cytochrome-c-t and lanthanum-chloride

Population surveys and animal experiments have shown that rare earth elements (REEs) cause neurological defects. However, the detailed mechanisms underlying these effects are still unclear. Given that lanthanum is commonly used for investigating into REEs-induced neurological defects, this study chose lanthanum chloride (LaCl3 ) to show that LaCl3 promotes mitochondrial apoptotic pathway in primary cultured rat astrocytes by regulating expression of Bcl-2 family proteins. The main findings of this study are (1) LaCl3 treatment (0.25, 0.5, and 1.0 mM for 12-48 h) induced the astrocytes damages with a concentration-dependent manner, which were confirmed with methyl thiazolyl tetrazolium and lactate dehydrogenase release assays, and morphological examination. (2) A 24 h treatment of LaCl3 concentration-dependently decreased mitochondrial membrane potential, increased cytochrome c release from mitochondria into cytosol, elevated caspase 9 and 3 expression, and promoted astrocyte apoptosis. (3) LaCl3 treatment increased the ratio of pro-apoptotic Bax and antiapoptotic Bcl-2 proteins, which in turn broke the balance among pro-apoptotic and antiapoptotic Bcl-2 family proteins, leading to astrocyte apoptosis. Our results indicate that LaCl3 alters Bcl-2 family protein expressions, which in turn promote mitochondrial apoptotic pathway, and thus astrocytic damage.

Topics: Animals; Apoptosis; Astrocytes; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Cells, Cultured; Cytochromes c; Cytosol; Lanthanum; Membrane Potential, Mitochondrial; Mitochondria; Primary Cell Culture; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar

As a representative element of lanthanide, lanthanum has been widely used in various fields and eventually entered environment and accumulated in human body. Epidemiological and experimental evidences indicated that lanthanum has neurotoxicity; however, the detailed mechanism is still elusive. Here, we chose primary cerebral cortical neurons as model in vitro to investigate the mechanism underlying the toxic effects of lanthanum chloride (LaCl3). This study revealed the following findings: (1) LaCl3 treatment (0.01, 0.1, and 1.0 mM for 24 h) reduced the viability of cortical neurons and elevated apoptotic rate significantly in a dose-dependent manner. (2) LaCl3 triggered mitochondrial apoptotic pathway in cortical neurons, characterized with collapsed mitochondrial membrane potential, release of cytochrome c into cytosol, and increasing expression of activated caspase-3. (3) LaCl3 elevated intracellular Ca(2+) concentration, promoted reactive oxygen species generation, and upregulated pro-apoptotic Bax, whereas it downregulated anti-apoptotic Bcl-2 expression and consequently altered Bax/Bcl-2 ratio, which ultimately lead to neuronal mitochondrial apoptosis. Our results demonstrated that toxicity of lanthanum in cortical neurons perhaps partly attributed to enhanced mitochondrial apoptosis due to mitochondrial dysfunction modulated by Ca(2+) and Bcl-2 family.

Topics: Animals; Animals, Newborn; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Calcium; Caspase 3; Cell Survival; Cerebral Cortex; Cytochromes c; Dose-Response Relationship, Drug; Gene Expression; Humans; Lanthanum; Membrane Potential, Mitochondrial; Mice; Mitochondria; Neurons; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction