Jope R S, Johnson G V
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham 35294-0017.
Ciba Found Symp. 1992;169:254-62; discussion 262-7. doi: 10.1002/9780470514306.ch15.
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.
已在大鼠中研究了慢性口服铝给药后的神经化学应答。将铝（0.3%）添加到成年大鼠的饮用水中持续四周或更长时间，给断奶大鼠喂食铝持续八周。在成年大鼠中证实了选择性认知障碍。铝抑制钙通量和磷酸肌醇代谢，其一种产物（肌醇1,4,5-三磷酸）可调节细胞内钙水平。在断奶大鼠中，铝降低了海马体中肌醇1,4,5-三磷酸的体内浓度。发现成年和断奶大鼠的各个脑区中，环磷酸腺苷（cAMP）浓度增加了30 - 70%。铝在体外增强了激动剂刺激的cAMP产生，但对基础cAMP产生无影响。据推测，铝抑制刺激性G蛋白Gs的GTP酶活性，导致受体刺激后Gs的激活延长，cAMP产生增加。铝处理还增加了微管相关蛋白2（MAP - 2）和200 kDa神经丝蛋白（NF - H）的磷酸化，但其他几种磷蛋白未受影响。通过免疫印迹法测量了大鼠脑区中七种结构蛋白——MAP - 2、tau、NF - H、NF - M（150 kDa）、NF - L（68 kDa）、微管蛋白和血影蛋白的浓度。MAP - 2最一致地减少。这些研究表明，对大鼠慢性口服铝给药具有显著的神经化学后果。涉及三个作用位点：改变钙稳态、增强cAMP产生以及细胞骨架蛋白磷酸化状态和浓度的变化。
