title: Mechanisms of penitrem-induced cerebellar granule neuron death in vitro: possible involvement of GABAA receptors and oxidative processes.
abstract: The fungal neurotoxin penitrem A has previously been found to cause neurological disorders in animals and humans after ingestion of contaminated food and/or feed. It penetrates the blood-brain-barrier and causes cerebellar pathology in rats, including mild effects on granule neurons. The aim of the current study was to investigate the potential toxicity of penitrem A in rat cerebellar granule neurons in vitro, and to examine the involvement of the GABAA, AMPA and NMDA receptors, intracellular signalling pathways as well as the role of oxidative stress in penitrem A-induced neuronal death. Cerebellar granule cells were exposed to penitrem A, alone or together with different pharmacological agents, before cell survival was assessed with the MTT assay or formation of reactive oxygen species (ROS) was investigated with the DCF assay. Penitrem A caused a time- and concentration-dependent reduction in cell survival, as well as a concentration-dependent increase in ROS production. Co-incubation with diazepam, GABA, BAPTA-AM, vitamin E, SP600125 and cyclosporine A significantly reduced cell death. Our results show that penitrem A is toxic to cerebellar granule neurons in vitro. Further, ROS production and the GABAA receptor are likely to be involved in the induction of neuronal death following penitrem A exposure. A disruption of calcium homeostasis and activation of the JNK pathway may also play a role in penitrem A neurotoxicity.
authors: Institute of Basic Medical Sciences, Department of Biochemistry, University of Oslo, P.O. Box 1112 Blindern, N-0317 Oslo, Norway.
authors: H F
authors: HF
authors: Berntsen
authors: M B
authors: MB
authors: Wigestrand
authors: I L
authors: IL
authors: Bogen
authors: F
authors: F
authors: Fonnum
authors: S I
authors: SI
authors: Walaas
authors: A
authors: A
authors: Moldes-Anaya
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D009183:Mycotoxins / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D009183:Mycotoxins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; C003626:tremortin; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium