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Manganese-induced cytotoxicity in dopamine-producing cells.
Stredrick DL; Stokes AH; Worst TJ; Freeman WM; Johnson EA; Lash LH; Aschner M; Vrana KE
Neurotoxicology 2004 Jun; 25(4):543-553
Manganese (Mn) is an essential metal that, at excessive levels in the brain, produces extrapyramidal symptoms similar to those in patients with Parkinson's disease (PD). In the present study, Mn toxicity was characterized in a human neuroblastoma (SK-N-SH) cell line and in a mouse catecholaminergic (CATH.a) cell line. Mn was demonstrated to be more toxic in the catecholamine-producing CATH.a cells (EC50=60 M) than in non-catecholaminergic SK-N-SH cells (EC50=200 M). To test the hypothesis that the sensitivity of CATH.a cells to Mn is associated with their dopamine (DA) content, DA concentrations were suppressed in these cells by pretreatment with -methyl-para-tyrosine (AMPT). Treatment for 24 h with 100 M AMPT decreased intracellular DA, but offered no significant protection from Mn exposure (EC50=60 M). Additional studies were carried out to assess if Mn toxicity was dependent on glutathione (GSH) levels. CATH.a cells were significantly protected by the addition of 5 mM GSH (Mn EC50=200 M) and 10 mM N-acetyl cysteine (NAC) (Mn EC50=300 M), therefore, indirectly identifying intracellular ROS formation as a mechanism for Mn neurotoxicity. Finally, apoptotic markers of Mn-induced cell death were investigated. DNA fragmentation, caspase-3 activation, and apoptosis-related gene expression were studied in CATH.a cells. No internucleosomal fragmentation or caspase activation was evident, even in the presence of "supraphysiological" Mn concentrations. cDNA hydridization array analysis with two differing Mn concentrations and time points, identified no noteworthy mRNA inductions of genes associated with programmed cell death. In conclusion, DA content was not responsible for the enhanced sensitivity of CATH.a cells to Mn toxicity, but oxidative stress was implicated as a probable mechanism of cytotoxicity.
Metals; Neurotoxicology; Neurotoxins; Neurotoxic-effects; Cytotoxic-effects; Cytotoxins; Cytotoxicity; Author Keywords: CATH.a; Dopamine; DNA fragmentation; Manganese; Cytotoxicity
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083
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