Chronic exposure to aluminium impairs the glutamate-nitric oxide-cyclic GMP pathway in the rat in vivo

Aluminium is neurotoxic and is considered a possible etiologic factor in Al zheimer's disease, dialysis syndrome and other neurological disorders. The molecular mechanism of aluminium-induced impairment of neurological functio ns remains unclear. We showed that aluminium impairs the glutamate-nitric o xide-cGMP pathway in cultured neurons. The aim of this work was to assess b y in vivo brain microdialysis whether chronic administration of aluminium i n the drinking water (2.5% aluminium sulfate) also impairs the glutamate-ni tric oxide-cGMP pathway in the cerebellum of rats in vivo. Chronic exposure to aluminium reduced NMDA-induced increase of extracellular cGMP by ca 50% . The increase in extracellular cGMP induced by the nitric oxide generating agent S-nitroso-N-acetylpenicillamine was higher (240%) in rats treated wi th aluminium than in controls. Immunoblotting experiments showed that alumi nium reduced the cerebellar content of calmodulin and nitric oxide synthase by 34 and 15%, respectively. Basal activity of soluble guanylate cyclase w as decreased by 66% in aluminium-treated rats, while the activity after sti mulation with S-nitroso-N-acetylpenicillamine was similar to controls. Basa l cGMP in the cerebellar extracellular space was decreased by 50% in alumin ium-treated rats. These results indicate that chronic exposure to aluminium reduces the basal activity of guanylate cylcase and impairs the glutamate- nitric oxide-cGMP pathway in the animal in vivo. (C) 1999 Elsevier Science Ltd. All rights reserved.