Neurotoxic effects of dietary aluminium.
Neurochemical responses to chronic oral aluminium administration have been studied in rats. Aluminium (0.3%) was added to drinking water of adult rats for four weeks or longer and weanling rats were given aluminium for eight weeks. Selective cognitive impairment was demonstrated in the adult rats. Aluminium inhibited calcium flux and phosphoinositide metabolism, one product of which (inositol 1,4,5-trisphosphate) modulates intracellular calcium levels. In weanling rats aluminium decreased the in vivo concentration of inositol 1,4,5-trisphosphate in the hippocampus. An increase in cyclic AMP concentrations by 30-70% in various brain regions in adult and weanling rats was found. Aluminium enhanced agonist-stimulated but not basal cyclic AMP production in vitro. It was postulated that aluminium inhibits the GTPase activity of the stimulatory G protein, Gs, leading to prolonged activation of Gs after receptor stimulation and increased cyclic AMP production. Aluminium treatment also increased the phosphorylation of microtubule-associated protein 2 (MAP-2) and the 200 kDa neurofilament protein (NF-H) but several other phosphoproteins were unaffected. Concentrations of seven structural proteins--MAP-2, tau, NF-H, NF-M (150 kDa), NF-L (68 kDa), tubulin and spectrin--were measured in rat brain regions by immunoblot methods. MAP-2 was most consistently decreased. These studies show that chronic oral aluminium administration to rats has significant neurochemical consequences. Three sites of action are implicated: altered calcium homeostasis, enhanced cyclic AMP production, and changes in cytoskeletal protein phosphorylation states and concentrations.
Jope
R S
RS
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham 35294-0017.
Johnson
G V
GV
D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced; D000242:Cyclic AMP / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D009420:Nervous System / Q000187:drug effects*; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D051381:Rats
D010716:Phosphatidylinositols; D011506:Proteins; D000535:Aluminum; D000242:Cyclic AMP; D002118:Calcium