Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases.
Primary cultures of rat cerebellar neurons were used to study mechanisms of arsenic neurotoxicity. Exposure to 5, 10, or 15 microM sodium arsenite reduced cerebellar neuron viability and induced nuclear fragmentation and condensation as well as DNA degradation to oligonucleosome fragments. Exposure to 1 or 5 mM dimethylarsinic acid caused similar changes. Therefore, both inorganic arsenite and organic dimethylarsinic acid induce apoptosis in cerebellar neurons, with the inorganic form being more toxic. Cotreatment with cycloheximide or actinomycin D, inhibitors of protein or RNA synthesis, respectively, or with the caspase inhibitor zVAD, completely blocked arsenite-induced cerebellar neuron apoptosis. This implies that arsenite-induced cerebellar neuron apoptosis requires new gene expression and caspase activation. Interestingly, sodium arsenite selectively activated p38 and JNK3, but not JNK1 or JNK2 in cerebellar neurons. Blocking the p38 or JNK signaling pathways using the inhibitors SB203580 or CEP-1347 protected cerebellar neurons against arsenite-induced apoptosis. These data suggest that arsenite neurotoxicity may be due to apoptosis caused by activation of p38 and JNK3 MAP kinases.
Namgung
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Department of Environmental Health, University of Washington, Seattle, Washington 98195-7234, USA.
Xia
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D000818:Animals; D017209:Apoptosis; D020261:Arsenic Poisoning; D018053:Arsenites / Q000633:toxicity*; D002101:Cacodylic Acid / Q000633:toxicity; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D020258:Neurotoxicity Syndromes / Q000209:etiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017670:Sodium Compounds / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases
D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite; D002101:Cacodylic Acid; D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases