Aluminum maltolate-induced cytotoxicity in neuro-2a cells involves apoptosis and necrosis.
Toxicologist 2003 Mar; 72(S-1):23
Aluminum maltolate (Al-malt) has been shown to cause neurodegeneration following in-vivo exposure and apoptosis plays a prominent role. The objective of this study was to define the mode of cell death induced by Al-malt. Neuro-2a cells were treated with Al-malt for 24 h in the presence or absence of pretreatment with a variety of pharmacological agents. Al-malt concentration-dependently increased cell death as indicated by lactate dehydrogenase (LDH) release and the appearance of cells with hypodiploid DNA content. Flow cytometry using acridine orange (high-live, low-apoptotic) and ethidium bromide (necrotic) dual staining showed that 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 in Hoechst 33258 stained nuclei from Al-malt-treated cultures. Interestingly, pretreatment with cyclohexamide (CHX) markedly reduced Al-malt-induced apoptosis indicating that this mode of death is dependent on de-novo protein synthesis in the current culture model. Necrotic cell death was not prevented by CHX suggesting that only apoptosis was dependent on gene expression. Pretreatment with antioxidants and kinase inhibitors (mitogen activated protein kinases and PKC) did not reduce Al-malt toxicity suggesting independence from oxidative stress and major kinase signaling pathways. The results provide insight into the mechanisms of Al-malt neurotoxicity and support the involvement of this metal in neurodegeneration.
Aluminum-compounds; Metals; Metal-poisoning; Metal-compounds; Cellular-reactions; Cell-damage; In-vitro-studies; Neurotoxic-effects; Neurotoxicology; Neurotoxicity
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah