Induction of NF-kappaB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-kappaB and neuroprotection by antioxidants.
Haloperidol (HP), a dopamine receptor antagonist, is cytotoxic to mouse clonal hippocampal HT22 cells in a concentration-dependent manner and causes cell death by oxidative stress. The addition of HP to HT22 cells led to an increase in intracellular peroxides and a time-dependent drop in the intracellular glutathione levels. HP-induced oxidative cell death was prevented by the pineal hormone melatonin, its precursor N-acetyl serotonin, and most effectively by vitamin E (alpha-tocopherol). These antioxidants inhibited the intracellular peroxide accumulation and stabilized the glutathione content of HT22 cells after the challenge with HP. At the molecular level, HP specifically induced the DNA binding activity and the transcriptional activity of the redox-sensitive transcription factor NF-kappaB. This enhanced NF-kappaB activity could be blocked by the neuroprotective antioxidants. The specific suppression of NF-kappaB by its inhibitor IkappaBalpha partially protected the cells against HP, indicating that the activation of NF-kappaB may be involved in HP-induced oxidative cell death in vitro.
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Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Holsboer
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Behl
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C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006220:Haloperidol / Q000633:toxicity*; D006624:Hippocampus / Q000166:cytology; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D010545:Peroxides / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D018492:Dopamine Antagonists; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010545:Peroxides; D014810:Vitamin E; D012701:Serotonin; D005978:Glutathione; D006220:Haloperidol; D008550:Melatonin; C006389:N-acetylserotonin