Prenatal exposure to aluminum reduces expression of neuronal nitric oxide synthase and of soluble guanylate cyclase and impairs glutamatergic neurotransmission in rat cerebellum.
Exposure to aluminum (Al) produces neurotoxic effects in humans. However, the molecular mechanism of Al neurotoxicity remains unknown. Al interferes with glutamatergic neurotransmission and impairs the neuronal glutamate-nitric oxide-cyclic GMP (cGMP) pathway, especially in rats prenatally exposed to Al. The aim of this work was to assess whether Al interferes with processes associated with activation of NMDA receptors and to study the molecular basis for the Al-induced impairment of the glutamate-nitric oxide-cGMP pathway. We used primary cultures of cerebellar neurons prepared from control rats or from rats prenatally exposed to Al. Prenatal exposure to Al prevented glutamate-induced proteolysis of the microtubule-associated protein-2, disaggregation of microtubules, and neuronal death, indicating an impairment of NMDA receptor-associated signal transduction pathways. Prenatal exposure to Al reduced significantly the content of nitric oxide synthase and guanylate cyclase and increased the content of calmodulin both in cultured neurons and in the whole cerebellum. This effect was selective for proteins of the glutamate-nitric oxide-cGMP pathway as the content of mitogen-activated protein kinase and the synthesis of most proteins were not affected by prenatal exposure to Al. The alterations in the expression of proteins of the glutamate-nitric oxide-cGMP pathway could be responsible for some of the neurotoxic effects of Al.
Llansola
M
M
Laboratory of Neurobiology, Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.
Miñana
M D
MD
Montoliu
C
C
Saez
R
R
Corbalán
R
R
Manzo
L
L
Felipo
V
V
D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D006162:Guanylate Cyclase / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D009498:Neurotoxins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052248:Nitric Oxide Synthase Type I; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012995:Solubility; D009435:Synaptic Transmission / Q000187:drug effects; D014404:Tubulin / Q000032:analysis
D002147:Calmodulin; D008869:Microtubule-Associated Proteins; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D014404:Tubulin; D009569:Nitric Oxide; D018698:Glutamic Acid; D000535:Aluminum; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006162:Guanylate Cyclase