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 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.
Canales
J J
JJ
Laboratory of Neurobiology, Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Amadeo de Saboya 4, 46010 Valencia, Spain.
Corbalán
R
R
Montoliu
C
C
Llansola
M
M
Monfort
P
P
Erceg
S
S
Hernandez-Viadel
M
M
Felipo
V
V
D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D015398:Signal Transduction / Q000187:drug effects
D009569:Nitric Oxide; D018698:Glutamic Acid; D000535:Aluminum; D006152:Cyclic GMP