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 amyotr ophic lateral sclerosis (ALS). Although the mechanism of action is not known, aluminum has been shown to alter Ca2+ flux and homeostasis, an d facilitate peroxidation of membrane lipids. Since abnormal increases of intracellular Ca2+ and oxygen free radicals have both been implica ted in pathways leading to neurodegeneration, we examined the effect o f aluminum on these parameters in vitro using primary cultures of cere bellar granule cells. Exposure to glutamate (1-300 mu M) caused a conc entration-dependent uptake of Ca-45 in granule cells to a maximum of 2 80% of basal. Pretreatment with AlCl3 (1-1000 mu M) had no effect on C a-45 accumulation, but increased the uptake induced by glutamate. Simi larly, AlCl3 had no effect on intracellular free Ca2+ levels measured using fluorescent probe fura-2, but potentiated the increase induced b y glutamate. The production of reactive oxygen species (ROS) was exami ned using the fluorescent probe dichlorofluorescin. By itself, AlCl3 h ad little effect on ROS production. However, AlCl3 pretreatment potent iated the ROS production induced by 50 mu MFe2+. These results suggest that aluminum may facilitate increases in intracellular Ca2+ and ROS, and potentially contribute to neurotoxicity induced by other neurotox icants.