Altered calcium homeostasis: a possible mechanism of aluminium-induced neurotoxicity

Abstract

The effect of aluminium, A1(3+) (10 mg/kg body weight/day i.p.) for a period of 4 weeks was examined on the calcium homeostatic mechanisms in rat central nervous system. Incubation of synaptosomes prepared from rat brain, with aluminium in vitro had a detrimental effect on the activity of Ca2+ ATPase which could be reversed completely on exogenous addition of desferrioxamine (10 microM) and partially with glutathione (1 mM). In vivo administration also revealed a similar observation. A marked increase in the levels of intracellular calcium was observed after aluminium treatment. Concomitant to the increased levels of intracellular calcium, there was an increase in the levels of lipid peroxidation and a consequent decrease in fluidity of synaptic plasma membranes. In addition, aluminium also had an inhibitory effect on the depolarization-induced calcium uptake which was found to be of a competitive type. The biological activity of calcium regulatory proteins calmodulin and protein kinase C was considerably affected by aluminium. The results suggest that aluminium exerts its toxic effects by modification of the intracellular calcium messenger system with detrimental consequences on neuronal functioning.

Metal toxicity at the synapse: presynaptic, postsynaptic and long-term effects

“…This was shown both in vivo and in vitro. The largest inhibition was observed in the cerebral cortex (47.73%) followed by the hippocampus (45.95%) and the corpus striatum (38.74%) [20]. However, contrasting findings were determined by Johnson and coworkers who showed that aluminum sulfate, when given orally for a period of 4 months to male SpragueDawley rats, showed an increase in PKC specific activity by 60% and total activity by 70% in the soluble fraction of cerebral cortex homogenates [69].…”

“…Aluminum also blocked voltage-activated calcium channels in vivo in rats when given 10 mg per kg body weight per day intraperitoneally for 4 weeks. Inhibition was nearly 85% in the corpus striatum, 58% in the cerebral cortex, and 46% in the hippocampus [20].…”

“…For instance, aluminum blocks voltage gated calcium channels, decreases the biological activity of CaM, and also inhibits Ca 2+ ATPase [19,20]. In addition, if a metal interacts with an upstream target of a pathway, it may influence all the processes succeeding it.…”

“…Aluminum (Al 3+ ) decreased the biological activity of CaM both in vitro and in vivo where inhibition in vivo is largest in the hippocampus (36.56%), followed by the cerebral cortex (31.76%) and the corpus striatum (22.49%) [20]. Lead, however, had an opposite effect as lead acetate enhanced CaM activity both in vitro and in vivo resulting in an increase in CaM-dependent synaptic vesicle protein phosphorylation including the phosphorylation of proteins such as synapsin I.…”

The effects of aluminium and selenium supplementation on brain and liver antioxidant status in the rat

“…Zaman (1994) showed that Al stimulates NADPH oxidation and takes part in the process of free radical formation. Experimental animal models and cell culture studies reveal that aluminium affects the expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase and glutathione (GSH) possibly leading to membrane fragility as a consequence (Julka and Gill, 1996;Oteiza et al, 1993;Campbell et al, 1999). These data support the role of oxidative stress in aluminium induced cellular dysfunction and if this is indeed the case, antioxidants, such as selenium, may be protective.…”