CHRONIC EXPOSURE TO ALUMINUM IMPAIRS NEURONAL GLUTAMATE NITRIC-OXIDE CYCLIC-GMP PATHWAY

Humans are exposed to aluminum from environmental sources and therapeu tic treatments. However, aluminum is neurotoxic and is considered a po ssible etiologic factor in Alzheimer's disease and other neurological disorders. The molecular mechanism of aluminum neurotoxicity is not un derstood. We tested the effects of aluminum on the glutamate-nitric ox ide-cyclic GMP pathway in cultured neurons. Neurons were exposed to 50 mu M aluminum in culture medium for short-term (4 h) or longterm (8-1 4 days) periods, or rats were prenatally exposed, i.e., 3.7% aluminum sulfate in the drinking water, during gestation, Chronic (but not shor t-term) exposure of neurons to aluminum decreased glutamate-induced ac tivation of nitric oxide synthase by 38% and the formation of cyclic G MP by 77%. The formation of cyclic GMP induced by the nitric oxide-gen erating agent S-nitroso-N-acetylpenicillamine was reduced by 33%. In n eurons from rats prenatally exposed to aluminum but not exposed to it during culture, glutamate-induced formation of cyclic GMP was inhibite d by 81%, and activation of nitric oxide synthase was decreased by 85% . The formation of cyclic GMP induced by S-nitroso-N-acetylpenicillami ne was not affected, These results indicate that chronic exposure to a luminum impairs glutamate-induced activation of nitric oxide synthase and nitric oxide-induced activation of guanylate cyclase, Impairment o f the glutamate-nitric oxide-cyclic GMP pathway in neurons may contrib ute to aluminum neurotoxicity.