Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons.
Manganese (Mn) in excess is toxic to neurons of the globus pallidus, leading to a Parkinsonian-like syndrome. We used rat primary neuron cultures to examine the cellular events following manganese exposure. Following exposure to Mn(2+) for 48 h, striatal neurons showed dose-dependent losses of mitochondrial membrane potential and complex II activity. The Mn exposure effect on mitochondrial membrane potential was significant at every concentration measured (5, 50, and 500 microM), and the manganese exposure effect on complex II activity was significant at 50 and 500 microM. Exposure of striatal neurons to both Mn(2+) and the complex II inhibitor 3-nitropropionic acid resulted in additive toxicity. Striatal neurons exposed to 5 microM Mn(2+) for 48 h exhibited DNA fragmentation and decreases in the immunohistochemically detectable microtubule-associated protein MAP-2. These results indicate that manganese may trigger apoptotic-like neuronal death secondary to mitochondrial dysfunction. Rescue of neurons by apoptosis inhibitors may be helpful in treating manganese toxicity and similar neurodegenerative processes.
Malecki
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EA
Department of Neuroscience and Anatomy, College of Medicine, The Pennsylvania State University, Hershey, PA, USA. eam10@psu.edu
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004396:Coloring Agents / Q000493:pharmacokinetics; D003292:Convulsants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D053938:DNA Fragmentation / Q000187:drug effects* / Q000502:physiology; D042963:Electron Transport Complex II; D005333:Fetus; D008345:Manganese / Q000494:pharmacology*; D020149:Manganese Poisoning / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013778:Tetrazolium Salts / Q000493:pharmacokinetics; D013844:Thiazoles / Q000493:pharmacokinetics
D004396:Coloring Agents; D003292:Convulsants; D008869:Microtubule-Associated Proteins; D009097:Multienzyme Complexes; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D013778:Tetrazolium Salts; D013844:Thiazoles; D008345:Manganese; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; C022616:thiazolyl blue; C015392:3-nitropropionic acid