Molecular and Chemical Neuropathology

, Volume 32, Issue 1–3, pp 41–57

Aluminum potentiates glutamate-induced calcium accumulation and iron-induced oxygen free radical formation in primary neuronal cultures

  • William R. Mundy
  • Theresa M. Freudenrich
  • Prasad R. S. Kodavanti
Original Articles

Abstract

Aluminum is a neurotoxic metal that may be involved in the progression of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis (ALS). Although the mechanism of action is not known, aluminum has been shown to alter Ca2+ flux and homeostasis, and facilitate peroxidation of membrane lipids. Since abnormal increases of intracellular Ca2+ and oxygen free radicals have both been implicated in pathways leading to neurodegeneration, we examined the effect of aluminum on these parameters in vitro using primary cultures of cerebellar granule cells. Exposure to glutamate (1–300 μM) caused a concentration-dependent uptake of45Ca in granule cells to a maximum of 280% of basal. Pretreatment with AlCl3 (1–1000 μM) had no effect on45Ca accumulation, but increased the uptake induced by glutamate. Similarly, AlCl3 had no effect on intracellular free Ca2+ levels measured using fluorescent probe fura-2, but potentiated the increase induced by glutamate. The production of reactive oxygen species (ROS) was examined using the fluorescent probe dichlorofluorescin. By itself, AlCl3 had little effect on ROS production. However, AlCl3 pretreatment potentiated the ROS production induced by 50 μMFe2+. These results suggest that aluminum may facilitate increases in intracellular Ca2+ and ROS, and potentially contribute to neurotoxicity induced by other neurotoxicants.

Index Entries

Aluminum intracellular free calcium reactive oxygen species cerebellar granule cell neurotoxicity 

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References

  1. Abreo K., Glass J., and Sella M. (1990) Aluminum inhibits hemoglobin synthesis but enhances iron uptake in friend erythroleukemia cells.Kidney Int. 37, 677–681.PubMedCrossRefGoogle Scholar
  2. Alfrey A. C., Le Gendre G. R., and Kaehny W. D. (1976) The dialysis encephalopathy syndrome. Possible aluminum intoxication.N. Engl. J. Med. 294, 184–188.PubMedCrossRefGoogle Scholar
  3. Benzi G. and Moretti A. (1995) Are reactive oxygen species involved in Alzheimer's disease?Neurobiol. Aging 16, 661–674.PubMedCrossRefGoogle Scholar
  4. Blaustein M. P. (1988) Calcium transport and buffering in neurons.Trends Neurosci. 11, 438–443.PubMedCrossRefGoogle Scholar
  5. Bondy S. C. and Kirstein S. (1996) The promotion of iron-induced generation of reactive oxygen species in nerve tissue by aluminum.Mol. Chem. Neuropathol. 27, 185–194.PubMedGoogle Scholar
  6. Bondy S. C. and Lee D. K. (1993) Oxidative stress induced by glutamate receptor agonists.Brain Res. 610, 229–233.PubMedCrossRefGoogle Scholar
  7. Bradford M. M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.Anal. Biochem. 72, 248–254.PubMedCrossRefGoogle Scholar
  8. Büsselberg D., Platt B., Michael, D., Hass H. L., and Carpenter D. O. (1994) Mammalian voltage-activated calcium channel currents are blocked by Pb2+, Zn2+ and Al3+.J. Neurophysiol. 71, 1491–1497.PubMedGoogle Scholar
  9. Candy J. M., Klinowski J., Perry R. H., Perry E. K., Fairbairn A., Oakley A. E., Carpenter T. A., Atack J. R., Blessed G., and Edwardson J. A. (1986) Aluminosilicates and senile plaque formation in Alzheimer's disease.Lancet 1, 354–357.PubMedCrossRefGoogle Scholar
  10. Choi D. W. (1988) Glutamate neurotoxicity and diseases of the nervous system.Neuron 1, 623–634.PubMedCrossRefGoogle Scholar
  11. Choi J. H. and Yu B. P. (1995) Brain synaptosomal aging: free radicals and membrane fluidity.Free Radical Biol. Med. 18, 133–139.CrossRefGoogle Scholar
  12. Coyle J. T. and Puttfarcken P. (1993) Oxidative stress, glutamate, and neurodegenerative disorders.Science 262, 689–695.PubMedCrossRefGoogle Scholar
  13. Crapper D. R., Krishnan S. S., and Dalton A. J. (1973) Brain aluminum in Alzheimer's disease and experimental neurofibrillary degeneration.Science 180, 511–513.PubMedCrossRefGoogle Scholar
  14. Dawson R. Jr., Beal M. F., Bondy, S. C., DiMonte D. A., and Isom G. E. (1995) Excitotoxins, aging, and environmental neurotoxins: implications for understanding human neurodegenerative diseases.Toxicol. Appl. Pharmacol. 134, 1–17.PubMedCrossRefGoogle Scholar
  15. Deleers M. (1985) Cationic atmosphere and cation competition binding at negatively charged membranes: pathological implications of aluminum.Res. Commun. Chem. Pathol. Pharm. 49, 277–294.Google Scholar
  16. Didier M. Hèaulme M., Gonalons N., Soubrie P., Bockaert J., and Pin J. P. (1993) 35 mM K+-stimulated45Ca2+ uptake in cerebellar granule cell cultures mainly results from NMDA receptor activation.Eur. J. Pharmacol. 244, 57–65.PubMedCrossRefGoogle Scholar
  17. Doll R. (1993) Review: Alzheimer's disease and environmental aluminum.Age and Ageing 22, 138–153.PubMedCrossRefGoogle Scholar
  18. Eimerl S. and Schramm M. (1993) Potentiation of45Ca uptake and acute toxicity mediated by the N-methyl-D-aspartate receptor: the effect of metal binding agents and transition metal ions.J. Neurochem. 61, 518–525.PubMedCrossRefGoogle Scholar
  19. Fleming J. and Joshi J. G. (1987) Ferritin: isolation of aluminum-ferritin complex from brain.Proc. Natl. Acad. Sci. USA 84, 7866–7870.PubMedCrossRefGoogle Scholar
  20. Fraga C. G., Oteiza P. I., Golub M. S., Gershwin M. E., and Keen C. L. (1990) Effects of aluminum on brain lipid peroxidation.Toxicol. Lett. 51, 213–219.PubMedCrossRefGoogle Scholar
  21. Gallo V., Kingsbury A., Balazs R., and Jergensen O. S. (1987) The role of depolarization in the survival and differentiation of cerebellar granule cells in culture.J. Neurosci. 7, 2203–2213.PubMedGoogle Scholar
  22. Garruto R. M. (1991) Pacific paradigms of environmentally-induced neurological disorders: clinical, epidemiological and molecular perspecitives.NeuroToxicology 12, 347–378.PubMedGoogle Scholar
  23. Garruto R. M., Shankar S. K., Yanagihara R., Salazar A. M., Amyx H. L., and Gajdusek D. C. (1989) Low calcium, high aluminum diet-induced motor neuron pathology in cynomolgus monkeys.Acta Neuropathol. 78, 210–219.PubMedCrossRefGoogle Scholar
  24. Grynkiewicz G., Poenie M., and Tsien R. Y. (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties.J. Biol. Chem. 260, 3440–3450.PubMedGoogle Scholar
  25. Gupta A. and Shukla G. S. (1995) Effect of chronic aluminum exposure on the levels of conjugated dienes and enzymatic antioxidants in hippocampus and whole brain of rat.Bull. Environ. Contam. Toxicol. 55, 716–722.PubMedGoogle Scholar
  26. Gutteridge J. M. C., Quinlan G. J., Clark I., and Halliwell B. (1985) Aluminum salts accelerate peroxidation of membrane lipids stimulated by iron salts.Biochim. Biophys. Acta 835, 441–447.PubMedGoogle Scholar
  27. Halliwell B. and Gutteridge J. M. C. (1989)Free Radicals in Biology and Medicine. Clarendon, Oxford, pp. 350–353.Google Scholar
  28. Jacobs R. W., Doung T., Jones R. E., Trapp G. A., and Scheibel A. B. (1989) A reexamination of Al in AD: analysis by energy dispersive X-ray microprobe and flameless atomic absorption spectrophotometry.Can. J. Neurol. Sci. 16, 498–503.PubMedGoogle Scholar
  29. Johnston H. B., Thomas S. M., and Atterwill C. K. (1993) Aluminum and iron induced metabolic changes in neuroblastoma cell lines and rat primary neural cultures.Toxicol. In Vitro 7, 229–233.CrossRefPubMedGoogle Scholar
  30. King G. A., DeBoni U., and Crapper D. R. (1975) Effect of aluminum upon conditioned avoidance response acquisition in the absence of neurofibrillary degeneration.Pharmacol. Biochem. Behav. 3, 1003–1009.PubMedCrossRefGoogle Scholar
  31. Klatzo I., Wisniewski H., and Streicher E. (1965) Experimental production of neurofibrillary degeneration.J. Neuropathol. Exp. Neurol. 24, 187–199.PubMedGoogle Scholar
  32. Kodavanti P. R. S., Mundy W. R., Tilson H. A., and Harry G. J. (1993) Effects of selected neuroactive chemicals on calcium transporting systems in rat cerebellum and on survival of cerebellar granule cells.Fundam. Appl. Toxicol. 21, 308–316.PubMedCrossRefGoogle Scholar
  33. Koenig M. L. and Jope R. S. (1987) Aluminum inhibits the fast phase of voltage-dependent calcium influx into synaptosomes.J. Neurochem. 49, 316–320.PubMedCrossRefGoogle Scholar
  34. Lai J. C. K. and Blass J. P. (1984) Inhibition of brain glycolysis by aluminum.J. Neurochem. 42, 438–446.PubMedCrossRefGoogle Scholar
  35. LeBel C. P., Ischiropoulos H., and Bondy S. C. (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress.Chem. Res. Toxicol. 5, 227–231.PubMedCrossRefGoogle Scholar
  36. Martyn C. N., Barker D. J. P., Osmond C., Harris E. C., Edwardson J. A., and Lacey R. F. (1989) Geographical relation between Alzheimer's disease and aluminum in drinking water.Lancet 1(8629), 59–62.PubMedGoogle Scholar
  37. McDermott J. R., Smith A. I., Iqbal K., and Wisniewski H. M. (1979) Brain aluminum in aging and Alzheimer disease.Neurology 29, 809–814.PubMedGoogle Scholar
  38. Milani D., Guidolin D., Facci L., Pozzan T., Buso M., Leon A., and Skaper S. D. (1991) Excitatory amino acid-induced of alterations of cytoplasmic free Ca2+ in individual cerebellar granule neurons: role in neurotoxicity.J. Neurosci. Res. 28, 434–441.PubMedCrossRefGoogle Scholar
  39. Mundy W. R., Kodavanti P. R. S., Dulchinos V. F., and Tilson H. A. (1994) Aluminum alters calcium transport in plasma membrane and endoplasmic reticulum form rat brain.J. Biochem. Toxicol. 9, 17–23.PubMedCrossRefGoogle Scholar
  40. Ohtawa M., Seko M., and Takayama F. (1983) Effect of aluminum ingestion on lipid peroxidation in rats.Chem. Pharm. Bull. 31, 1415–1418.PubMedGoogle Scholar
  41. Olanow C. W. (1993) A radical hypothesis for neurodegeneration.Trends Neurosci. 16, 439–444.PubMedCrossRefGoogle Scholar
  42. Orrenius S. and Nicotera P. (1994) The calcium ion and cell death.J. Neural Transm. 43, 1–11.Google Scholar
  43. Oteiza P. I. (1994) A mechanism for the stimulatory effect of aluminum on iron-induced lipid peroxidation.Arch. Biochem. Biophys. 308, 374–379.PubMedCrossRefGoogle Scholar
  44. Oteiza P. I., Fraga C. G., and Keen C. L. (1993) Aluminum has both oxidant and antioxidant effects in mouse brain membranes.Arch. Biochem. Biophys. 300, 517–521.PubMedCrossRefGoogle Scholar
  45. Oyama Y., Tomiyoshi F., Ueno S., Furukawa K., and Chikahisa L. (1994) Methylmercury-induced augmentation of oxidative metabolism in cerebellar neurons dissociated from the rat: its dependence on intracellular Ca2+.Brain Res. 660, 154–157.PubMedCrossRefGoogle Scholar
  46. Pendlebury W. W., Beal M. F., Kowall N. W., and Solomon P. R. (1987) Results of immunocytochemical, neurochemical and behavioral studies in aluminum-induced neurofilamentous degeneration.J. Neural Trans. 24, 213–217.Google Scholar
  47. Perl D. P. and Brody A. R. (1980) Alzheimer's disease: x-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons.Science 208, 297–299.PubMedCrossRefGoogle Scholar
  48. Platt B., Haas H., and Büsselberg D. (1994) Aluminum reduces glutamate-activated currents of rat hippocampal neurones.NeuroReport 5, 2329–2332.PubMedCrossRefGoogle Scholar
  49. Rifat S. L., Eastwood M. R., Crapper McLachlan D. R., and Cory P. N. (1990) Effects of exposure of miners to aluminum powder.Lancet 336, 1162–1165.PubMedCrossRefGoogle Scholar
  50. Schapira A. H. V. (1995) Oxidative stress in Parkinson's disease.Neuropathol. Appl. Neurobiol. 21, 3–9.PubMedCrossRefGoogle Scholar
  51. Shi B. and Haug, A. (1990) Aluminum uptake by neuroblastoma cells.J. Neurochem. 55, 551–558.PubMedCrossRefGoogle Scholar
  52. Shi B. and Haug, A. (1992) Aluminum interferes with signal transduction in neuroblastoma cells.Pharmacol. Toxicol. 71, 308–313.PubMedGoogle Scholar
  53. Shi B., Chou K., and Haug A. (1993) Aluminum impacts elements of the phosphoinositide signalling pathway in neuroblastoma cells.Mol. Cell. Biochem. 121, 109–118.PubMedCrossRefGoogle Scholar
  54. Shuttleworth T. J. and Thompson J. L. (1991) Effect of temperature on receptor-activated changes in [Ca2+] and their determinations using fluorescent probes.J. Biol. Chem. 266, 1410–1414.PubMedGoogle Scholar
  55. Siegel N. and Haug A. (1983) Aluminum interaction with calmodulin. Evidence for altered structure and function from optical and enzymatic studies.Biochim. Biophys. Acta 744, 36–45.PubMedGoogle Scholar
  56. Solomon P. R., Pingree T. M., Baldwin D., Koota D., Perl D. P., and Pendlebury W. W. (1988) Disrupted retention of the classically conditioned nictitating membrane response in rabbits with aluminum-induced neurofibrillary degeneration.NeuroToxicology 9, 209–222.PubMedGoogle Scholar
  57. Stohs S. J. and Bagchi D. (1995) Oxidative mechanisms in the toxicity of metal ions.Free Radical Biol. Med. 18, 321–336.CrossRefGoogle Scholar
  58. Suhayda C. G. and Haug A. (1984) Organic acids prevent aluminum-induced conformational changes in calmodulin.Biochem. Biophys. Res. Commun. 119, 376–381.PubMedCrossRefGoogle Scholar
  59. Trapp G. A., Miner G. D., Zimmerman R. L., Master A. R., and Heston L. L. (1978) Aluminum levels in brain in Alzheimer's disease.Biol. Psychiatry 13, 709–718.PubMedGoogle Scholar
  60. Verity M. A. (1992) Ca2+ dependent processes as mediators of neurotoxicity.NeuroToxicology 13, 139–148.PubMedGoogle Scholar
  61. Wettstein A., Aepple J., Gautschi K., and Peters M. (1991) Failure to find a relationship between mnestic skills of octogenarians and aluminum in drinking water.Int. Arch. Occup. Environ. Health 63, 97–103.PubMedCrossRefGoogle Scholar
  62. White D. M., Longstreth W. T., Rosenstock L., Claypoole H. J., Brodkin C. A., and Townes B. D. (1992) Neurologic syndrome in 25 workers from an aluminum smelting plant.Arch. Intern. Med. 152, 1443–1448.PubMedCrossRefGoogle Scholar
  63. Willis M. R. and Savory J. (1983) Aluminum poisoning: dialysis encephalopathy, osteomalacia, and anaemia.Lancet 2(8340), 29–34.CrossRefGoogle Scholar
  64. Wisniewski H. M., Sturman J. A., and Shek J. W. (1980) Aluminum chloride-induced neurofibrillary changes in the developing rabbit: a chronic animal model.Ann. Neurol. 8, 479–490.PubMedCrossRefGoogle Scholar
  65. Xie C. X., St. Pyrek J., Porter W. H., and Yokel R. A. (1995) Hydroxyl radical generation in rat brain in initiated by iron but not aluminum, as determined by microdialysis with salicylate trapping and GC-MS analysis.NeuroToxicology 16, 489–496.PubMedGoogle Scholar
  66. Yasui M., Yase Y., and Ota K. (1991) Evaluation of magnesium, calcium, aluminum metabolism in rats and monkeys maintained on calcium deficient diets.NeuroToxicology 12, 139.Google Scholar

Copyright information

© Humana Press Inc 1997

Authors and Affiliations

  • William R. Mundy
    • 1
  • Theresa M. Freudenrich
    • 1
  • Prasad R. S. Kodavanti
    • 1
  1. 1.Neurotoxicology Division, National Health and Environmental Effects Research LaboratoryUS Environmental Protection AgencyResearch Triangle Park

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