Apoptosis and necrosis: two distinct events induced by cadmium in cortical neurons in culture

Abstract

1 Cadmium is an extremely toxic metal commonly found in industrial workplaces, a food contaminant and a major component of cigarette smoke. Cadmium can severely damage several organs, including the brain. In this work, we have studied both the cadmium toxicity on rat cortical neurons in culture and the possible protective eect of serum. 2 Our results indicate that: (1) cadmium is taken up by the neurons in a dose and serum dependent way; (2) cadmium, at concentrations from 1 mM or 10 mM (depending on the absence or the presence of serum) up to 100 mM, decreases the metabolic capacity, which was evaluated by the XTT (tetrazolium salt) test; (3) cadmium induces apoptosis and LDH (lactate dehydrogenase) release in a dose dependent way; (4) in a serum-free medium, the cadmium-induced apoptosis is accompanied by caspase-3 activation; (5) both the caspase-3 activation and the cadmium-induced apoptosis are reversed by N-acethyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO), a selective caspase-3 inhibitor, indicating that the caspase-3 pathway is involved in cadmium-induced apoptosis in cortical neurons; and (6) the cadmium concentrations which produce caspase-3 activation do not modify the intracellular ATP levels; however, higher cadmium concentrations lead to both intracellular ATP depletion and ATP release, but do not increase the caspase-3 activity, indicating that cadmium also produces cellular death by necrosis. 3 These results suggest that cadmium induces either apoptosis or necrosis in rat cortical neurons, depending on the cadmium concentration.

Cadmium Renal Toxicity <i>via</i> Apoptotic Pathways

“…5,6) Apoptosis disorders induce a disruption of tissue homeostasis and functions and are associated with many diseases, such as cancer, neurodegenerative disease and toxin-induced disease. 7) Cadmium can induce apoptosis in various tissues and cultured cells, including mouse liver, 8) rat kidney and testis, [9][10][11][12][13] human T cell line (CEM-C12 cells), lymphoma U937 cells, normal hepatocytes, liver L-02 cells, fetal lung fibroblast MRC-5 cells and prostate epithelial cells, [14][15][16][17][18][19] mouse mesangial cells, 20) rat lung epithelial cells, cortical neurons and renal tubular epithelial cells, [21][22][23] and porcine kidney LLC-PK 1 cells. 24) These observations indicate that cell death of the proximal tubule cells in the kidney through apoptotic pathways is one of the key events in cadmium-induced renal toxicity.…”

A molecular technique for detecting the liberation of intracellular zinc in cultured neurons

“…We were interested in showing this process in neurons as we have previously observed that changes in intracellular Zn 2+ following its liberation from intracellular sites (Aizenman et al, 2000) can result in the activation of MAPK-dependent cell death pathways (Du et al, 2002;McLaughlin et al, 2001;Pal et al, 2003). These molecular pathways may therefore be also activated, albeit indirectly, by Cd 2+ , a highly neurotoxic metal (López et al, 2003). However, since there are no available chelators that can effectively distinguish between Cd 2+ and Zn 2+ , we are unable to determine at this point the relative contribution of Zn 2+ liberation to Cd 2+ neurotoxicity.…”

Resveratrol inhibits cadmium induced neuronal apoptosis by modulating calcium signalling pathway via regulation of MAPK/mTOR network

“…mTOR has been widely recognized as a central controller of cell proliferation, growth and survival (Bjornsti and Houghton, 2004). Cadmium-induced inhibition of cell proliferation and cell viability has been reported (Lopez et al, 2003;Kim et al, 2005). Akt positively regulates mTOR, leading to increased phosphorylation of ribosomal p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), the downstream effector molecules of mTOR (Bjornsti and Houghton, 2004).…”