Journal of Inorganic Biochemistry 87 (2001) 63–69 www.elsevier.com / locate / jinorgbio Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in vivo: molecular mechanisms and implications for neuropathology ´ Juan J. Canales, Regina Corbalan, Carmina Montoliu, Marta Llansola, Pilar Monfort, Slaven Erceg, * Mariluz Hernandez-Viadel, Vicente Felipo ´ ´ ´ Laboratory of Neurobiology, Instituto de Investigaciones Citologicas, Fundacion Valenciana de Investigaciones Biomedicas, Amadeo de Saboya 4, 46010 Valencia, Spain Received 31 March 2001; received in revised form 1 May 2001; accepted 10 May 2001 Abstract Aluminium (Al) is a neurotoxicant and appears as a possible etiological factor in Alzheimer’s disease and other neurological disorders. The mechanisms of Al neurotoxicity are presently unclear but evidence has emerged suggesting that Al accumulation in the brain can alter neuronal signal transduction pathways associated with glutamate receptors. In cerebellar neurons in culture, long term-exposure to Al added ‘in vitro’ impaired the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activation of NO synthase and NO-induced activation of the cGMP generating enzyme, guanylate cyclase. Prenatal exposure to Al also affected strongly the function of the glutamate-NO-cGMP pathway. In cultured neurons from rats prenatally exposed to Al, we found reduced content of NO synthase and of guanylate cyclase, and a dramatic decrease in the ability of glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP pathway was also strongly impaired in cerebellum of rats chronically treated with Al, as assessed by in vivo brain microdialysis in freely moving rats. These findings suggest that the impairment of the Glu-NO-cGMP pathway in the brain may be responsible for some of the neurological alterations induced by Al.  2001 Elsevier Science B.V. All rights reserved. 1. Introduction by a muscle cell, and activation of this cell can result in muscle contraction. One essential process in living organisms is signal Chemical toxicants such as aluminium (Al) may produce transduction, which is used by cells to communicate with toxic effects by interfering with one or more steps in a other cells or to recognise changes in the external environ- signal transduction pathway. If a compound interferes with ment and adapt to these changes. In signal transduction, the signal transduction pathway through which a receptor there is usually a receptor in the cellular membrane that for growth factors modulates cell proliferation, exposure to recognizes the external signal and initiates a series of it can lead to cellular growth and to cancer. Alternatively, signal transduction pathways or chemical reactions that if a chemical interferes with signal transduction pathways leads finally to a biological response. For example, the associated with receptors for neurotransmitters, it may alter extracellular signal may be a growth factor that can the communication between neurons, impair cerebral func- activate specific receptors and modulate cell proliferation. tion, and trigger neurological alterations or neuronal In the case of neurotransmission, neurons communicate degeneration. with other neurons and other cells by releasing a neuro- The toxicity of Al has been the subject of much debate transmitter that stimulates a specific receptor in the post- in recent decades. Humans are exposed to Al from dietary synaptic cell and activates signal transduction pathways sources, from Al usage in industry and from antacid intake. that mediate specific biological responses. For example, a Al is neurotoxic and is considered today as a putative neuron can release a neurotransmitter that may be detected etiological factor in the pathogenesis of a range of neuro- degenerative disorders, including Alzheimer’s disease [1– 3] and amyotrophic lateral sclerosis [4,5], as well as other *Corresponding author. Tel.: 134-96-339-1250; fax: 134-96-360- human illnesses such as osteomalacia [6] and microcytic 1453. E-mail address: vfelipo@ochoa.fib.es (V. Felipo). anemia [7]. 0162-0134 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0162-0134(01)00316-6