Aluminum potentiates glutamate-induced calcium accumulation and iron-induced oxygen free radical formation in primary neuronal cultures.
Aluminum is a neurotoxic metal that may be involved in the progression of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis (ALS). Although the mechanism of action is not known, aluminum has been shown to alter Ca2+ flux and homeostasis, and facilitate peroxidation of membrane lipids. Since abnormal increases of intracellular Ca2+ and oxygen free radicals have both been implicated in pathways leading to neurodegeneration, we examined the effect of aluminum on these parameters in vitro using primary cultures of cerebellar granule cells. Exposure to glutamate (1-300 microM) caused a concentration-dependent uptake of 45Ca in granule cells to a maximum of 280% of basal. Pretreatment with AlCl3 (1-1000 microM) had no effect on 45Ca accumulation, but increased the uptake induced by glutamate. Similarly, AlCl3 had no effect on intracellular free Ca2+ levels measured using fluorescent probe fura-2, but potentiated the increase induced by glutamate. The production of reactive oxygen species (ROS) was examined using the fluorescent probe dichlorofluorescin. By itself, AlCl3 had little effect on ROS production. However, AlCl3 pretreatment potentiated the ROS production induced by 50 microM Fe2+. These results suggest that aluminum may facilitate increases in intracellular Ca2+ and ROS, and potentially contribute to neurotoxicity induced by other neurotoxicants.
Mundy
W R
WR
Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. MUNDY.WILLIAM@EPAMAIL.EPA.GOV
Freudenrich
T M
TM
Kodavanti
P R
PR
D000535:Aluminum / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005456:Fluorescent Dyes; D005609:Free Radicals / Q000378:metabolism; D016257:Fura-2; D018698:Glutamic Acid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D002132:Calcium Radioisotopes; D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D005609:Free Radicals; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000535:Aluminum; D002118:Calcium; D016257:Fura-2