toxicity. Primary cultured cortical neurons were used to study the cellular mechanisms underlying cyanide-induced cytotoxicity. After exposure to KCN (100-300 microM) for 24 h, cortical neurons underwent apoptosis as characterized by positive TUNEL staining. Reactive oxygen species (ROS) play an important role in cyanide-induced neuronal apoptosis; immediately after cyanide (100-300 microM) treatment, ROS generation was observed and continued to be elevated for up to 3 h. NMDA receptor activation and subsequent Ca(2+) influx contribute in part to cyanide-induced ROS formation, since the selective NMDA receptor antagonist MK801 and intracellular Ca(2+) chelator BAPTA blocked ROS generation. Interestingly, caspases, recently reported to be involved in neuronal apoptosis, play a role in the late phase of ROS production after cyanide stimulation. Z-VAD, a nonspecific caspase inhibitor, blocked ROS generated 1 h after cyanide treatment, but it had no effect on ROS generated immediately after cyanide treatment. Nuclear factor kappaB (NF-kappaB), a redox-sensitive transcription factor, was activated dose dependently after cyanide treatment. Blockade of ROS generation by MK801, Z-VAD, and various antioxidants also blocked the activation of NF-kappaB. SN50, a synthetic peptide which inhibits the nuclear translocation of NF-kappaB, blocked cyanide-induced apoptotic cell death. These results indicate that NF-kappaB plays an important role in cyanide-induced apoptosis in cortical neurons, and the caspases may contribute in part to the activation of NF-kappaB after cyanide treatment by inducing the late phase of ROS generation.
authors.affiliation: Neurotoxicology Laboratory, Purdue University, West Lafayette, Indiana 47907-1333, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shou
authors.forename: P G
authors.initials: PG
authors.lastname: Gunasekar
authors.forename: J L
authors.initials: JL
authors.lastname: Borowitz
authors.forename: G E
authors.initials: GE
authors.lastname: Isom
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D020287:In Situ Nick-End Labeling; D016328:NF-kappa B / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D011042:Poisons / Q000633:toxicity*; D011190:Potassium Cyanide / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D018696:Neuroprotective Agents; D011042:Poisons; D017382:Reactive Oxygen Species; D016291:Dizocilpine Maleate; D020169:Caspases; D011190:Potassium Cyanide