Studies of aluminum neurobehavioral toxicity in the intact mammal
Received: 12 September 1993 Accepted: 13 July 1994 DOI:
Cite this article as: Yokel, R.A., Allen, D.D. & Meyer, J.J. Cell Mol Neurobiol (1994) 14: 791. doi:10.1007/BF02088685 Summary
1. Aluminum (Al) has been implicated in neurotoxic syndromes in several conditions, including Alzheimer's disease (AD). The developmental stage of the mammalian brain most susceptible to Al was determined in rabbits systemically exposed to Al during the prenatal, postnatal, or second month or for 1 month as adults or as aged subjects. Eyeblink reflex classical conditioning showed an Al-induced learning deficit only in the adult and aged rabbits.
2. 4-Aminopyridine, which was reported to improve learning in AD subjects, attenuated this Al-induced learning deficit.
3. Conditioned eyeblink acquisition is slower in AD subjects than controls, supporting the Al-loaded rabbit as a model of some AD effects.
4. To determine if the Al-loaded rabbit modeled the AD cholinergic deficit, acetylcholine (Ach) overflow was measured in rabbit hippocampus using microdialysis. Aluminum pretreatment reduced basal and potassium-stimulated Ach overflow compared to controls.
5. Acetylcholine overflow increased as control rabbits acquired the conditioned eyeblink reflex, then subsequently decreased, although conditioned eyeblink performance continued. In contrast, Al-loaded rabbits showed a delay in conditioned eyeblink acquisition and greatly attenuated Ach overflow. The Al-induced attenuation of Ach overflow may contribute to the Al-induced learning deficit.
6. Brain Al entry was studied using microdialysis of blood, brain, and lateral ventricle. Aluminum rapidly entered the brain and lateral ventricle. Frontal cortical Al was greater than lateral ventricular Al, suggesting that Al primarily enters the brain through the cerebral microvasculature.
7. The brain/blood Al ratio was always significantly less than 1. This ratio was influenced by the Al form administered, brain site and animal species. Thus, there appears to be an active process moving Al out of brain extracellular fluid (ECF).
8. Brain and blood dialysate Ach concentrations were not different after cyanide addition to the dialysate, supporting the conclusion that an active process moves Al out of brain ECF.
Key words acetylcholine aluminum blood-brain barrier classical conditioning learning microdialysis rabbit rat References
Alfrey, A. C., LeGendre, G. R., and Kaehny, W. D. (1976). The dialysis encephalopathy syndrome.
N. Engl. J. Med.
Alfrey, A. C., Hegg, A., and Craswell, P. (1980). Metabolism and toxicity of aluminum in renal failure.
Am. J. Clin. Nutr.
Allen, D. D., and Yokel, R. A. (1992). Dissimilar aluminum and gallium permeation of the blood-brain barrier demonstrated by in vivo microdialysis.
Allen, D. D., Orvig, C., and Yokel, R. A. (1994). Pharmacokinetics and distribution of tris(maltolato) aluminum(III) into the central nervous system.
Allen, D. D., Orvig, C., and Yokel, R. A. Evidence for energy-dependent transport of aluminum out of brain extracellular fluid.
Neuro Toxicology (in press).
Barnes, N. M., Costall, B., Fell, A. F., and Naylor, R. J. (1987). An HPLC assay procedure of sensitivity and stability for measurement of acetylcholine and choline in neuronal tissue.
Beal, M. F., Mazurek, M. F., Ellison, D. W., Kowall, N. W., Solomon, P. R., and Pendlebury, W. W. (1989). Neurochemical characteristics of aluminum-induced neurofibrillary degeneration in rabbits.
Benveniste, E., and Hüttemeier, P. C. (1990). Microdialysis-theory and application.
Collingridge, G. L. (1985). Long-term potentiation in the hippocampus: Mechanisms of initiation and modulation by neurotransmitters.
Crapper, D. R., and Dalton, A. J. (1973). Alterations in short-term retention, conditioned avoidance response acquisition and motivation following aluminum induced neurofibrillary degeneration.
DeBoni, U., Otvos, A., Scott, J. W., and Crapper, D. R. (1976). Neurofibrillary degeneration induced by systemic aluminum.
Döllken, A. (1987). Über die Wirkung des Aluminum unter besorderer Berucksichtigung der durch das Aluminum Resursachten Lasionen in Zental Nervensystem.
Arch. Exp. Pathol. Pharmakol.
Finnegan, M. M., Rettig, S. J., and Orvig, C. (1986). A neutral water-soluble aluminum complex of neurological interest.
J. Am. Chem. Soc.
Gormezano, I. (1966). Classical conditioning. In
Experimental Methods and Instrumentation in Psychology
(J. B. Sidowski, Ed.), McGraw-Hill, New York, pp. 385–420.
Hofstetter, J. R., Vincent, I., Bugiani, O., Ghetti, B., and Richter, J. A. (1987). Aluminum-induced decreases in choline acetyltransferase, tryosine hydroxylase, and glutamate decarboxylase in selected regions of rabbit brain.
King, G. A., De Boni, U., and Crapper, D. R. (1975). Effect of aluminum upon conditioned avoidance response acquisition in the absence of neurofibrillary degeneration.
Pharmacol. Biochem. Behav.
Klatzo, I., Wiśniewski, H., and Streicher, E. (1965). Experimental production of neurofibrillary degeneration. 1. Light microscopic observations.
J. Neuropathol. Exp. Neurol.
Lai, J. C. K., Guest, J. F., Leung, T. K. C., Lim, L., and Davison, A. N. (1980). The effects of cadmium, manganese and aluminium on sodium-potassium-activated and magnesium-activated adenosine triphosphatase activity and choline uptake in rat brain synaptosomes.
Lavond, D. G., Kim, J. J., and Thompson, R. F. (1993). Mammalian brain substrates of aversive classical conditioning.
Annu. Rev. Psychol.
Lovell, M. A., Ehmann, W. D., and Markesbery, W. R. (1993). Laser microprobe analysis of brain aluminum in Alzheimer's disease.
Mamounas, L. A., Thompson, R. F., Lynch, G., and Baudry, M. (1984). Classical conditioning of the rabbit eyeblink response increases glutamate receptor binding in hippocampal synaptic membranes.
Proc. Natl. Acad. Sci.
McLaughlin, A. I. G., Kazantzis, G., King, E., Teare, D., Porter, R. J., and Owen, R. (1962). Pulmonary fibrosis and encephalopathy associated with the inhalation of aluminium dust.
Br. J. Ind. Med.
Nelson, W. O., Karpishin, T. B., Rettig, S. J., and Orvig, C. (1988). Aluminum and gallium compounds of 3-hydroxy-4-pyridinones: Synthesis, characterization, and crystallography of biologically active complexes with unusual hydrogen bonding.
Nordberg, A. (1992). Biological markers and the cholinergic hypothesis in Alzheimer's disease.
Acta Neurol. Scand. Suppl.
Petit, T. L., Biederman, G. B., and McMullen, P. A. (1980). Neurofibrillary degeneration, dendritic dying back and learning-memory deficits after aluminum administration: Implications for brain aging.
Petit, T. L., Biederman, G. B., Jonas, P., and LeBoutillier, J. C. (1985). Neurobehavioral development following aluminum administration in infant rabbits.
Rabe, A., Moon, H. L., Shek, J., and Wisniewski, H. M. (1982). Learning deficit in immature rabbits with aluminum-induced neurofibrillary changes.
Rifat, S. L., Eastwood, M. R., Crapper Mclachlan, D. R., and Corey, P. N. (1990). Effect of exposure of miners to aluminium powder.
Sideman, S., and Manor, D. (1982). The dialysis dementia syndrome and aluminum intoxication.
Sjögren, B., Gustavsson, P., and Hogstedt, C. (1990). Neuropsychiatric symptoms among welders exposed to neurotoxic metals.
Br. J. Ind. Med.
Solomon, P. R., Solomon, S. D., Vander Schaaf, E., and Perry, H. E. (1983). Altered activity in the hippocampus is more detrimental to classical conditioning than removing the structure.
Solomon, P. R., Levine, E., Bein, T., and Pendlebury, W. W. (1991). Disruption of classical conditioning in patients with Alzheimer's disease.
Spofforth, J. (1921). Case of aluminium poisoning.
Thompson, R. F., Berger, T. W., Berry, S. D., Hoehler, F. K., Kettner, R. E., and Weisz, D. J. (1980). Hippocampal substrate of classical conditioning.
Wesseling, H., Agoston, S., VanDam, G. B. P., Pasma, J., DeWit, D. J., and Havinga, H. (1984). Effects of 4-aminopyridine in elderly patients with Alzheimer's disease.
N. Engl. J. Med.
White, D. M., Longstreth, W. T., Rosenstock, L., Claypoole, K. H. J., Brodkin, C. A., and Townes, B. D. (1992). Neurologic syndrome in 25 workers from an aluminum smelting plant.
Arch. Intern. Med.
Wisniewski, H., Narkiewicz, O., and Wisniewska, K. (1967). Topography and dynamcis of neurofibrillary degeneration in aluminum encephalopathy.
Wisniewski, H. M., Sturman, J. A., and Shek, J. W. (1980). Aluminum chloride induced neurofibrillary changes in the developing rabbit: A chronic animal model.
Woodruff-Pak, D. S. (1988). Aging and classical conditioning: Parallel studies in rabbits and humans.
Woodruff-Pak, D. S., Finkbiner, R. G., and Sasse, D. K. (1990). Eyeblink conditioning discriminates Alzheimer's patients from non-demented aged.
Yasui, M., Yase, Y., Ota, K., and Garruto, R. M. (1991). Aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii peninsula of Japan.
Yokel, R. A. (1983a). Persistent aluminum accumulation after prolonged systemic aluminum exposure.
Biol. Tr. Elem. Res.
Yokel, R. A. (1983b). Repeated systemic aluminum exposure effects on classical conditioning of the rabbit.
Neurobehav. Toxicol. Teratol.
Yokel, R. A. (1985). Toxicity of gestational aluminum exposure to the maternal rabbit and offspring.
Toxicol. Appl. Pharmacol.
Yokel, R. A. (1987). Toxicity of aluminum exposure to the neonatal and immature rabbit.
Fund Appl. Toxicol.
Yokel, R. A. (1989). Aluminum produces age related behavioral toxicity in the rabbit.
Yokel, R. A., Lidums, V., Mcnamara, P. J., and Ungerstedt, U. (1991). Aluminum distribution into brain and liver of rats and rabbits following intravenous aluminum lactate or citrate: A microdialysis study.
Toxicol. Appl. Pharmacol.
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