Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in vivo: molecular mechanisms and implications for neuropathology

Aluminium (Al) is a neurotoxicant and appears as a possible etiological fac tor in Alzheimer's disease and other neurological disorders. The mechanisms of Al neurotoxicity are presently unclear but evidence has emerged suggest ing that Al accumulation in the brain can alter neuronal signal transductio n pathways associated with glutamate receptors. In cerebellar neurons in cu lture, long term-exposure to Al added 'in vitro' impaired the glutamate-nit ric oxide (NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activa tion of NO synthase and NO-induced activation of the cGMP generating enzyme , guanylate cyclase. Prenatal exposure to Al also affected strongly the fun ction of the glutamate-NO-cGMP pathway. In cultured neurons from rats prena tally exposed to Al, we found reduced content of NO synthase and of guanyla te cyclase, and a dramatic decrease in the ability of glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP pathway was also stron gly impaired in cerebellum of rats chronically treated with Al, as assessed by in vivo brain microdialysis in freely moving rats. These findings sugge st that the impairment of the Glu-NO-cGMP pathway in the brain may be respo nsible for some of the neurological alterations induced by Al. (C) 2001 Els evier Science B.V. All rights reserved.