In Vitro Studies of Neurotoxicant Effects on Cellular Homeostasis

  • Gerald J. Audesirk
  • Ronald B. Tjalkens
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


Homeostasis in neurons is regulated by interactions among many signaling pathways. We will loosely define the term “signaling pathways” to include any molecular mechanisms that transduce external environmental stimuli (e.g., neurotransmitters, hormones, or contact with other cells) and/or intracellular metabolic conditions (e.g., intracellular free Ca2+ ion concentrations, redox status, or ATP demand) into cellular responses such as process growth, synthesis of neurotransmitters and/or their receptors, or changes in cellular respiration. This definition includes the interlinked pathways that lead to alterations in protein kinase or phosphatase activity and activation or repression of gene transcription and, perhaps less familiar mechanisms such as the stimulation of mitochondrial matrix enzymes by elevations in intramitochondrial Ca2+.


Nitric Oxide Stress Protein Reactive Nitrogen Species Toxicant Effect Dependent Inactivation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Trenkner, E. (1991) Cerebellar cells in culture, in Culturing Nerve Cells (Banker, G. and Goslin, K., eds.), MIT Press, Cambridge, MA, pp. 283–307.Google Scholar
  2. 2.
    Milani, D., Candeo, P., Favaron, M., Blackstone, C. D., and Manev, H. (1993) A subpopulation of cerebellar granule neurons in culture expresses a functional mGluR1 metabotropic glutamate receptor: effect of depolarizing growing conditions. Receptors Channels 1, 243–250.PubMedGoogle Scholar
  3. 3.
    Wheeler, B. C. and Brewer, G. J. (1994) Selective hippocampal neuritogenesis: axon growth on laminin or pleiotrophin, dendrite growth on poly-d-lysine. Soc. Neurosci. Abstract. 20, 1292.Google Scholar
  4. 4.
    Glowacka, D. and Wagner, J. A. (1990) Role of the cAMP-dependent protein kinase and protein kinase C in regulating the morphological differentiation of PC12 cells. J. Neurosci. Res. 25, 453–462.PubMedGoogle Scholar
  5. 5.
    Greene, L. A., Sobeih, M. M., and Teng, K. K. (1991) Methodologies for the culture and experimental use of the PC12 rat pheochromocytoma cell line, in Culturing Nerve Cells (Banker, G. and Goslin, K., eds.), MIT Press, Cambridge, MA, pp. 208–226.Google Scholar
  6. 6.
    Armstrong, D. and Eckert, R. (1987) Voltage-activated calcium channels that must be phosphorylated to respond to membrane depolarization. Proc. Natl. Acad. Sci. USA 84, 2518–2522.PubMedGoogle Scholar
  7. 7.
    Kavalali, E. T., Hwang, K. S., and Plummer, M. R. (1997) cAMP-dependent enhancement of dihydropyridine-sensitive calcium channel availability in hippocampal neurons. J. Neurosci. 17, 5334–5348.PubMedGoogle Scholar
  8. 8.
    McCarron, J. G., McGeown, J. G., Reardon, S., Ikebe, M., Fay, F. S., and Walsh, J. V., Jr. (1992) Calcium-dependent enhancement of calcium current in smooth muscle by calmodulin-dependent protein kinase II. Nature 357, 74–77.PubMedGoogle Scholar
  9. 9.
    Schuhmann, K., Romanin, C., Baumgartner, W., and Groschner, K. (1997) Intracellular Ca2+ inhibits smooth muscle L-type Ca2+ channels by activation of protein phosphatase 2B and by direct interaction with the channel. J. Gen. Physiol. 110, 503–513.PubMedGoogle Scholar
  10. 10.
    Stea, A., Soong, T. W., and Snutch, T. P. (1995) Determinants of PKC-dependent modulation of a family of neuronal calcium channels. Neuron 15, 929–940.PubMedGoogle Scholar
  11. 11.
    Yuan W. and Bers, D. M. (1994) Ca-dependent facilitation of cardiac Ca current is due to Ca-calmodulin-dependent protein kinase. Am. J. Physiol. 267, H982–H993.PubMedGoogle Scholar
  12. 12.
    Zhu, Y. and Ikeda, S. R. (1994) Modulation of Ca2+-channel currents by protein kinase C in adult rat sympathetic neurons. J. Neurophysiol. 72, 1549–1560.PubMedGoogle Scholar
  13. 13.
    Lieberman, D. N. and Mody, I. (1994) Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature 369, 235–239.PubMedGoogle Scholar
  14. 14.
    Raman, I. M., Tong, G., and Jahr, C. E. (1996) β-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron 16, 415–421.PubMedGoogle Scholar
  15. 15.
    Spigelman, I., Tymianski, M., Wallace, C. M., Carlen, P. L., and Velumian, A. A. (1996) Modulation of hippocampal synaptic transmission by low concentrations of cell-permeant Ca2+ chelators: effects of Ca2+ affinity, chelator structure and binding kinetics. Neuroscience 75, 559–572.PubMedGoogle Scholar
  16. 16.
    Sun, L. R. and Suszkiw, J. B. (1995) Extracellular inhibition and intracellular enhancement of Ca2+ currents by Pb2+ in bovine adrenal chromaffin cells. J. Neurophysiol. 74, 574–581.PubMedGoogle Scholar
  17. 17.
    Lee, A., Wong, S. T., Gallagher, D., et al. (1999) Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature 399, 155–159.PubMedGoogle Scholar
  18. 18.
    Qin, N., Olcese, R., Bransby, M., Lin, T., and Birnbaumer, L. (1999) Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin. Proc. Natl. Acad. Sci. USA 96, 2435–2438.PubMedGoogle Scholar
  19. 19.
    Zuhlke, R. D., Pitt, G. S., Deisseroth, K., Tsien, R. W., and Reuter, H. (1999) Calmodulin supports both inactivation and facilitation of L-type calcium channels. Nature 399, 159–162.PubMedGoogle Scholar
  20. 20.
    Ehlers, M. D., Zhang, S., Bernhardt, J. P., and Huganir, R. L. (1996) Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84, 745–755.PubMedGoogle Scholar
  21. 21.
    Zhang, S., Ehlers, M. D., Bernhardt, J. P., Su, C.-T., and Huganir, R. L. (1998) Calmodulin mediates calcium-dependent inactivation of N-methyl-d-aspartate receptors. Neuron 21, 443–453.PubMedGoogle Scholar
  22. 22.
    Ehlers, M. D. and Augustine, G. J. (1999) Calmodulin at the channel gate. Nature 399, 105–108.PubMedGoogle Scholar
  23. 23.
    Levitan, I. B. (1999) It is calmodulin after all! Mediator of the calcium modulation of multiple ion channels. Neuron 22, 645–648.PubMedGoogle Scholar
  24. 24.
    Goldstein, G. W. and Ar, D. (1983) Lead activates calmodulin sensitive processes. Life Sci. 33, 1001–1006.PubMedGoogle Scholar
  25. 25.
    Habermann, E., Crowell, K., and Janicki, P. (1983) Lead and other metals can substitute for Ca2+ in calmodulin. Arch. Toxicol. 54, 61–70.PubMedGoogle Scholar
  26. 26.
    Kern, M., Wisniewski, M., Cabell, L., and Audesirk, G. (2000) Inorganic lead and calcium interact positively in activation of calmodulin. Neuro Toxicology 21, 353–364.Google Scholar
  27. 27.
    Omkumar, R. V., Kiely, M. J., Rosenstein, A. J., Min, K.-T., and Kennedy, M. B. (1996) Identification of a phosphorylation site for calcium/calmodulin-dependent protein kinase II in the NR2B subunit of the N-methyl-d-aspartate receptor. J. Biol. Chem. 271, 31,670–31,678.PubMedGoogle Scholar
  28. 28.
    Barria, A., Derkach, V., and Soderling, T. (1997) Identification of the Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptor. J. Biol. Chem. 272, 32,727–32,730.PubMedGoogle Scholar
  29. 29.
    Derkach, V., Barria, A., and Soderling, T. R. (1999) Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl. Acad. Sci. USA 96, 3269–3274.PubMedGoogle Scholar
  30. 30.
    Roche, K. W., O’Brien, R. J., Mamnien, A. L., Bernhardt, J., and Huganir, R. L. (1996) Characterization of multiple phosphorylation sites on the AMPA receptor GluRl subunit. Neuron 16, 1179–1186.PubMedGoogle Scholar
  31. 31.
    Fenster, C. P., Beckman, M. L., Parker, J. C, et al. (1999) Regulation of α4β2 nicotinic receptor desensitization by calcium and protein kinase C. Mol. Pharmacol. 55, 432–443.PubMedGoogle Scholar
  32. 32.
    Voitenko, S. V., Bobryshev, A. Y., and Skok, V. I. (2000) Intracellular regulation of neuronal nicotinic cholinoreceptors. Neurosci. Behav. Physiol. 30, 19–25.PubMedGoogle Scholar
  33. 33.
    Wecker, L., Guo, X., Rycerz, A. M., and Edwards, S. C. (2001) Cyclic AMP-dependent protein kinase A (PKA) and protein kinase C phosphorylate sites in the amino acid sequence corresponding to the M3/M4 cytoplasmic domain of α4 neuronal nicotinic receptor subunits. J. Neurochem. 76, 711–720.PubMedGoogle Scholar
  34. 34.
    Isosaki, M., Minami, N., and Nakashima, T. (1994) Pharmacological evidence for regulation of Na+-Ca2+ exchange by Ca2+/calmodulin-dependent protein kinase in isolated bovine adrenal medullary cells. J. Pharmacol. Exp. Ther. 270, 104–110.PubMedGoogle Scholar
  35. 35.
    Sonnenburg, W. K., Wayman, G. A., Storm, D. R., and Beavo, J. A. (1998) Cyclic nucleotide regulation by calmodulin, in Calmodulin and Signal Transduction (Van Eldik, L. J. and Watterson, D. M., eds.), Academic, San Diego, CA, pp. 237–286.Google Scholar
  36. 36.
    Tomsig, J. L. and Suszkiw, J. B. (1995) Multisite interactions between Pb2+ and protein kinase C and its role in norepinephrine release from bovine adrenal chromaffin cells. J. Neurochem. 64, 2667–2673.PubMedGoogle Scholar
  37. 37.
    Long, G. J., Rosen, J. F., and Schanne, F. A. X. (1994) Lead activation of protein kinase C from rat brain. Determination of free calcium, lead, and zinc by 19F NMR. J. Biol. Chem. 269, 834–837.PubMedGoogle Scholar
  38. 38.
    Kodavanti, P. R. S., Shafer, T. J., Ward, T. R., et al. (1994) Differential effects of polychlorinated biphenyl congeners on phosphoinositide hydrolysis and protein kinase C translocation in rat cerebellar granule cells. Brain Res. 662, 75–82.PubMedGoogle Scholar
  39. 39.
    Kodavanti, P. R. S., Ward, T. R., McKinney, J. D., and Tilson, H. A. (1995) Increased [3H]phorbol ester binding in rat cerebellar granule cells by polychlorinated biphenyl mixtures and congeners: structure-activity relationships. Toxicol. Appl. Pharmacol. 130, 140–148.PubMedGoogle Scholar
  40. 40.
    Kodavanti, P. R. S. and Ward, T. R. (1998) Interactive effects of environmentally relevant polychlorinated biphenyls and dioxins on [3H]phorbol ester binding in rat cerebellar granule cells. Environ. Health Perspect. 106, 479–486.PubMedGoogle Scholar
  41. 41.
    Bagchi, D., Bagchi, M., Tang, L., and Stohs, S. J. (1997) Comparative in vitro and in vivo protein kinase C activation by selected pesticides and transition metal salts. Toxicol. Lett. 91, 31–37.PubMedGoogle Scholar
  42. 42.
    Kern, M. and Audesirk, G. (2000a) Stimulatory and inhibitory effects of inorganic lead on calcineurin. Toxicology 150, 173–180.Google Scholar
  43. 43.
    Enan, E. and Matsumura, F. (1992) Specific inhibition of calcineurin by type II synthetic pyrethroid insecticides. Biochem. Pharmacol. 43, 1777–1784.PubMedGoogle Scholar
  44. 44.
    Enz, A. and Pombo-Villar, E. (1997) Class II pyrethroids: noninhibitors calcineurin. Biochem. Pharmacol. 54, 321–323.PubMedGoogle Scholar
  45. 45.
    Fakata, K. L., Swanson, S. A., Vorce, R. L., and Stemmer, P. M. (1998) Pyrethroid insecticides as phosphatase inhibitors. Biochem. Pharmacol. 55, 2017–2022.PubMedGoogle Scholar
  46. 46.
    Matsuda, T., Takuma, K., and Baba, A. (1997) Na+-Ca2+ exchanger: physiology and pharmacology. Jpn. J. Pharmacol. 74, 1–20.PubMedGoogle Scholar
  47. 47.
    Racay, P., Kaplan, P., and Lehotsky, J. (1996) Control of Ca2+ homeostasis in neuronal cells. Gen. Physiol. Biophys. 15, 193–210.PubMedGoogle Scholar
  48. 48.
    Brandt, P. C. and Vanaman, T. C. (1998) Calmodulin and ion flux regulation, in Calmodulin and Signal Transduction (Van Eldik, L. J. and Watterson, D.M., eds.), Academic, San Diego, CA, pp. 397–471.Google Scholar
  49. 49.
    Carafoli, E. (1991) Calcium pump of the plasma membrane. Physiol. Rev. 71, 129–153.PubMedGoogle Scholar
  50. 50.
    Miller, R. J. (1991) The control of neuronal Ca2+ homeostasis. Prog. Neurobiol. 37, 255–285.PubMedGoogle Scholar
  51. 51.
    Simons, T. J. B. (1984) Active transpot of lead by human red blood cells. FEBS Lett. 172, 250–254.PubMedGoogle Scholar
  52. 52.
    Simons, T. J. B. (1988) Active transport of lead by the calcium pump in human red blood cells. J. Physiol. 405, 105–113.PubMedGoogle Scholar
  53. 53.
    Calderon-Salinas, J. V., Quintanar-Escorza, M. A., Hernandez-Luna, C. E., and Gonzalez-Martinez, M. T. (1999) Effect of lead on the calcium transport in human erythrocyte. Hum. Exp. Toxicol. 18, 146–153.PubMedGoogle Scholar
  54. 54.
    Mas-Oliva, J. (1989) Effect of lead on the erythrocyte (Ca2+, Mg2+)-ATPase activity. Calmodulin involvement. Mol. Cell. Biochem. 89, 87–93.PubMedGoogle Scholar
  55. 55.
    Duchen, M. R. (1999) Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death. J. Physiol. 516, 1–17.PubMedGoogle Scholar
  56. 56.
    Rizzuto, R., Pinton, P., Brini, M., Chiesa, A., Filippin, L., and Pozzan, T. (1999) Mitochondria as biosensors of calcium microdomains. Cell Calcium 26, 193–199.PubMedGoogle Scholar
  57. 57.
    Rutter, G. A. and Rizzuto, R. (2000) Regulation of mitochondrial metabolism by ER Ca2+ release: an intimate connection. Trends Biochem. Sci. 25, 215–221.PubMedGoogle Scholar
  58. 58.
    Wang, G. J. and Thayer, S. A. (1996) Sequestration of glutamate-induced Ca2+ loads by mitochondria in cultured rat hippocampal neurons. J. Neurophysiol. 76, 1611–1621.PubMedGoogle Scholar
  59. 59.
    Werth, J. L. and Thayer, S. A. (1994) Mitochondria buffer physiological calcium loads in cultured rat dorsal root ganglion neurons. J. Neurosci. 14, 348–356.PubMedGoogle Scholar
  60. 60.
    Colegrove, S. L., Albrecht, M. A., and Friel, D. D. (2000) Dissection of mitochondrial Ca2+ uptake and release fluxes in situ after depolarization-evoked [Ca2+]i elevations in sympathetic neurons. J. Gen. Physiol. 115, 351–369.PubMedGoogle Scholar
  61. 61.
    Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X. (1996) Induction of apoptotic program in cell-free extracts: requirements for dATP and cytochrome c. Cell 86, 147–157.PubMedGoogle Scholar
  62. 62.
    Smaili, S.S., Hus, Y.-T., Youle, R. J., and Russell, J. T. (2000) Mitochondria in Ca2+ signaling and apoptosis. J. Bioenerg. Biomembr. 32, 35–46.PubMedGoogle Scholar
  63. 63.
    Buratti, R., Prestipino, G., Menegazzi, P., Treves, S., and Zorzato, F. (1995) Calcium dependent activation of skeletal muscle Ca2+ release channel (ryanodine receptor) by calmodulin. Biochem. Biophys. Res. Commun. 213, 1082–1090.PubMedGoogle Scholar
  64. 64.
    Missiaen, L., Parys, J. B., Weidema, A. F., et al. (1999) The bell-shaped Ca2+ dependence of the inositol 1,4,5-trisphosphate-induced Ca2+ release is modulated by Ca2+/calmodulin. J. Biol. Chem. 274, 13,748–13,751.PubMedGoogle Scholar
  65. 65.
    Kodavanti, P. R. S., Ward, T. R., McKinney, J. D., and Tilson, H. A. (1996) Inhibition of microsomal and mitochondrial Ca2+ sequestration in rat cerebellum by polychlorinated biphenyl mixtures and congeners: structure-activity relationships. Arch. Toxicol. 70, 150–157.PubMedGoogle Scholar
  66. 66.
    Wong, P. W., Brackney, W. R., and Pessah, I. N. (1997) Ortho-substituted polychlorinated biphenyls alter microsomal calcium transport by direct interaction with ryanodine receptors of mammalian brain. J. Biol. Chem. 272, 15,145–15,153.PubMedGoogle Scholar
  67. 67.
    Kodavanti, P. R. S., Shin, D., Tilson, H. A., and Harry, G. J. (1993) Comparative effects of two polychlorinated biphenyl congeners on calcium homeostasis in rat cerebellar granule cells. Toxicol. Appl. Pharmacol. 123, 97–106.PubMedGoogle Scholar
  68. 68.
    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
  69. 69.
    Minta, A., Kao, J. P. Y., and Tsien, R. Y. (1989) Fluorescent indicators for cytosolic calcium based on rhodamine and fluorscein chromophores. J. Biol. Chem. 264, 8171–8178.PubMedGoogle Scholar
  70. 70.
    Hinkle, P. M., Shanshala, E. D., and Nelson, E. J. (1992) Measurement of intracellular cadmium with fluorescent dyes. Further evidence for the role of calcium channels in cadmium uptake. J. Biol. Chem. 267, 25,553–25,559.PubMedGoogle Scholar
  71. 71.
    Ferguson, C., Kern, M., and Audesirk, G. (2000) Nanomolar concentrations of inorganic lead increase Ca2+ efflux and decrease intracellular free Ca2+ ion concentrations in cultured rat hippocampal neurons by a calmodulin-dependent mechanism. NeuroToxicology 21, 365–378.PubMedGoogle Scholar
  72. 72.
    Dyatlov, V. A., Dyatlova, O. M., Parsons, P. J., Lawrence, D. A., and Carpenter, D. O. (1998) Lipopolysaccharide and interleukin-6 enhance lead entry into cerebellar neurons: application of a new and sensitive flow cytometric technique to measure intracellular lead and calcium concentrations. NeuroToxicology 19, 293–302.PubMedGoogle Scholar
  73. 73.
    He, L., Poblenz, A. T., Medrano, C. J., and Fox, D. A. (2000) Lead and calcium produce rod photoreceptor cell apoptosis by opening the mitochondrial permeability transition pore. J. Biol. Chem. 275, 12175–12184.PubMedGoogle Scholar
  74. 74.
    Arslan, P., DiVirgilio, F., Beltrame, M., Tsien, R. Y., and Pozzan, T. (1985) Cytosolic Ca2+ homeostasis in Ehrlich and Yoshida carcinomas. A new, membrane-permeant chelator of heavy metals reveals that these ascites tumor cell lines have normal cytosolic free Ca2+. J. Biol. Chem. 260, 2719–2727.PubMedGoogle Scholar
  75. 75.
    Halliwell, B. (1992) Reactive oxygen species and the central nervous system. J. Neurochem. 59, 1609–1623.PubMedGoogle Scholar
  76. 76.
    Kelly, S. A., Havrilla, C. M., Brady, T. C., Abramo, K. H., and Levin, E. D. (1998) Oxidative stress in toxicology: established mammalian and emerging piscine model systems. Environ. Health. Perspect. 106, 375–384.PubMedGoogle Scholar
  77. 77.
    Kowaltowski, A. J. and Vercesi, A. E. (1999) Mitochondrial damage induced by conditions of oxidative stress. Free Radical. Biol. Med. 26, 463–471.Google Scholar
  78. 78.
    Nicholls, D. G. and Budd, S. L. (2000) Mitochondria and neuronal survival. Physiol. Rev. 80, 315–360.PubMedGoogle Scholar
  79. 79.
    Olanow, C. W. (1993) A radical hypothesis for neurodegeneration. Trends Neurosci. 16, 439–444.PubMedGoogle Scholar
  80. 80.
    Sastre, J., Pallardo, F. V., Garcia de al Asuncion, J., and Vina, J. (2000) Mitochondria, oxidative stress and aging. Free Radical Res. 32, 189–198.Google Scholar
  81. 81.
    Johnson, R. M., Goyette, G., Jr., Ravindranath, Y., and Ho, Y.-S. (2000) Red cells from glutathione peroxidase-1-deficient mice have nearly normal defenses against endogenous peroxides. Blood 96, 1985–1988.PubMedGoogle Scholar
  82. 82.
    Dringen, R., Kussmaul, L., Gutterer, J. M., Hirrlinger, J., and Hamprecht, B. (1999) The glutathione system of peroxide detoxification is less efficient in neurons than in astroglial cells. J. Neurochem. 72, 2523–2530.PubMedGoogle Scholar
  83. 83.
    Halliwell, B., Zhao, K., and Whiteman, M. (1999) Nitric oxide and peroxynitrite. The ugly, the uglier and the not so good. Free Radical Res. 31, 651–669.Google Scholar
  84. 84.
    Murphy, M. P., Packer, M. A., Scarlett, J. L., and Martin, S. W. (1998) Peroxynitrite: a biologically significant oxidant. Gen. Pharmacol. 31, 179–186.PubMedGoogle Scholar
  85. 85.
    Di Donato, S. (2000) Disorders related to mitochondrial membranes: pathology of the respiratory chain and neurodegeneration. J. Inherit. Metab. Dis. 23, 247–263.PubMedGoogle Scholar
  86. 86.
    Pitkanen, S. and Robinson, B. H. (1996) Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J. Clin. Invest. 98, 345–351.PubMedGoogle Scholar
  87. 87.
    Capaldi, R. A. (2000) The changing face of mitochondrial research. Trends Biochem. Sci. 25, 212–214.PubMedGoogle Scholar
  88. 88.
    Murphy, A. N., Fiskum, G, and Beal, M. F. (1999) Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J. Cerebral Blood Flow Metab. 19, 231–245.Google Scholar
  89. 89.
    Bindokas, V. P., Jordan J., Lee, C. C., and Miller, R. J. (1996) Superoxide production in rat hippocampal neurons: sensitive imaging with ethidine. J. Neurosci. 16, 1324–1336.PubMedGoogle Scholar
  90. 90.
    Dugan, L. L., Sensi, S. L., Canzoniero, L. M. T., et al. (1995) Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-d-aspartate. J. Neurosci. 15, 6377–6388.PubMedGoogle Scholar
  91. 91.
    Nicholls, D. G. and Ward, M. W. (2000) Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts. Trends Neurosci. 23, 166–174.PubMedGoogle Scholar
  92. 92.
    Reynolds, I. J. and Hastings, T. G. (1995) Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J. Neurosci. 15, 3318–3327.PubMedGoogle Scholar
  93. 93.
    Patel, M., Day, B. J., Crapo, J. D., Fridovich, I., and McNamara, J. O. (1996) Requirement for superoxide in excitotoxic cell death. Neuron 16, 345–355.PubMedGoogle Scholar
  94. 94.
    Lipton, S. A. (1999) Neuronal protection and destruction by NO. Cell Death Differ. 6, 943–951.PubMedGoogle Scholar
  95. 95.
    Chiueh, C. C. and Rauhala, P. (1999) The redox pathway of S-nitrosoglutathione, glutathione and nitric oxide in cell to neuron communications. Free Radical Res. 31, 641–650.Google Scholar
  96. 96.
    Choi, Y.-B., Tenneti, L., Le, D. A., et al. (2000) Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neurosci. 3, 15–21.PubMedGoogle Scholar
  97. 96a.
    Liu, L. and Stamler, J. S. (1999) NO: an inhibitor of cell death. Cell Death Differ. 6, 937–942.PubMedGoogle Scholar
  98. 97.
    Beltran, B., Orsi, A., Clementi, E., and Moncada, S. (2000) Oxidative stress and S-nitrosylation of proteins in cells. Br. J. Pharmacol. 129, 953–960.PubMedGoogle Scholar
  99. 98.
    Heales, S. J. R., Bolanos, J. P., Stewart, V. C., Brookes, P. S., Land, J. M., and Clark, J. B. (1999) Nitric oxide, mitochondria and neurological disease. Biochim. Biophys. Acta 1410, 215–228.PubMedGoogle Scholar
  100. 99.
    Brookes, P. S., Bolanos, J. P., and Heales, S. J. R. (1999) The assumption that nitric oxide inhibits mitochondrial ATP synthesis is correct. FEBS Lett. 446, 261–263.PubMedGoogle Scholar
  101. 100.
    Tolias, C. M., McNeil, C. J., Kazlauskaite, J., and Hillhouse, E. W. (1999) Superoxide generation from constitutive nitric oxide synthase in astrocytes in vitro regulates extracellular nitric oxide availability. Free Radical Biol. Med. 26, 99–106.Google Scholar
  102. 101.
    Kitamura, Y., Matsuoka, Y., Nomura, Y., and Taniguchi, T. (1998) Induction of inducible nitric oxide synthase and heme oxygenase-1 in rat glial cells. Life Sci. 62, 1717–1721.PubMedGoogle Scholar
  103. 102.
    MacRitchie, A. N., Jun, S. S., Chen, Z., et al. (1997) Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ. Res. 81, 355–362.PubMedGoogle Scholar
  104. 103.
    Bredt, D. S., Ferris, C. D., and Snyder, S. H. (1992) Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase: identification of flavin and calmodulin binding sites. J. Biol. Chem. 267, 10,976–10,981.PubMedGoogle Scholar
  105. 104.
    Brune, B. and Lapetina, E. G. (1991) Phosphorylation of nitric oxide synthase by protein kinase A. Biochem. Biophys. Res. Commun. 181, 921–926.PubMedGoogle Scholar
  106. 105.
    Dinerman, J. L., Steiner, J. P., Dawson, T. M., Dawson, V., and Snyder, S. H. (1994) Cyclic nucleotide dependent phosphorylation of neuronal nitric oxide synthase inhibits catalytic activity. Neuropharmacology 33, 1245–1251.PubMedGoogle Scholar
  107. 106.
    Nakane, M., Mitchell, J., Forstermann, U., and Murad, F. (1991) Phosphorylation by calcium calmodulin-dependent protein kinase II and protein kinase C modulates the activity of nitric oxide synthase. Biochem. Biophys. Res. Commum. 180, 1396–1402.Google Scholar
  108. 107.
    Hu, J., Ferreira, A., and Van Eldik, L. J. (1997) S100beta induces neuronal cell death through nitric oxide release from astrocytes. J. Neurochem. 69, 2294–2301.PubMedGoogle Scholar
  109. 108.
    Stewart, V. C., Sharpe, M. A., Clark, J. B., and Heales, S. J. (2000). Astrocyte-derived nitric oxide causes both reversible and irreversible damage to the neuronal mitochondrial respiratory chain. J. Neurochem. 75, 694–700.PubMedGoogle Scholar
  110. 109.
    Dawson, V. L., Brahmbhatt, H. P., Mong, J. A., and Dawson, T. M. (1994) Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures. Neuropharmacology 33, 1425–1430.PubMedGoogle Scholar
  111. 110.
    Cardenas, A., Moro, M. A., Hurtado, O., et al. (2000). Implication of glutamate in the expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices. J. Neurochem. 74, 2041–2048.PubMedGoogle Scholar
  112. 111.
    Lecanu, L., Verrecchia, C., Margaill, I., Boulu, R. G., and Plotkine, M. (1998). iNOS contribution to the NMDA-induced excitotoxic lesion in the rat striatum. Br. J. Pharmacol. 125, 584–590.PubMedGoogle Scholar
  113. 112.
    Weingarten, P., Bermak, J., and Zhou, Q. Y. (2001). Evidence for non-oxidative dopamine cytotoxicity: potent activation of NF-kappa B and lack of protection by antioxidants. J. Neurochem. 76, 1794–1804.PubMedGoogle Scholar
  114. 113.
    Hunot, S., Brugg, B., Ricard, D., et al. (1997). Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with parkinson disease. Proc. Natl. Acad. Sci. USA 94, 7531–7536.PubMedGoogle Scholar
  115. 114.
    Seegers, H., Grillon, E., Trioullier, Y., Vath, A., Verna, J. M., and Blum, D. (2000). Nuclear factor-kappa B activation in permanent intraluminal focal cerebral ischemia in the rat. Neurosci. Lett. 288, 241–245.PubMedGoogle Scholar
  116. 115.
    Ying, W., Anderson, C. M., Chen, Y., et al. (2000) Differing effects of copper, zinc superoxide dismutase overexpression on neurotoxicity elicited by nitric oxide, reactive oxygen species, and excitotoxins. J. Cereb. Blood Flow Metab. 20, 359–368.PubMedGoogle Scholar
  117. 116.
    Dringen, R. and Hamprecht, B. (1997) Involvement of glutathione peroxidase and catalase in the disposal of exogenous hydrogen peroxide by cultured astroglial cells. Brain Res. 759, 67–75.PubMedGoogle Scholar
  118. 117.
    Bolanos J. P., Heales, S. J. R., Land, J. M., and Clark, J. B. (1995) Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurones and astrocytes in primary cultures. J. Neurochem. 64, 1965–1972.PubMedGoogle Scholar
  119. 118.
    Huang, J. and Philbert, M. A. (1995) Distribution of glutathione-related enzyme systems in mitochondria and cytosol of cultured cerebellar astrocytes and granule cells. Brain Res. 680, 16–22.PubMedGoogle Scholar
  120. 119.
    Philbert, M. A., Beiswanger, C. M., Manson, M. M., et al. (1995) Glutathione S-transferases and γ-glutamyl transpeptidase in the rat nervous system: a basis for differential susceptibility to neurotoxicants. NeuroToxicology 16, 349–362.PubMedGoogle Scholar
  121. 120.
    Barker, J. E., Bolanos, J. P., Land, J. M., Clark, J. B., and Heales, S. J. R. (1996) Glutathione protects astrocytes from peroxynitrite-mediated mitochondrial damage: implications for neuronal/astrocytic trafficking and neurodegeneration. Dev. Neurosci. 18, 391–396.PubMedGoogle Scholar
  122. 121.
    Wüllner, U., Seyfried, J., Groscurth, P., et al. (1999) Glutathione depletion and neuronal cell death: the role of reactive oxygen intermediates and mitochondrial function. Brain Res. 826, 53–62.PubMedGoogle Scholar
  123. 122.
    Holtzman, D., Shen Hsu, J., and Mortell, P. (1978) In vitro effects of inorganic lead on isolated rat brain mitochondrial respiration. Neurochem. Res. 3, 195–206.Google Scholar
  124. 123.
    Wielgus-Serafinska, E., Zawadzka A., and Falkus, B. (1980) The effect of lead acetate on rat liver mitochondria. Acta Physiol. Pol. 31, 659–668.PubMedGoogle Scholar
  125. 124.
    Holtzman, D., DeVries, C., Nguyen, H., Olson, J., and Bensch, K. (1984) Maturation of resistance to lead encephalopathy: cellular and subcellular mechanisms. NeuroToxicology 5, 97–124.PubMedGoogle Scholar
  126. 125.
    Holtzman, D., Olson, J. E., DeVries, C., and Bensch, K. (1987) Lead toxicity in primary cultured cerebral astrocytes and cerebellar granule neurons. Toxicol. Appl. Pharmacol. 89, 211–225.PubMedGoogle Scholar
  127. 126.
    Medrano, C. J., Shulman, L. M., and Fox, D. A. (1993) Lead-induced alterations in retinal energy metabolism. Toxicologist 13, 166.Google Scholar
  128. 127.
    Van Rossum, G. D., Kapoor, S. C., and Rabinowitz, M. S. (1985) Effects of inorganic lead in vitro on ion exchanges and respiratory metabolism of rat kidney cortex. Arch. Toxicol. 56, 175–181.PubMedGoogle Scholar
  129. 128.
    Schanne, F. A. X., Moskal, J. R., and Gupta, R. K. (1989) Effect of lead on intracellular free calcium ion concentration in a presynaptic neuronal model: 19F-NMR study of NG108-15 cells. Brain Res. 503, 308–311.PubMedGoogle Scholar
  130. 129.
    Quinlan, G. J., Halliwell, B., Moorhouse, C. P., and Gutteridge, J. M. (1988) Action of lead(II) and aluminum(III) ions on iron-stimulated lipid peroxidation in liposomes, erythrocytes and rat liver microsomal fractions. Biochim. Biophys. Acta 962, 196–200.PubMedGoogle Scholar
  131. 130.
    Bondy, S. C. and Guo, S. X. (1996) Lead potentiates iron-induced formation of reactive oxygen species. Toxicol. Lett. 87, 109–112.PubMedGoogle Scholar
  132. 131.
    Naarala, J. T., Loikkanen, J. J., Ruotsalainen, M. H., and Savolainen, K. M. (1995) Lead amplifies glutamate-induced oxidative stress. Free Radical Biol. Med. 19, 689–693.Google Scholar
  133. 132.
    Loikkanen, J. J., Naarala, J. T., and Savolainen, K. M. (1998) Modification of glutamate-induced oxidative stress by lead: the role of extracellular calcium. Free Radical Biol. Med. 24, 377–384.Google Scholar
  134. 133.
    Ariza, M. E., Bijur, G. N., and Williams, M. V. (1998) Lead and mercury mutagenesis: role of H2O2, superoxide dismutase, and xanthine oxidase. Environ. Mol. Mutagen. 31, 352–361.PubMedGoogle Scholar
  135. 134.
    Mylroie, A. A., Collins, H., Umbles, C., and Kyle, J. (1986) Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol. Appl. Pharmacol. 82, 512–520.PubMedGoogle Scholar
  136. 135.
    Narayanan, P. K., Carter, W. O., Ganey, P. E., Roth, R. A., Voytik-Harbin, S. L., and Robinson, J. P. (1998) Impairment of human neutrophil oxidative burst by polychlorinated biphenyls: inhibition of superoxide dismutase activity. J. Leukocyte Biol. 63, 216–224.PubMedGoogle Scholar
  137. 136.
    Ou, Y. C., White, C. C., Krejsa, C. M., Ponce, R. A., Kavanagh, T. J., and Faustman, E. M. (1999) The role of intracellular glutathione in methylmercury-induced toxicity in embryonic neuronal cells. NeuroToxicology 20, 793–804.PubMedGoogle Scholar
  138. 137.
    Campbell, A., Prasad, K. N., and Bondy, S. C. (1999) Aluminum-induced oxidative events in cell lines: glioma are more responsive than neuroblastoma. Free Radical Biol. Med. 26, 1166–1171.Google Scholar
  139. 138.
    Eysseric, H., Gonthier, B., Soubeyran, A., Richard, M. J., Daveloose, D., and Barret, L. (2000) Effects of chronic ethanol exposure on acetaldehyde and free radical production by astrocytes in culture. Alcohol 21, 117–125.PubMedGoogle Scholar
  140. 139.
    Jindal, V. and Gill, K. D. (1999) Ethanol potentiates lead-induced inhibition of rat brain antioxidant defense systems. Pharmacol. Toxicol. 85, 16–21.PubMedGoogle Scholar
  141. 140.
    Sandhir, R., Julka, D., and Gill, K. D. (1994) Lipoperoxidative damage on lead exposure in rat brain and its implications on membrane bound enzymes. Pharmacol. Toxicol. 74, 66–71.PubMedGoogle Scholar
  142. 141.
    Sugawara, E., Nakamura, K., Miyake, T., Fukumura, A., and Seki, Y. (1991) Lipid peroxidation and concentration of glutathione in erythrocytes from workers exposed to lead. Br. J. Ind. Med. 48, 239–242.PubMedGoogle Scholar
  143. 142.
    Adonaylo, V. N. and Oteiza, P. I. (1999) Lead intoxication: antioxidant defenses and oxidative damage in rat brain. Toxicology 135, 77–85.PubMedGoogle Scholar
  144. 143.
    Correa, M., Miquel, M., Sanchis-Segura, C., and Aragon, C. M. (1999) Effects of chronic lead administration on ethanol-induced locomotor and brain catalase activity. Alcohol 19, 43–49.PubMedGoogle Scholar
  145. 144.
    Legare, M. E., Barhoumi, R., Burghardt, R. C., and Tiffany-Castiglioni, E. (1993) Low-level lead exposure in cultured astroglia: identification of cellular targets with vital fluorescent probes. Neurotoxicology 14, 267–272.PubMedGoogle Scholar
  146. 145.
    Gonick, H. C., Ding, Y., Bondy, S. C., Ni, Z., and Vaziri, N. D. (1997) Lead-induced hypertension: interplay of nitric oxide and reactive oxygen species. Hypertension 30, 1487–1492.PubMedGoogle Scholar
  147. 146.
    Swanson, S. P. and Angle, C. R. (1995) Lead stimulates nitric oxide synthase of cultured cerebellar granule cells: another toxic manifestation due to activation of protein kinase C? Toxicologist 15, 9.Google Scholar
  148. 147.
    Mittal, C. K., Harrell, W. B., and Mehta, C. S. (1995) Interaction of heavy metal toxicants with brain constitutive nitric oxide synthase. Mol. Cell. Biochem. 149/150, 263–265.Google Scholar
  149. 148.
    Quinn, M. R. and Harris, C. L. (1995) Lead inhibits Ca2+-stimulated nitric oxide activity from rat cerebellum. Neurosci. Lett. 196, 65–68.PubMedGoogle Scholar
  150. 149.
    Shinyashiki, M., Kumagai, Y., Nakajima, H., et al. (1998) Differential changes in rat brain nitric oxide synthase in vivo and in vitro by methylmercury. Brain Res. 798, 147–155.PubMedGoogle Scholar
  151. 150.
    Eckhardt, W., Bellmann, K., and Kolb, H. (1999) Regulation of inducible nitric oxide synthase expression in β cells by environmental factors: heavy metals. Biochem. J. 338, 695–700.PubMedGoogle Scholar
  152. 151.
    Tian, L. and Lawrence, D. A. (1996) Metal-induced modulation of nitric oxide production in vitro by murine macrophages: lead, nickel and cobalt utilize different mechanisms. Toxicol. Appl. Pharmacol. 141, 540–547.PubMedGoogle Scholar
  153. 152.
    Dhouib, M. and Lugnier, A. (1996) Induction of nitric oxide synthase by chlorinated pesticides (p,p’-DDT, chlordane, endosulfan) in rat liver. Cent. Eur. J. Public Health 4(Suppl.), 48.PubMedGoogle Scholar
  154. 153.
    Craig, E. A., Weissman, J. S., and Horwich, A. L. (1994) Heat shock proteins and molecular chaperones: mediators of protein conformation and turnover in the cell. Cell 78, 365–372.PubMedGoogle Scholar
  155. 154.
    Ikeda, M., Komachi, H., Sato, I., Himi, T., Yuasa, T., Murota, S. (1999) Induction of neuronal nitric oxide synthase by methylmercury in the cerebellum. J. Neurosci. Res. 55, 352–356.PubMedGoogle Scholar
  156. 155.
    De Maio, A. (1999) Heat shock proteins: facts, thoughts and dreams. Shock 11, 1–12.PubMedGoogle Scholar
  157. 156.
    Welch, W. J. (1992) Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease. Physiol. Rev. 72, 1063–1081.PubMedGoogle Scholar
  158. 157.
    Welch, W. J. (1993) Heat shock proteins functioning as molecular chaperones: their roles in normal and stressed cells. Phil. Trans. R. Soc. Lond. B 339, 327–333.Google Scholar
  159. 158.
    Ang, D., Liberek, K., Skowyra, D., Zylicz, M., and Georgopoulos, C. (1991) Biological role and regulation of the universally conserved heat shock proteins. J. Biol. Chem. 266, 24,233–24,236.PubMedGoogle Scholar
  160. 159.
    Galbraith, R. (1999) Heme oxygenase: who needs it? Proc. Soc. Exp. Biol. Med. 222, 299–305.PubMedGoogle Scholar
  161. 160.
    Maines, M. D. (1997) The heme oxygenase system: a regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 37, 517–554.PubMedGoogle Scholar
  162. 161.
    Ryter, S. W. and Tyrrell, R. M. (2000) The heme synthesis and degradation pathways: role in oxidant sensitivity. Free Radical Biol. Med. 28, 289–309.Google Scholar
  163. 162.
    Alam, J. (1994) Multiple elements within the 5′ distal enhancer of the mouse heme oxygenase-1 gene mediate induction by heavy metals. J. Biol. Chem. 269, 25,049–25,056.PubMedGoogle Scholar
  164. 163.
    Elbirt, K. K. and Bonkovsky, H. L. (1999) Heme oxygenase: recent advances in understanding its regulation and role. Proc. Assoc. Am. Physicians 111, 438–447.PubMedGoogle Scholar
  165. 164.
    Lavrovsky, Y., Schwartzman, M. L., Levere, R. D., Kappas, A., and Abraham, N. G. (1994) Identification of binding sites for transcription factors NF-B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc. Natl. Acad. Sci. USA 91, 5987–5991.PubMedGoogle Scholar
  166. 165.
    Vincent, S. R., Das, S., and Maines, M. D. (1994) Brain heme oxygenase isoenzymes and nitric oxide synthase are co-localized in select neurons. Neuroscience 63, 223–231.PubMedGoogle Scholar
  167. 166.
    Nakaso, K., Kitayama, M., Fukuda, H., et al. (2000) Oxidative stress-related proteins A170 and heme oxygenase-1 are differently induced in the rat cerebellum under kainate-mediated excitotoxicity. Neurosci. Lett. 282, 57–60.PubMedGoogle Scholar
  168. 167.
    Nakaso, K., Kitayama, M., Fukuda, H., et al. (1999) Induction of heme oxygenase-1 in the rat brain by kainic acid-mediated excitotoxicity: the dissociation of mRNA and protein expression in the hippocampus. Biochem. Biophys. Res. Comm. 259, 91–96.PubMedGoogle Scholar
  169. 168.
    Ewing, J. F., Haber, S. N., and Maines, M. D. (1992) Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: hyperthermia causes rapid induction of mRNA and protein. J. Neurochem. 58, 1140–1149.PubMedGoogle Scholar
  170. 169.
    Gissel, C., Doutheil, J., and Paschen, W. (1997) Activation of heme oxygenase-1 expression by disturbance of endoplasmic reticulum calcium homeo-stasis in rat neuronal culture. Neurosci. Lett. 231, 75–78.PubMedGoogle Scholar
  171. 170.
    Linden, T., Doutheil, J., and Paschen, W. (1998) Role of calcium in the activation of erp72 and heme oxygenase-1 expression on depletion of endoplasmic reticulum calcium stores in rat neuronal cell culture. Neurosci. Lett. 247, 103–106.PubMedGoogle Scholar
  172. 171.
    Dwyer, B. E., Nishimura, R. N., Lu, S.-Y., and Alcaraz, A. (1996) Transient induction of heme oxygenase after cortical stab wound injury. Mol. Brain Res. 38, 251–259.PubMedGoogle Scholar
  173. 172.
    Ewing, J. F. and Maines, M. D. (1991) Rapid induction of heme oxygenase mRNA and protein by hyperthermia in rat brain: Heme oxygenase 2 is not a heat shock protein. Proc. Natl. Acad. Sci. USA 88, 5364–5368.PubMedGoogle Scholar
  174. 173.
    McCoubrey, W. K., Huang, T. J., and Maines, M. D. (1997) Isolation and characterization of a cDNA from the rat brain the encodes hemoprotein heme oxygenase-3. Eur. J. Biochem. 247, 725–732.PubMedGoogle Scholar
  175. 174.
    Le, W.-D., Xie, W.-J., and Appel, S. H. (1999) Protective role of heme oxygenase-1 in oxidative stress-induced neuronal injury. J. Neurosci. Res. 56, 652–658.PubMedGoogle Scholar
  176. 175.
    Dwyer, B. E., Nishimura, R. N., and Lu, S.-Y. (1995) Differential expression of heme oxygenase-1 in cultured neurons and astrocytes determined by the aid of a new heme oxygenase antibody. Response to oxidative stress. Mol. Brain Res. 30, 37–47.PubMedGoogle Scholar
  177. 176.
    Foresti, R., Sarathchandra, P., Clark, J. E., Green, C. J., and Motterlini, R. (1999) Peroxynitrite induces haem oxygenase-1 in vascular endothelial cells: a link to apoptosis. Biochem. J. 339, 729–736.PubMedGoogle Scholar
  178. 177.
    Dennery, P. A., Sridhar, K. J., Lee, C. S., et al. (1997) Heme oxygenase-mediated resistance to oxygen toxicity in hamster fibroblasts. J. Biol. Chem. 272, 14,937–14,942.PubMedGoogle Scholar
  179. 178.
    Otterbein, L. E., Kolls, J. K., Mantell, L. L., Cook, J. L., Alam, J., and Choi, A. M. K. (1999) Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J. Clin. Invest. 103, 1047–1054.PubMedGoogle Scholar
  180. 179.
    Suttner, D. M. and Dennery, P. A. (1999) Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB J. 13, 1800–1809.PubMedGoogle Scholar
  181. 180.
    Ewing, J. F. and Maines, M. D. (1993) Glutathione depletion induces heme oxygenase-1 (HSP32) mRNA and protein in rat brain. J. Neurochem. 60, 1512–1519.PubMedGoogle Scholar
  182. 181.
    Abraham, N. G., Lavrovsky, Y., Schwartzman, M. L., et al. (1995) Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity. Proc. Natl. Acad. Sci. USA 92, 6798–6802.PubMedGoogle Scholar
  183. 182.
    Regan, R. F., Guo, Y., and Kumar, N. (2000) Heme oxygenase-1 induction protects murine cortical astrocytes from hemoglobin toxicity. Neurosci. Lett. 282, 1–4.PubMedGoogle Scholar
  184. 183.
    Hegazy, K. A., Dunn, M. W., and Sharma, S. C. (2000) Functional human heme oxygenase has a neuroprotective effect on adult rat ganglion cells after pressure-induced ischemia. NeuroReport 11, 1185–1189.PubMedGoogle Scholar
  185. 184.
    Takeda, A., Perry, G., Abraham, N. G., et al. (2000) Overexpression of heme oxygenase in neuronal cells, the possible interaction with tau. J. Biol. Chem. 275, 5395–5399.PubMedGoogle Scholar
  186. 185.
    Panahian, N., Yoshiura, M., and Maines, M. D. (1999) Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. J. Neurochem. 72, 1187–1203.PubMedGoogle Scholar
  187. 186.
    Chen, K., Gunter, K., and Maines, M. D. (2000a) Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. J. Neurochem. 75, 304–313.PubMedGoogle Scholar
  188. 187.
    Poss, K. D. and Tonegawa, S. (1997b) Reduced stress defense in heme oxygenase 1-deficient cells. Proc. Natl. Acad. Sci. USA 94, 10,925–10,930.PubMedGoogle Scholar
  189. 188.
    Eisenstein, R. S., Garcia, M. D., Pettingell, W., and Munro, H. N. (1991) Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proc. Natl. Acad. Sci. USA 88, 688–692.PubMedGoogle Scholar
  190. 189.
    Ferris, C. D., Jaffrey, S. R., Sawa, A., et al. (1999) Haem oxygenase-1 prevents cell death by regulating cellular iron. Nature Cell Biol. 1, 152–157.PubMedGoogle Scholar
  191. 190.
    Minetti, M., Mallozzi, C., DiStasi, A. M. M., and Pietraforte, D. (1998) Bilirubin is an effective antioxidant of peroxynitrite-mediated protein oxidation in human blood plasma. Arch. Biochem. Biophys. 352, 165–174.PubMedGoogle Scholar
  192. 191.
    Stocker, R., Yamamoto Y., McDonagh, A. F., Glazer, A. N., and Ames, B. N. (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235, 1043–1046.PubMedGoogle Scholar
  193. 192.
    Neuzil J., and Stocker, R. (1993) Bilirubin attenuates radical-mediated damage to serum albumin. FEBS Lett. 331, 281–284.PubMedGoogle Scholar
  194. 193.
    Dore, S., Takahashi, M., Ferris, C. D., Hester, L. D., Guastella, D., and Snyder, S. H. (1999) Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc. Natl. Acad. Sci. USA 96, 2445–2450.PubMedGoogle Scholar
  195. 194.
    Lee, A. S. (1987) Coordinated regulation of a set of genes by glucose and calcium ionophores in mammalian cells. Trends Biochem. Sci. 12, 20–23.Google Scholar
  196. 195.
    Lee, A. S. (1992) Mammalian stress response: induction of the glucose-regulated protein family. Curr. Opin. Cell Biol. 4, 267–273.PubMedGoogle Scholar
  197. 196.
    Wang, S., Longo, F. M., Chen, J., et al. (1993) Induction of glucose regulated protein (grp78) and inducible heat shock protein (hsp70) mRNAs in rat brain after kainic acid seizures and focal ischemia. Neurochem. Int. 23, 575–582.PubMedGoogle Scholar
  198. 197.
    Li, W. W., Alexandre, S., Cao, X., and Lee, A. S. (1993) Transactivation of the grp78 promoter by Ca2+ depletion: a comparative analysis with A23187 and the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. J. Biol. Chem. 268, 12,003–12,009.PubMedGoogle Scholar
  199. 198.
    Stevens, J. L., Liu, H., Halleck, M., Bowes, R. C., Chen, Q. M., and van de Water, B. (2000) Linking gene expression to mechanisms of toxicity. Toxicol. Lett. 112–113, 479–486.PubMedGoogle Scholar
  200. 199.
    Chen, L. Y., Chiang, A. S., Hung, J. J., Hung, H. I., and Lai, Y. K. (2000) Thapsigargin-induced grp78 expression is mediated by the increase of cytosolic free calcium in 9L rat brain tumor cells. J. Cell. Biochem. 78, 404–416.PubMedGoogle Scholar
  201. 200.
    Yang, Y., Turner, R. S., and Gaut, J. R. (1998) The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Aβ40 and Aβ42 secretion. J. Biol. Chem. 273, 25,552–25,555.PubMedGoogle Scholar
  202. 201.
    Yu, Z., Luo, H., Fu, W., and Mattson, M. P. (1999) The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis: suppression of oxidative stress and stabilization of calcium homeostasis. Exp. Neurol. 155, 302–314.PubMedGoogle Scholar
  203. 202.
    Opanashuk, L. A. and Finkelstein, J. N. (1995) Induction of newly synthesized proteins in astroglial cells exposed to lead. Toxicol. Appl. Pharmacol. 131, 21–30.PubMedGoogle Scholar
  204. 203.
    Opanashuk, L. A., and Finkelstein, J. N. (1995) Relationship of lead-induced proteins to stress response proteins in astroglial cells. J. Neurosci. Res. 42, 623–632.PubMedGoogle Scholar
  205. 204.
    Audesirk, G., Ferguson, C. A., Kern, M., and Cabell, L. (1997) Cultured rat hippocampal neurons and astrocytes differ greatly in the induction of protein synthesis by inorganic lead. Soc. Neurosci. Abstracts 23, 2209.Google Scholar
  206. 205.
    Qian, Y., Harris, E. D., Zheng, Y., and Tiffany-Castiglioni, E. (2000) Lead targets GRP78, a molecular chaperone, in C6 rat glioma cells. Toxicol. Appl. Pharmacol. 163, 260–266.PubMedGoogle Scholar
  207. 206.
    Tully, D. B., Collins, B. J., Overstreet, J. D., et al. (2000) Effects of arsenic, cadmium, chromium, and lead on gene expression regulated by a battery of 13 different promoters in recombinant HepG2 cells. Toxicol. Appl. Pharmacol. 168, 79–90.PubMedGoogle Scholar
  208. 207.
    Ferguson, C., Kern, M., and Audesirk, G. (2000) Nanomolar concentrations of inorganic lead increase Ca2+ efflux and decrease intracellular free Ca2+ ion concentrations in cultured rat hippocampal neurons by a calmodulin-dependent mechanism. NeuroToxicology 21, 365–378.PubMedGoogle Scholar
  209. 208.
    Timblin, C. R., Janssen, Y. M., Goldberg, J. L., and Mossman, B. T. (1998) GRP78, HSP72/73, and cJun stress protein levels in lung epithelial cells exposed to asbestos, cadmium, or H2O2. Free Radical Biol. Med. 24, 632–642.Google Scholar
  210. 209.
    Miles, M. F., Wilke, N., Elliot, M., Tanner, W., and Shah, S. (1994) Ethanol-reponsive genes in neural cells include the 78-kilodalton glucose-regulated protein (GRP78) and the 94-kilodalton glucose-regulated protein (GRP94) molecular chaperones. Mol. Pharmacol. 46, 873–879.PubMedGoogle Scholar
  211. 210.
    Tunici, P., Schiaffonati, L., Rabellotti, E., Tiberio, L., Perin, A., and Sessa, A. (1999) In vivo modulation of 73 kDa heat shock cognate and 78 kDa glucose-regulating protein gene expression in rat liver and brain by ethanol. Alcohol Clin. Exp. Res. 23, 1861–1867.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2004

Authors and Affiliations

  • Gerald J. Audesirk
    • 1
  • Ronald B. Tjalkens
    • 2
    • 3
  1. 1.Department of BiologyUniversity of Colorado at DenverDenver
  2. 2.Department of Veterinary Anatomy and Public Health, College of Veterinary MedicineTexas A&M UniversityCollege Station
  3. 3.Center for Environmental and Rural HealthCollege Station

Personalised recommendations