ToxSci Advance Access originally published online on November 10, 2004
Toxicological Sciences 2005 83(2):329-339; doi:10.1093/toxsci/kfi028
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Toxicological Sciences vol. 83 no. 2 © Society of Toxicology 2005; all rights reserved.
Aluminum-Maltolate Induces Apoptosis and Necrosis in Neuro-2a Cells: Potential Role for p53 Signaling
* Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602, and Research Center for Resistant Cells, College of Medicine, Chosun University, Gwangju 501-759, South Korea
Received September 21, 2004; accepted November 1, 2004
Aluminum maltolate (Al-malt) causes neurodegeneration following in vivo exposure, and apoptosis plays a prominent role. The objective of this study was to define the form of cell death induced by Al-malt and to establish an in vitro model system amenable to mechanistic investigations of Al-malt-induced cell death. Neuro-2a cells, a murine neuroblastoma cell line, were treated with Al-malt for 24 h, following which mode of cell death and alterations in apoptosis-related gene expression were studied. Al-malt concentration-dependently increased cell death. The mode of cell death was a combination of apoptosis and necrosis. Treatment with Al-malt resulted in caspase 3 activation and the externalization of phosphatidyl serine, both indicative of apoptosis. In addition, nuclear condensation and fragmentation were evident. Interestingly, pretreatment with cycloheximide (CHX), a potent protein synthesis inhibitor markedly reduced Al-malt-induced apoptosis, indicating that altered gene expression was critical for this form of cell death. Pretreatment with CHX had no effect on necrosis induced by Al-malt. Analysis of gene expression showed that p53 mRNA was increased following treatment with Al-malt. This increase was accompanied by a marked inhibition of Bcl2 expression and an increase in BAX expression, a pattern of gene expression suggestive of a pro-apoptotic shift. Results show for the first time that p53 is induced by Al in neuron-like cells and suggest that the p53-dependent intrinsic pathway may be responsible for Al-induced apoptosis. Future studies investigating the role of p53 in Al neurotoxicity both in vivo and in vitro are warranted.
Key Words: aluminum; maltolate; apoptosis; necrosis; caspase 3; neurodegeneration; neurotoxicity; Neuro-2a; p53; Bcl2; BAX.
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