Chronic Exposure to Aluminum Impairs Neuronal Glutamate‐Nitric Oxide‐Cyclic GMP Pathway

Abstract

Humans are exposed to aluminum from environmental sources and therapeutic treatments. However, aluminum is neurotoxic and is considered a possible etiologic factor in Alzheimer's disease and other neurological disorders. The molecular mechanism of aluminum neurotoxicity is not understood. We tested the effects of aluminum on the glutamate‐nitric oxide‐cyclic GMP pathway in cultured neurons. Neurons were exposed to 50 µM aluminum in culture medium for short‐term (4 h) or long‐term (8–14 days) periods, or rats were prenatally exposed, i.e., 3.7% aluminum sulfate in the drinking water, during gestation. Chronic (but not short‐term) exposure of neurons to aluminum decreased glutamate‐induced activation of nitric oxide synthase by 38% and the formation of cyclic GMP by 77%. The formation of cyclic GMP induced by the nitric oxide‐generating agent S‐nitroso‐N‐acetylpenicillamine was reduced by 33%. In neurons from rats prenatally exposed to aluminum but not exposed to it during culture, glutamate‐induced formation of cyclic GMP was inhibited by 81%, and activation of nitric oxide synthase was decreased by 85%. The formation of cyclic GMP induced by S‐nitroso‐N‐acetylpenicillamine was not affected. These results indicate that chronic exposure to aluminum impairs glutamate‐induced activation of nitric oxide synthase and nitric oxide‐induced activation of guanylate cyclase. Impairment of the glutamate‐nitric oxide‐cyclic GMP pathway in neurons may contribute to aluminum neurotoxicity.

Protective Role of Lithium in Ameliorating the Aluminium-induced Oxidative Stress and Histological Changes in Rat Brain

“…Therefore, our results also support to the hypothesis that much of the oxidative damage induced in vivo by Al intoxication is through ROS (Cucarella et al 1998;Bondy et al 1998b). Bondy and Kirstein (1996) have shown that Al along with iron promote the generation of ROS.…”

Effect of chronic accumulation of aluminum on renal function, cortical renal oxidative stress and cortical renal organic anion transport in rats

“…Although aluminum is present in only trace amounts in most biological systems, this cation accumulates in certain disease states such as end-stage renal disease (Quarles 1991;Cucarella et al 1998). Such accumulation is implicated in the pathogenesis of suppressed parathyroid hormone secretion, bone disease, anemia, and of the central nervous Al-treated rats (n=9) received a solution containing aluminum lactate during 12 weeks (0.57 mg Al/100 g bodyweight, i.p., three times per week).…”

Aluminum‐mediated metabolic changes in rat serum and urine: A proton nuclear magnetic resonance study

“…However, the role of Al in AD is controversial and is yet to be defined, but this issue is of great interest, since Al is present in high concentrations in food, water supply, and pharmaceutical products. The Al deposition in brain (neurons and glia) affects the normal metabolic pathways following the production of neurotransmitters such as glutamate and GABA [3] and affects the tricarboxylic acid (TCA) cycle either directly or indirectly, and eventually the mitochondrial metabolic pathways are altered [4]. Although the liver is considered as the major site for detoxification of toxic metabolites, the amount of Al deposition is observed to be more prominent in the liver as well as in plasma [5].…”