The Role of Glial Nitric Oxide in Neurotoxicity and Central Nervous System Diseases

  • Kathleen M. K. Boje
Part of the Contemporary Neuroscience book series (CNEURO)


Neuroglia (“nerve glue”) were first identified in the late 1800s, and were so named because these cells surrounded neurons. Today it is recognized that these cells are not simply “packing material” for neurons, but serve in many important capacities. Glia facilitate neuronal migration during development, assist in the maintenance of the neuronal milieu for normal neurotransmission, produce neurotrophic factors, participate in immunological responses within the central nervous system (CNS), and surround the brain microvasculature to constitute the blood-brain barrier (1–3). Glia differ from their neuronal counterparts in that glia compose 20–50% of the total brain volume, possess nonsynapsing cellular extensions, and retain the ability to replicate. Glia can be classified into three broad categories: astrocytes (both fibrous and protoplasmic), microglia, and oligodendroglia. Each of these types can be subdivided into finer distinctions, depending on morphological and functional specifications (1,2,4).


Nitric Oxide Nitric Oxide Experimental Autoimmune Encephalomyelitis Experimental Allergic Encephalomyelitis Human Astrocyte 
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.
    Montgomery, D. L. (1994) Astrocytes: Form, functions, and roles in disease. Vet. Pathol. 31, 145–167.PubMedCrossRefGoogle Scholar
  2. 2.
    Frohman, E. M., Van Den Noort, S., and Gupta, S. (1989) Astrocytes and intra-cerebral immune responses. J. Clin. Immunol. 9 (1), 1–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Merrill, J. E. and Jonakait, G. M. (1995) Interactions of the nervous and immune systems in development, normal brain homeostasis, and disease. FASEB J. 9, 611–618.PubMedGoogle Scholar
  4. 4.
    Raine, C. S. (1989) Neurocellular anatomy, in Basic Neurochemistry: Molecular, Cellular, and Medical Aspects ( Siegel, G. J., Agranoff, B., Albers, R. W., and Molinoff, P. eds.), Raven, New York, pp. 3–33.Google Scholar
  5. 5.
    Frei, K. and Fontana, A. (1989) Immune regulatory functions of astrocytes and microglial cells within the central nervous system, in Neuroimmune Networks: Physiology and Diseases ( Goetzl, E. J. and Spector, N. H., ed.), Alan R. Liss, New York, pp. 127–136.Google Scholar
  6. 6.
    Fierz, W. and Fontana, A. (1986) The role of astrocytes in the interaction between the immune and nervous system, in Astrocytes: Cell Biology and Pathology of Astrocytes, vol. 3. ( Fedoroff, S. and Vernadakis, A., eds.), Academic, Orlando, FL, pp. 203–229.Google Scholar
  7. 7.
    Gehrmann, J., Matsumoto, Y., and Kreutzberg, G. W. (1995) Microglia: Intrinsic immuneffector cell of the brain. Brain Res. Rev. 20, 269–287.PubMedCrossRefGoogle Scholar
  8. 8.
    Mucke, L. and Eddleston, M. (1993) Astrocytes in infectious and immune-mediated diseases of the central nervous system. FASEB J. 7, 1226–1232.PubMedGoogle Scholar
  9. 9.
    Owens, T., Renno, T., Taupin, V., and Krakowski, M. (1994) Inflammatory cytokines in the brain: Does the CNS shape immune responses? Immunol. Today 15 (12), 566–570.PubMedCrossRefGoogle Scholar
  10. 10.
    Eddleston, M. and Mucke, L. (1993) Molecular profile of reactive astrocytesimplication for their role in neurologic disease. Neuroscience 54 (1), 15–36.PubMedCrossRefGoogle Scholar
  11. 11.
    Malhotra, S. K., Shnitka, T. K., and Elbrink, J. (1990) Reactive astrocytes-a review. Cytobios 61, 133–160.PubMedGoogle Scholar
  12. 12.
    Boje, K. M. and Arora, P. K. (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res. 587 (2), 250–256.PubMedCrossRefGoogle Scholar
  13. 13.
    Chao, C. C., Hu, S., Molitor, T. W., Shaskan, E. G., and Peterson, P. K. (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J. Immunol. 149 (8), 2736–2741.PubMedGoogle Scholar
  14. 14.
    Galea, E., Feinstein, D. L., and Reis, D. J. (1992) Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc. Natl. Acad. Sci. USA 89(22), 10,945–10, 949.Google Scholar
  15. 15.
    Simmons, M. L. and Murphy, S. (1992) Induction of nitric oxide synthase in glial cells. J. Neurochem. 59 (3), 897–905.PubMedCrossRefGoogle Scholar
  16. 16.
    Zielasek, J., Tausch, M., Toyka, K. V., and Hartung, H.-P. (1992) Production of nitrite by neonatal rat microglial cells/brain macrophages. Cell Immunol. 141, 111–120.PubMedCrossRefGoogle Scholar
  17. 17.
    Schmidt, H. H. H. W. and Walter, U. (1994) NO at work. Cell 78, 919–928.PubMedCrossRefGoogle Scholar
  18. 18.
    Dawson, T. M. and Dawson, V. L. (1995) Nitric oxide: actions and pathological roles. The Neuroscientist 1 (1), 7–18.CrossRefGoogle Scholar
  19. 19.
    Forstermann, U., Gath, I., Schwarz, P., Closs, E. I., and Kleinert, H. (1995) Isoforms of nitric oxide synthase: properties, cellular distribution and expressional control. Biochem. Pharmacol. 50 (9), 1321–1332.PubMedCrossRefGoogle Scholar
  20. 20.
    Kerwin, J. F. and Heller, M. (1994) The arginine-nitric oxide pathway: a target for new drugs. Med. Res. Rev. 14 (1), 23–74.PubMedCrossRefGoogle Scholar
  21. 21.
    Moncada, S. and Higgs, E. A. (1995) Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J. 9 (13), 1319–1330.PubMedGoogle Scholar
  22. 22.
    Nathan, C. and Xie, Q. W. (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78 (6), 915–918.PubMedCrossRefGoogle Scholar
  23. 23.
    Kobzik, L., Reid, M. B., Bredt, D. S., and Stamler, J. S. (1994) Nitric oxide in skeletal muscle. Nature 372(6506), 546–548.Google Scholar
  24. 24.
    Dinerman, J. L., Dawson, T. M., Schell, D. J., Snowman, A., and Snyder, S. H. (1994) Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: implications for synaptic plasticity. Proc. Natl. Acad. Sci. USA 91 (10), 4214–4218.PubMedCrossRefGoogle Scholar
  25. 25.
    MacNaul, K. L. and Hutchinson, N. I. (1993) Differential expression of iNOS and cNOS mRNA in human vascular smooth muscle cells and endothelial cells under normal and inflammatory conditions. Biochem. Biophys. Res. Commun. 196 (3), 1330–1334.PubMedCrossRefGoogle Scholar
  26. 26.
    Agullo, L. and Garcia, A. (1992) Different receptors mediate stimulation of nitric oxide-dependent cyclic GMP formation in neurons and astrocytes in culture. Biochem. Biophys. Res. Commun. 182 (3), 1362–1368.PubMedCrossRefGoogle Scholar
  27. 27.
    Agullo, L., Baltrons, M. A., and Garcia, A. (1995) Calcium-dependent nitric oxide formation in glial cells. Brain Res. 686 (2), 160–168.PubMedCrossRefGoogle Scholar
  28. 28.
    Egberongbe, Y. I., Gentleman, S. M., Falkai, P., Bogerts, B., Polak, J. M., and Roberts, G. W. (1994) The distribution of nitric oxide synthase immunoreactivity in the human brain. Neuroscience 59(3), 561–578.Google Scholar
  29. 29.
    Kugler, P. and Drenckhahn, D. (1996) Astrocytes and bergmann glia as an important site of nitric oxide synthase I. Glia 16 (2), 165–173.PubMedCrossRefGoogle Scholar
  30. 30.
    Murphy, S., Minor, R. L., Jr., Welk, G., and Harrison, D. G. (1990) Evidence for an astrocyte-derived vasorelaxing factor with properties similar to nitric oxide. J. Neurochem. 55 (1), 349–351.PubMedCrossRefGoogle Scholar
  31. 31.
    Boje, K. M. and Skolnick, P. (1992) Nitric oxide does not mediate the neurotrophic effects of excitatory amino acids in cultured cerebellar granule neurons. Eur. J. Pharmacol. 212 (2–3), 151–158.PubMedCrossRefGoogle Scholar
  32. 32.
    Boje, K. M. and Fung, H. L. (1990) Endothelial nitric oxide generating enzyme(s) in the bovine aorta: subcellular location and metabolic characterization. J. Pharmacol. Exp. Ther. 253 (1), 20–26.PubMedGoogle Scholar
  33. 33.
    Hiki, K., Hattori, R., Kawai, C., and Yui, Y. (1992) Purification of insoluble nitric oxide synthase from rat cerebellum. J. Biochem. 111 (5), 55–68.Google Scholar
  34. 34.
    Michel, T., Li, G. K., and Busconi, L. (1993) Phosphorylation and subcellular translocation of endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 90 (13), 6252–6256.PubMedCrossRefGoogle Scholar
  35. 35.
    Pollock, J. S., Forstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H. H. W., Nakane, M., and Murad, F. (1991) Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc. Natl. Acad. Sci. USA 88(23), 10,480–10, 488.Google Scholar
  36. 36.
    Sessa, W. C., Barber, C. M., and Lynch, K. R. (1993) Mutation of N-myristoylation site converts endothelial cell nitric oxide synthase from a membrane to a cytosolic protein. Circ. Res. 72 (4), 921–924.PubMedCrossRefGoogle Scholar
  37. 37.
    Hevel, J. M., White, K. A., Marletta, M. A. (1991) Purification of the inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein. J. Biol. Chem. 266(34), 22,789–22, 791.Google Scholar
  38. 38.
    Stuehr, D. J., Cho, H. J., Kwon, N. S., Weise, M. F., and Nathan, C. F. (1991) Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc. Natl. Acad. Sci. USA 88 (17), 7773–7777.PubMedCrossRefGoogle Scholar
  39. 39.
    Wood, P. L., Choksi, S., and Bocchini, V. (1994) Inducible microglial nitric oxide synthase: a large membrane pool. Neuroreport 5 (8), 977–980.PubMedCrossRefGoogle Scholar
  40. 40.
    Nathan, C. and Xie, Q. W. (1994) Regulation of biosynthesis of nitric oxide. J. Biol. Chem. 269(19), 13,725–13, 728.Google Scholar
  41. 41.
    Bredt, D. S., Hwang, P. M., Glatt, C. E., Lowenstein, C., Reed, R. R., and Snyder, S. H. (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351(6329), 714–718.Google Scholar
  42. 42.
    Xie, Q. W., Cho, H. J., Calaycay, J., Mumford, R. A., Swiderek, K. M., Lee, T. D., Ding, A., Troso, T., and Nathan, C. (1992) Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256 (5054), 225–228.PubMedCrossRefGoogle Scholar
  43. 43.
    Cho, H. J., Xie, Q. W., Calaycay, J., Mumford, R. A., Swiderek, K. M., Lee, T. D., and Nathan, C. (1992) Calmodulin is a subunit of nitric oxide synthase from macrophages. J. Exp. Med. 176 (2), 599–604.PubMedCrossRefGoogle Scholar
  44. 44.
    Galea, E., Reis, D. J., and Feinstein, D. L. (1994) Cloning and expression of inducible nitric oxide synthase from rat astrocytes. J. Neurosci. Res. 37 (3), 406–414.PubMedCrossRefGoogle Scholar
  45. 45.
    Bloch, K. D., Wolfram, J. R., Brown, D. M., Roberts, J. D., Jr., Zapol, D. G., Lepore, J. J., Filippov, G., Thomas, J. E., Jacob, H. J., and Bloch, D. B. (1995) Three members of the nitric oxide synthase II gene family (NOS2A, NOS2B, and NOS2C) colocalize to human chromosome 17. Genomics 27 (3), 526–530.PubMedCrossRefGoogle Scholar
  46. 46.
    Marletta, M. A. (1994) Nitric oxide synthase: aspects concerning structure and catalysis. Cell 78 (6), 927–930.PubMedCrossRefGoogle Scholar
  47. 47.
    Korytko, P. J. and Boje, K. M. K. (1996) Pharmacological characterization of nitric oxide production in a rat model of meningitis. Neuropharmacology 35, 231–237.PubMedCrossRefGoogle Scholar
  48. 48.
    Olken, N. M. and Marletta, M. A. (1993) NG-methyl-L-arginine functions as an alternate substrate and mechanism-based inhibitor of nitric oxide synthase. Biochemistry 32 (37), 9677–9685.PubMedCrossRefGoogle Scholar
  49. 49.
    Olken, N. M., Osawa, Y., and Marletta, M. A. (1994) Characterization of the inactivation of nitric oxide synthase by NG-methyl-L--arginine: evidence for heme loss. Biochemistry 33(49), 14, 784–14, 791.Google Scholar
  50. 50.
    Rengasamy, A. and Johns, R. A. (1993) Regulation of nitric oxide synthase by nitric oxide. Mol. Pharmacol. 44 (1), 124–128.PubMedGoogle Scholar
  51. 51.
    Colasanti, M., Persichini, T., Menegazzi, M., Mariotto, S., Giordano, E., Caldarera, C. M., Sogos, V., Lauro, M., and Suzuki, M. (1995) Induction of nitric oxide synthase mRNA expression. Suppression by exogenous nitric oxide. J. Biol. Chem. 270(45), 26,731–26, 733.Google Scholar
  52. 52.
    Arnelle, D. R. and Stamler, J. S. (1995) NO+, NO, and NO- donation by Snitrosothiols: implications for regulation of physiological functions by S-nitrosylation and acceleration of disulfide formation. Arch. Biochem. Biophys. 318 (2), 279–285.PubMedCrossRefGoogle Scholar
  53. 53.
    Beckman, J. S., Chen, J., Crow, J. P., and Ye, Y. Z. (1994) Reactions of nitric oxide, superoxide and peroxynitrite with superoxide dismutase in neurodegeneration. Prog. Brain Res. 103, 371–380.PubMedCrossRefGoogle Scholar
  54. 54.
    Crow, J. P. and Beckman, J. S. (1995) The role of peroxynitrite in nitric oxide-mediated toxicity. Curr. Topics Microbiol. Immunol. 196, 57–73.CrossRefGoogle Scholar
  55. 55.
    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 (11), 1425–1430.PubMedCrossRefGoogle Scholar
  56. 56.
    Merrill, J. E., Ignarro, L. J., Sherman, M. P., Melinek, J., and Lane, T.E. (1993) Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 151 (4), 2132–2141.PubMedGoogle Scholar
  57. 57.
    Boje, K. M. K. (1995) Inhibition of nitric oxide synthase partially attenuates alterations in the blood-cerebrospinal fluid barrier during experimental meningitis in the rat. Eur. J. Pharmacol. 272 (2–3), 297–300.PubMedCrossRefGoogle Scholar
  58. 58.
    Boje, K. M. K. (1996) Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis. Brain Res. 720, 75–83.PubMedCrossRefGoogle Scholar
  59. 59.
    Borgerding, R. A. and Murphy, S. (1995) Expression of inducible nitric oxide synthase in cerebral endothelial cells is regulated by cytokine-activated astrocytes. J. Neurochem. 65 (3), 1342–1347.PubMedCrossRefGoogle Scholar
  60. 60.
    Mitrovic, B., Ignarro, L. J., Montestruque, S., Smoll, A., and Merrill, J. E. (1994) Nitric oxide as a potential pathological mechanism in demyelination: its differential effects on primary glial cells in vitro. Neuroscience 61 (3), 575–585.PubMedCrossRefGoogle Scholar
  61. 61.
    Mitrovic, B., Ignarro, L. J., Vinters, H. V., Akers, M. A., Schmid, I., Uittenbogaar, T. C., and Merrill, J. E. (1995) Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes. Neuroscience 65 (2), 531–539.PubMedCrossRefGoogle Scholar
  62. 62.
    Stamler, J. S. (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78 (6), 931–936.PubMedCrossRefGoogle Scholar
  63. 63.
    Stamler, J. S., Singel, D. J., and Loscalzo, J. (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258, 1898–1902.PubMedCrossRefGoogle Scholar
  64. 64.
    Stamler, J. S. (1995) S-nitrosothiols and the bioregulatory actions of nitrogen oxides through reactions with thiol groups. Curr. Topics Microbiol. Immunol. 196, 19–36.CrossRefGoogle Scholar
  65. 65.
    Lipton, S. A., Singel, D. J., and Stamler, J. S. (1994) Neuroprotective and neuro-destructive effects of nitric oxide and redox congeners. Ann NY Acad. Sci. 738, 382–387.PubMedCrossRefGoogle Scholar
  66. 66.
    Chao, C. C., Hu, S., and Peterson, P. K. (1995) Modulation of human microglial cell superoxide production by cytokines. J. Leukocyte Biol. 58 (1), 65–70.PubMedGoogle Scholar
  67. 67.
    Colton, A. C. and Gilbert, D. L. (1987) Production of superoxide by a CNS macrophage, the microglia. FEBS Lett. 233, 284–288.CrossRefGoogle Scholar
  68. 68.
    Hu, S. X., Sheng, W. S., Peterson, P. K., and Chao, C. C. (1995) Cytokine modulation of murine microglial cell superoxide production. Glia 13 (1), 45–50.PubMedCrossRefGoogle Scholar
  69. 69.
    Beckman, J. S. (1994) Peroxynitrite versus hydroxyl radical: the role of nitric oxide in superoxide-dependent cerebral injury. Ann NY Acad. Sci. 738, 69–75.PubMedCrossRefGoogle Scholar
  70. 70.
    Ischiropoulos, H., Zhu, L., and Beckman, J. S. (1992) Peroxynitrite formation from macrophage-derived nitric oxide. Arch. Biochem. Biophys. 298 (2), 446–451.PubMedCrossRefGoogle Scholar
  71. 71.
    Bolanos, J. P., Peuchen, S., Heales, S. J., Land, J. M., and Clark, J. B. (1994) Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J. Neurochem. 63 (3), 910–916.PubMedCrossRefGoogle Scholar
  72. 72.
    Brown, G. C., Bolanos, J. P., Heales, S., and Clark, J. B. (1995) Nitric oxide produced by activated astrocytes rapidly and reversibly inhibits cellular respiration. Neurosci. Lett. 193 (3), 201–204.PubMedCrossRefGoogle Scholar
  73. 73.
    Drapier, J.-C. and Hibbs, J. B. J. (1988) Differentiation of murine macrophages to express nonspecific cytoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrphage effector cells. J. Immunol. 140, 2829–2838.PubMedGoogle Scholar
  74. 74.
    Hibbs, J. B. J., Taintor, R. R., Vavrin, Z., and Rachlin, E. M. (1988) Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem. Biophys. Res. Commun. 157, 87–94.PubMedCrossRefGoogle Scholar
  75. 75.
    Dimmeler, S., Lottspeich, F., and Brune, B. (1992) Nitric oxide causes ADP-ribosylation and inhibition of glyceraldehyde-3–phosphate dehydrogenase. J. Biol. Chem. 267(24), 16,771–16, 774.Google Scholar
  76. 76.
    Curran, R. D., Ferrari, F. K., Kispert, P. H., Stadler, J., Stuehr, D. J., Simmons, R. L., and Billiar, T. R. (1991) Nitric oxide and nitric oxide-generating compounds inhibit hepatocyte protein synthesis. FASEB J. 5, 2085–2092.PubMedGoogle Scholar
  77. 77.
    Kwon, N. S., Stuehr, D. J., and Nathan, C. (1991) Inhibition of tumor cell ribonucleotide reductase by macrophage-derived nitric oxide. J. Exp. Med. 174, 761–768.PubMedCrossRefGoogle Scholar
  78. 78.
    Wink, D. A., Kasprzak, K. S., Maragos, C. M., Elespuru, R. K., Misra, M., Dunams, T. M., Cebula, T. A., Koch, W. H., Andrews, A. W., Allen, J. S., et al. (1991) DNA deaminating ability and genotoxicity of nitric oxide and its progenitors. Science 254 (5034), 1001–1003.PubMedCrossRefGoogle Scholar
  79. 79.
    Zhang, J., Dawson, V. L., Dawson, T. M., and Snyder, S. H. (1994) Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science 263 (5147), 687–689.PubMedCrossRefGoogle Scholar
  80. 80.
    Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., and Freeman, B. A. (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. USA 87(4), 1620–1624.Google Scholar
  81. 81.
    Brunelli, L., Crow, J. P., and Beckman, J. S. (1995) The comparative toxicity of nitric oxide and peroxynitrite to Escherichia coli. Arch. Biochem. Biophys. 316 (1), 327–334.PubMedCrossRefGoogle Scholar
  82. 82.
    Zhu, L., Gunn, C., and Beckman, J. S. (1992) Bactericidal activity of peroxynitrite. Arch. Biochem. Biophys. 298 (2), 452–457.PubMedCrossRefGoogle Scholar
  83. 83.
    Radi, R., Beckman, J. S., Bush, K. M., and Freeman, B. A. (1991) Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide. J. Biol. Chem. 266 (7), 4244–4250.PubMedGoogle Scholar
  84. 84.
    Radi, R., Beckman, J. S., Bush, K. M., and Freeman, B. A. (1991) Peroxynitriteinduced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch. Biochem. Biophys. 288 (2), 481–487.PubMedCrossRefGoogle Scholar
  85. 85.
    Haddad, I. Y., Pataki, G., Hu, P., Galliani, C., Beckman, J. S., and Matalon, S. (1994) Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J. Clin. Invest. 94(6), 2407–2413.Google Scholar
  86. 86.
    Ischiropoulos, H., Zhu, L., Chen, J., Tsai, M., Martin, J. C., Smith, C. D., and Beckman, J. S. (1992) Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch. Biochem. Biophys. 298 (2), 431–437.PubMedCrossRefGoogle Scholar
  87. 87.
    Beckman, J. S., Carson, M., Smith, C. D., and Koppenol, W. H. (1993) ALS, SOD and peroxynitrite. Nature 364 (6438), 584.PubMedCrossRefGoogle Scholar
  88. 88.
    Geller, D. A., Lowenstein, C. J., Shapiro, R. A., Nussler, A. K., Di Silvio, M., Wang, S. C., Nakayama, D. K., Simmons, R. L., Snyder, S. H., and Billiar, T. R. (1993) Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc. Natl. Acad. Sci. USA 90 (8), 3491–3495.PubMedCrossRefGoogle Scholar
  89. 89.
    Charles, I. G., Palmer, R. M., Hickery, M. S., Bayliss, M. T., Chubb, A. P., Hall, V. S., Moss, D. W., and Moncada, S. (1993) Cloning characterization, and expression of a cDNA encoding an inducible nitric oxide synthase from the human chondrocyte. Proc. Natl. Acad. Sci. USA 90(23), 11,419–11, 423.Google Scholar
  90. 90.
    Nicolson, A. G., Haites, N. E., McKay, N. G., Wilson, H. M., MacLeod, A. M., and Benjamin, N. (1993) Induction of nitric oxide synthase in human mesangial cells. Biochem. Biophys. Res. Commun. 193 (3), 1269–1274.PubMedCrossRefGoogle Scholar
  91. 91.
    Becherel, P. A., Mossalayi, M. D., Ouaaz, F., Le Goff, L., Dugas, B., Paul-Eugene, N., Frances, C., Chosidow, O., Kilchherr, E., Guillosson, J. J., et al. (1994) Involvement of cyclic AMP and nitric oxide in immunoglobulin E-dependent activation of Fc epsilon RII/CD23 + normal human keratinocytes. J. Clin. Invest. 93 (5), 2275–2279.PubMedCrossRefGoogle Scholar
  92. 92.
    Asano, K., Chee, C. B., Gaston, B., Lilly, C. M., Gerard, C., Drazen, J. M., and Stamler, J. S. (1994) Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc. Natl. Acad. Sci. USA 91(21), 10,089–10, 093.Google Scholar
  93. 93.
    Guo, F. H., De Raeve, H. R., Rice, T. W., Stuehr, D. J., Thunnissen, F. B., and Erzurum, S. C. (1995) Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. Proc. Natl. Acad. Sci. USA 92 (17), 7809–7813.PubMedCrossRefGoogle Scholar
  94. 94.
    Rosenkranz-Weis, P., Sessa, W. C., Milstien, S., Kaufman, S., Watson, C. A., and Pober, J. S. (1994) Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J. Clin. Invest. 93 (5), 2236–2243.CrossRefGoogle Scholar
  95. 95.
    Park, C. S., Pardhasaradhi, K., Gianotti, C., Villegas, E., and Krishna, G. (1994) Human retina expresses both constitutive and inducible isoforms of nitric oxide synthase mRNA. Biochem. Biophys. Res. Commun. 205 (1), 85–91.PubMedCrossRefGoogle Scholar
  96. 96.
    Corbett, J. A., Sweetland, M. A., Wang, J. L., Lancaster, J. R., Jr., and McDaniel, M. (1993) Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc. Natl. Acad. Sci. USA 90 (5), 1731–1735.PubMedCrossRefGoogle Scholar
  97. 97.
    Goode, H. F., Howdle, P. D., Walker, B. E., and Webster, N. R. (1995) Nitric oxide synthase activity is increased in patients with sepsis syndrome. Clin. Sci. 88 (2), 131–133.PubMedGoogle Scholar
  98. 98.
    Ochoa, J. B., Udekwu, A. O., Billiar, T. R., Curran, R. D., Cerra, F. B., Simmons, R. L., and Peitzman, A. B. (1991) Nitrogen oxide levels in patients after trauma and during sepsis. Ann. Surg. 214 (5), 621–626.PubMedCrossRefGoogle Scholar
  99. 99.
    Milstien, S., Sakai, N., Brew, B. J., Krieger, C., Vickers, J. H., Saito, K., and Heyes, M. P. (1994) Cerebrospinal fluid nitrite/nitrate levels in neurologic diseases. J. Neurochem. 63 (3), 1178–1180.PubMedCrossRefGoogle Scholar
  100. 100.
    Visser, J. J., Scholten, R. J., and Hoekman, K. (1994) Nitric oxide synthesis in meningococcal meningitis. Ann. Intern. Med. 120 (4), 345–346.PubMedGoogle Scholar
  101. 101.
    Hibbs, J. B., Jr., Westenfelder, C., Taintor, R., Vavrin, Z., Kablitz, C., Baranowski, R. L., Ward, J. H., Menlove, R. L., McMurry, M. P., and Kushner, J. P. et al. (1992) Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J. Clin. Invest. 89 (3), 867–877.PubMedCrossRefGoogle Scholar
  102. 102.
    Ochoa, J. B., Curti, B., Peitzman, A. B., Simmons, R. L., Billiar, T. R., Hoffman, R., Rault, R., Longo, D. L., Urba, W. J., and Ochoa, A. C. (1992) Increased circulating nitrogen oxides after human tumor immunotherapy: correlation with toxic hemodynamic changes. J. Natl. Canc. Inst. 84 (11), 864–867.CrossRefGoogle Scholar
  103. 103.
    Chartrain, N. A., Geller, D. A., Koty, P. P., Sitrin, N. F., Nussler, A. K., Hoffman, E. P., Billiar, T. R., Hutchinson, N. I., and Mudgett, J. S. (1994) Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J. Biol. Chem. 269 (9), 6765–6772.PubMedGoogle Scholar
  104. 104.
    Fabian, R. H. and Rea, H. C. (1993) Neuronal toxicity by macrophages in mixed brain cell culture is augmented by antineuronal IgG and dependent upon nitric oxide synthesis. J. Neuroimmunol. 44 (1), 95–102.PubMedCrossRefGoogle Scholar
  105. 105.
    Lee, S. C., Dickson, D. W., Liu, W., and Brosnan, C. F. (1993) Induction of nitric oxide synthase activity in human astrocytes by interleukin-1 beta and interferon-gamma. J. Neuroimmunol. 46 (1–2), 19–24.PubMedCrossRefGoogle Scholar
  106. 106.
    Lee, S. C., Dickson, D. W., Brosnan, C. F., and Casadevall, A. (1994) Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism. J. Exp. Med. 180 (1), 365–369.PubMedCrossRefGoogle Scholar
  107. 107.
    Koka, P., He, K., Zack, J. A., Kitchen, S., Peacock, W., Fried, I., Tran, T., Yashar, S. S., and Merrill, J. E. (1995) Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain. J. Exp. Med. 182 (4), 941–951.PubMedCrossRefGoogle Scholar
  108. 108.
    Brosnan, C. F., Battistini, L., Raine, C. S., Dickson, D. W., Casadevall, A., and Lee, S. C. (1994) Reactive nitrogen intermediates in human neuropathology—an overview. Dev. Neurosci. 16 (3–4), 152–161.PubMedCrossRefGoogle Scholar
  109. 109.
    Walker, D. G., Kim, S. U., and McGeer, P. L. (1995) Complement and cytokine gene expression in cultured microglial derived from postmortem human brains. J. Neurosci. Res. 40 (4), 478–493.PubMedCrossRefGoogle Scholar
  110. 110.
    Dawson, T. M., Bredt, D. S., Fotuhi, M., Hwang, P. N., and Snyder, S. H. (1991) Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc. Natl. Acad. Sci. USA 88 (17), 7797–7801.PubMedCrossRefGoogle Scholar
  111. 111.
    Hope, B. T., Michael, G. J., Knigge, K. M., and Vincent, S. R. (1991) Neuronal NADPH diaphorase is a nitric oxide synthase. Proc. Natl. Acad. Sci. USA 88 (7), 2811–2814.PubMedCrossRefGoogle Scholar
  112. 112.
    Chao, C. C., Gekker, G., Hu, S., and Peterson, P. K. (1994) Human microglial cell defense against Toxoplasma gondii. The role of cytokines. J. Immunol. 152 (3), 1246–1252.PubMedGoogle Scholar
  113. 113.
    Lee, S. C., Kress, Y., Dickson, D. W., and Casadevall, A. (1995) Human microglia mediate anti-cryptococcus neoformans activity in the presence of specific antibody. J. Neuroimmunol. 62 (1), 43–52.PubMedCrossRefGoogle Scholar
  114. 114.
    Peterson, P. K., Hu, S., Anderson, W. R., And Chao, C. C. (1994) Nitric oxide production and neurotoxicity mediated by activated microglia from human versus mouse brain. J. Infect. Dis. 170 (2): 457–460.PubMedCrossRefGoogle Scholar
  115. 115.
    Colasanti, M., Persichini, T., Dipucchio, T., Gremo, F., and Lauro, G. M. (1995) Human ramified microglial cells produce nitric oxide upon Escherichia coli lipopolysaccharide and tumor necrosis factor alpha stimulation. Neurosci. Lett. 200 (2), 144–146.PubMedCrossRefGoogle Scholar
  116. 116.
    Page, G. K. and Morton, A. J. (1995) Correlation of neuronal loss with increased expression of NADPH diaphorase in cultured rat cerebellum and cerebral cortex. Brain Res. 697 (1–2), 157–168.PubMedCrossRefGoogle Scholar
  117. 117.
    Skaper, S. D., Facci, L., and Leon, A. (1995) Inflammatory mediator stimulation of astrocytes and meningeal fibroblasts induces neuronal degeneration via the nitridergic pathway. J. Neurochem. 64 (1), 266–276.PubMedCrossRefGoogle Scholar
  118. 118.
    Demerle-Pallardy, C., Lonchampt, M. O., Chabrier, P. E., and Braquet, P. (1993) Nitric oxide synthase induction in glial cells: effect on neuronal survival. Life Sci. 52 (23), 1883–1890.PubMedCrossRefGoogle Scholar
  119. 119.
    Chao, C. C., Hu, S. X., Sheng, W. S., Bu, D. F., Bukrinsky, M. I., and Peterson, P. K. (1996) Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism. Glia 16 (3), 276–284.PubMedCrossRefGoogle Scholar
  120. 120.
    Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., and Lipton, S. A. (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. USA 92 (16), 7162–7166.PubMedCrossRefGoogle Scholar
  121. 121.
    Albina, J. E., Cui, S., Mateo, R. B., and Reichner, J. S. (1993) Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J. Immunol. 150 (11), 5080–5085.PubMedGoogle Scholar
  122. 122.
    Sarih, M., Souvannavong, V., and Adam, A. (1993) Nitric oxide synthase induces macrophage death by apoptosis. Biochem. Biophys. Res. Commun. 191 (2), 503–508.PubMedCrossRefGoogle Scholar
  123. 123.
    Estevez, A. G., Radi, R., Barbeito, L., Shin, J. T., Thompson, J. A., and Beckman, J. S. (1995) Peroxynitrite-induced cytotoxicity in PC12 cells: evidence for an apoptotic mechanism differentially modulated by neurotrophic factors. J. Neurochem. 65 (4), 1543–1550.PubMedCrossRefGoogle Scholar
  124. 124.
    Cui, S., Reichner, J. S., Mateo, R. B., and Albina, J. E. (1994) Activated murine macrophages induce apoptosis in tumor cells through nitric oxide-dependent or -independent mechanisms. Canc. Res. 54 (9), 2462–2467.Google Scholar
  125. 125.
    Boje, K. M., Wong, G., and Skolnick, P. (1993) Desensitization of the NMDA receptor complex by glycinergic ligands in cerebellar granule cell cultures. Brain Res. 603, 207–214.PubMedCrossRefGoogle Scholar
  126. 126.
    Goldberg, M. P., Weiss, J. H., Pham, P. C., and Choi, D. W. (1987) N-methyl-Daspartate receptors mediate hypoxic neuronal injury in cortical culture. J. Pharmacol. Exp. Ther. 243, 754–791.Google Scholar
  127. 127.
    Boje, K. M. K. (1994) In vitro and in vivo studies with glycine partial agonists: a novel strategy for preventing NMDA receptor-mediated tissue damage, in Direct and Allosteric Control of Glutamate Receptors ( Palfreyman, M. G., Reynolds, I. J., and Skolnick, P, eds.), CRC, Boca Raton, FL, pp. 119–126.Google Scholar
  128. 128.
    Cotman, C. W., Bridges, R. J., Taube, J. S., Clark, A. S., Geddes, J. W., and Monaghan, D. T. (1989) The role of the NMDA receptor in central nervous system plasticity and pathology. J. NIH Res. 1, 65–74.Google Scholar
  129. 129.
    Lipton, S. A., Singel, D. J., and Stamler, J. S. (1994) Nitric oxide in the central nervous system. Prog. Brain Res. 103, 359–364.PubMedCrossRefGoogle Scholar
  130. 130.
    Hewett, S. J., Csernansky, C. A., and Choi, D. W. (1994) Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS. Neuron 13 (2), 487–494.PubMedCrossRefGoogle Scholar
  131. 131.
    Chao, C. C., Hu, S. X., Ehrlich, L., and Peterson, P. K. (1995) Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity—involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behay. Immunity 9 (4), 355–365.CrossRefGoogle Scholar
  132. 132.
    Kowall, N. W. (1994) Beta amyloid neurotoxicity and neuronal degeneration in Alzheimer’s disease. Neurobiol. Aging 15 (2), 257–258.PubMedCrossRefGoogle Scholar
  133. 133.
    Cotman, C. W. and Anderson, A. J. (1995) A potential role for apoptosis in neuro-degeneration and Alzheimer’s disease. Mol. Neurobiol. 10 (1), 19–45.PubMedCrossRefGoogle Scholar
  134. 134.
    Meda, L., Cassatella, M. A., Szendrei, G. I., Otvos, L., Jr., Baron, P., Villalba, M., Ferrari, D., and Rossi, F. (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374 (6523), 647–650.PubMedCrossRefGoogle Scholar
  135. 135.
    Goodwin, J. L., Uemura, E., and Cunnick, J. E. (1995) Microglial release of nitric oxide by the synergistic action of beta-amyloid and IFN-gamma. Brain Res. 692 (1–2), 207–214.PubMedCrossRefGoogle Scholar
  136. 136.
    Le, W. D., Colom, L. V., Xie, W. J., Smith, R. G., Alexianu, M., and Appel, S. H. (1995.) Cell death induced by beta-amyloid 1–40 in MES 23.5 hybrid clone: the role of nitric oxide and NMDA-gated channel activation leading to apoptosis. Brain Res. 686(1), 49–60.Google Scholar
  137. 137.
    Lockhart, B. P., Benicour, T. C., Junien, J. L., and Privat, A. (1994) Inhibitors of free radical formation fail to attenuate direct beta-amyloid (25–35) peptide-mediated neurotoxicity in rat hippocampal cultures. J. Neurosci. Res. 39 (4), 494–505.PubMedCrossRefGoogle Scholar
  138. 138.
    Poser, C. M. (1994) Notes on the pathogenesis of multiple sclerosis. Clin. Neurosci. 2 (3–4), 258–265.PubMedGoogle Scholar
  139. 139.
    Stone, L. A., Smith, E., Albert, P. S., Bash, C. N., Maloni, H., Frank, J. A., and McFarland, H. F. (1995) Blood-brain barrier disruption on contrast-enhanced MRI in patients with mild relapsing-remitting multiple sclerosis: relationship to course, gender, and age. Neurology 45 (6), 1122–1126.PubMedCrossRefGoogle Scholar
  140. 140.
    Power, C. and Johnson, R. T. (1995) HIV-1 associated dementia: clinical features and pathogenesis. Can. J. Neurol. Sci. 22 (2), 92–100.PubMedGoogle Scholar
  141. 141.
    Zhang, J., Benveniste, H., Klitzman, B., and Piantadosi, C. A. (1995) Nitric oxide synthase inhibition and extracellular glutamate concentration after cerebral ischemia/ reperfusion. Stroke 26 (2), 298–304.PubMedCrossRefGoogle Scholar
  142. 142.
    Stewart, D. J. (1994) A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors. J. Neurol. Oncol. 20 (2), 121–139.CrossRefGoogle Scholar
  143. 143.
    Tunkel, A. R. and Scheld, W. M. (1993) Pathogenesis and pathophysiology of bacterial meningitis. Ann. Rev. Med. 44, 103–120.PubMedCrossRefGoogle Scholar
  144. 144.
    Barinaga, M. (1995) Antibodies linked to rare epilepsy. Science 268, 362–363.PubMedCrossRefGoogle Scholar
  145. 145.
    Rogers, S. W., Andrews, P. I., Gahring, L. C., Whisenand, T., Cauley, K., Crain, B., Hughes, T. E., Heinemann, S. F., and McNamara, J. O. (1994) Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science 265 (5172), 648–651.PubMedCrossRefGoogle Scholar
  146. 146.
    Kilbourn, R. G. and Belloni, P. (1990) Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J. Natl. Cancer Inst. 82 (9), 772–776.PubMedCrossRefGoogle Scholar
  147. 147.
    Boje, K. M. K. (1995) Cerebrovascular permeability changes during experimental meningitis in the rat. J. Pharmacol. Exp. Ther. 274 (3), 1199–1203.PubMedGoogle Scholar
  148. 148.
    Cobbs, C. S., Brenman, J. E., Aldape, K. D., Bredt, D. S., and Israel, M. A. (1995) Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res. 55 (4), 727–730.PubMedGoogle Scholar
  149. 149.
    Kohno, K., Ohta, S., Furuta, S., Kohno, K., Kumon, Y., and Sakaki, S. (1995) Intraventricular administration of nitric oxide synthase inhibitors prevents delayed neuronal death in gerbil hippocampal CAI neurons. Neurosci. Lett. 199 (1), 65–68.PubMedCrossRefGoogle Scholar
  150. 150.
    Zhang, F. Y., Casey, R. M., Ross, M. E., and Iadecola, C. (1996) Aminoguanidine ameliorates and L-arginine worsens brain damage from intraluminal middle cerebral artery occlusion. Stroke 27, 317–323.PubMedCrossRefGoogle Scholar
  151. 151.
    Wallace, M. N. and Bisland, S. K. (1994) NADPH-diaphorase activity in activated astrocytes represents inducible nitric oxide synthase. Neuroscience 59 (4), 905–919.PubMedCrossRefGoogle Scholar
  152. 152.
    Schmidt, W., Wolf, G., Calka, J., and Schmidt, H. H. H. W. (1995) Evidence for bidirectional changes in nitric oxide synthase activity in the rat striatum after excitotoxically (quinolinic acid) induced degeneration. Neuroscience 67 (2), 345–356.PubMedCrossRefGoogle Scholar
  153. 153.
    Endoh, M., Maiese, K., and Wagner, J. (1994) Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia. Brain Res. 651 (1–2), 92–100.PubMedCrossRefGoogle Scholar
  154. 154.
    Nakashima, M. N., Yamashita, K., Kataoka, Y., Yamashita, Y. S., and Niwa, M. (1995) Time course of nitric oxide synthase activity in neuronal, glial, and endothelial cells of rat striatum following focal cerebral ischemia. Cell. Mol. Neurobiol. 15 (3), 341–349.PubMedCrossRefGoogle Scholar
  155. 155.
    Okuda, Y., Nakatsuji, Y., Fujimura, H., Esumi, H., Ogura, T., Yanagihara, T., and Sakoda, S. (1995) Expression of the inducible isoform of nitric oxide synthase in the central nervous system of mice correlates with the severity of actively induced experimental allergic encephalomyelitis. J. Neuroimmunol. 62 (1), 103–112.PubMedCrossRefGoogle Scholar
  156. 156.
    Lin, R. F., Lin, T. S., Tilton, R. G., and Cross, A. H. (1993) Nitric oxide localized to spinal cords of mice with experimental allergic encephalomyelitis: an electron paramagnetic resonance study. J. Exp. Med. 178 (2), 643–638.PubMedCrossRefGoogle Scholar
  157. 157.
    Van Dam, A. M., Bauer, J., Man-A-Hing, W. K., Marquette, C., Tilders, F. J., and Berkenbosch, F. (1995) Appearance of inducible nitric oxide synthase in the rat central nervous system after rabies virus infection and during experimental allergic encephalomyelitis but not after peripheral administration of endotoxin. J. Neurosci. Res. 40 (2), 251–260.PubMedCrossRefGoogle Scholar
  158. 158.
    Ludowyk, P. A., Hughes, W., Hugh, A., Willenborg, D. O., Rockett, K. A., and Parish, C. R. (1993) Astrocytic hypertrophy: an important pathological feature of chronic experimental autoimmune encephalitis in aged rats. J. Neuroimmunol. 48(2), 121–134.Google Scholar
  159. 159.
    MacMicking, J. D., Willenborg, D. O., Weidemann, M. J., Rockett, K. A., and Cowden, W. B. (1992) Elevated secretion of reactive nitrogen and oxygen intermediates by inflammatory leukocytes in hyperacute experimental autoimmune encephalomyelitis: Enhancement by the soluble products of encephalitogenic T cells. J. Exp. Med. 176 (1), 303–07.PubMedCrossRefGoogle Scholar
  160. 160.
    Cross, A. H., Misko, T. P., Lin, R. F., Hickey, W. J., Trotter, J., and Tilton, R. G. (1994) Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. J. Clin. Invest. 93 (6), 2684–2690.PubMedCrossRefGoogle Scholar
  161. 161.
    Fuchs, D., Baier-Bitterlich, G., and Wachter, H. (1995) Nitric oxide and AIDS dementia. N. Engl. J. Med. 333 (8), 521–522.PubMedCrossRefGoogle Scholar
  162. 162.
    Lipton, S. A. and Gendelman, H. E. (1995) Dementia associated with the acquired immunodeficiency syndrome. N. Engl. J. Med. 332 (14), 934–940.PubMedCrossRefGoogle Scholar
  163. 163.
    Bukrinsky, M. I., Nottet, H. S., Schmidtmayerova, H., Dubrovsky, L., Flanagan, C. R., Mullins, M. E., Lipton, S. A., and Geldelman, H. E. (1995) Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)infected monocytes: implications for HIV-associated neurological disease. J. Exp. Med. 181 (2), 735–745.PubMedCrossRefGoogle Scholar
  164. 164.
    Dighiero, P., Reux, I., Hauw, J. J., Fillet, A. M., Courtois, Y., and Goureau, O (1994)Expression of inducible nitric oxide synthase in cytomegalovirus-infected glial cells of retinas from AIDS patients. Neurosci. Lett. 166(1), 31–34.Google Scholar
  165. 165.
    Koedel, U., Bernatowicz, A., Paul, R., Frei, K., Fontana, A., and Pfister, H. W. (1995) Experimental pneumococcal meningitis: cerebrovascular alterations, brain edema, and meningeal inflammation are linked to the production of nitric oxide. Ann. Neurol. 37 (3), 313–323.PubMedCrossRefGoogle Scholar
  166. 166.
    Tureen, J. (1995) Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. J. Clin. Invest. 95, 1086–1091.PubMedCrossRefGoogle Scholar
  167. 167.
    Pfister, H. W., Bernatowicz, A., Kodel, U., and Wick, M. (1995) Nitric oxide production in bacterial meningitis. Neurol. Neurosurg. Psychiatry 58, 384–385.CrossRefGoogle Scholar
  168. 168.
    Lu, J., Kaur, C., and Ling, E. A. (1995) Histochemical demonstration of nitric oxide synthase-like immunoreactivity in epiplexus cells and choroid epithelia in the lateral ventricles of postnatal rat brain induced by an intracerebral injection of lipopolysaccharide. Brain Res. 699 (2), 275–285.PubMedCrossRefGoogle Scholar
  169. 169.
    Campbell, I., Samimi, A., and Chiang, C. S. (1994) Expression of the inducible nitric oxide synthase. Correlation with neuropathology and clinical features in mice with lymphocytic choriomeningitis. J. Immunol. 153 (8), 3622–3629.PubMedGoogle Scholar
  170. 170.
    Brosnan, C. F., Cannella, B., Battistini, L., and Raine, C. S. (1995) Cytokine localization in multiple sclerosis lesions: correlation with adhesion molecule expression and reactive nitrogen species. Neurology. 45 (6 Suppl 6), S16–S21.PubMedCrossRefGoogle Scholar
  171. 171.
    Johnson, A. W., Land, J. M., Thompson, E. J., Bolanos, J. P., Clark, J. B., and Heales, S. J. (1995) Evidence for increased nitric oxide production in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 58(1), 107.Google Scholar
  172. 172.
    Boullerne, A. I., Petry, K. G., Meynard, M., and Geffard, M. (1995) Indirect evidence for nitric oxide involvement in multiple sclerosis by characterization of circulating antibodies directed against conjugated Snitrosocysteine. J. Neuroimmunol. 60 (1–2), 117–124.PubMedCrossRefGoogle Scholar
  173. 173.
    Bo, L., Dawson, T. M., Wesselingh, S., Mork, S., Choi, S., Kong, P. A., Hanley, D., and Trapp, B. D. (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann. Neurol. 36 (5), 778–786.PubMedCrossRefGoogle Scholar
  174. 174.
    Claudio, L., Raine, C. S., and Brosnan, C. F. (1995) Evidence of persistent blood-brain barrier abnormalities in chronic-progressive multiple sclerosis. Acta Neuropathol. 90 (3), 228–238.PubMedCrossRefGoogle Scholar
  175. 175.
    Karupiah, G., Xie, Q. W., Buller, R. M., Nathan, C., Duarte, C., and MacMicking, J. D. (1993) Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science 261 (5127), 1445–1448.PubMedCrossRefGoogle Scholar
  176. 176.
    Chao, C. C., Anderson, W. R., Hu, S., Gekker, G., Martella, A., and Peterson, P. K. (1993) Activated microglia inhibit multiplication of Toxoplasma gondii via a nitric oxide mechanism. Clin. Immunol. Immunopathol. 67 (2), 178–183.PubMedCrossRefGoogle Scholar
  177. 177.
    Peterson, P. K., Gekker, G., Hu, S., and Chao, C. C. (1995) Human astrocytes inhibit intracellular multiplication of Toxoplasma gondii by a nitric oxide-mediated mechanism. J. Infect. Dis. 171 (2), 516–518.PubMedCrossRefGoogle Scholar
  178. 178.
    Peterson, P. K., Gekker, G., Hu, S., and Chao, C. C. (1993) Intracellular survival and multiplication of Toxoplasma gondii in astrocytes. J. Infect. Dis. 168 (6), 1472–1478.PubMedCrossRefGoogle Scholar
  179. 179.
    Hooper, D. C., Ohnishi, S. T., Kean, R., Numagami, Y., Dietzschold, B., and Koprowski, H. (1995) Local nitric oxide production in viral and autoimmune diseases of the central nervous system. Proc. Natl. Acad. Sci. USA 92(12), 5312–5316.Google Scholar
  180. 180.
    Dietzschold, B. (1995) The role of nitric oxide in the pathogenesis of virus-induced encephalopathies. Curr. Topics Microbiol. Immunol. 196, 51–56.CrossRefGoogle Scholar
  181. 181.
    Sun, N. and Perlman, S. (1995) Spread of a neurotropic coronavirus to spinal cord white matter via neurons and astrocytes. J. Virol. 69 (2), 633–641.PubMedGoogle Scholar
  182. 182.
    Bi, Z. B., Quandt, P., Komatsu, T., Barna, M., and Reiss, C. S. (1995) Interleukin12 promotes enhanced recovery from vesicular stomatitis virus infection of the central nervous system. J. Immunol. 155 (12), 5684–5689.PubMedGoogle Scholar
  183. 183.
    Bi, Z., Barna, M., Komatsu, T., and Reiss, C. S. (1995) Vesicular stomatitis virus infection of the central nervous system activates both innate and acquired immunity. J. Virol. 69 (10), 6466–6472.PubMedGoogle Scholar
  184. 184.
    Jia, Y. S., Wang, X. A., and Ju, G. (1994) Nitric oxide synthase expression in vagal complex following vagotomy in the rat. Neuroreport 5 (7), 793–796.PubMedCrossRefGoogle Scholar
  185. 185.
    Zhang, Z. G., Chopp, M., Gautam, S., Zaloga, C., Zhang, R. L., Schmidt, H. H. H. W., Pollock, J. S., and Forstermann, U. (1994) Upregulation of neuronal nitric oxide synthase and mRNA, and selective sparing of nitric oxide synthase-containing neurons after focal cerebral ischemia in rat. Brain Res. 654 (1), 85–95.CrossRefGoogle Scholar
  186. 186.
    Zhang, Z. G., Chopp, M., Zaloga, C., Pollock, J. S., and Forstermann, U. (1993) Cerebral endothelial nitric oxide synthase expression after focal cerebral ischemia in rats. Stroke 24 (12), 2016–2021.PubMedCrossRefGoogle Scholar
  187. 187.
    Kadowaki, K., Kishimoto, J., Leng, G., and Emson, P. C. (1994) Upregulation of nitric oxide synthase (NOS) gene expression together with NOS activity in the rat hypothalamo-hypophysial system after chronic salt loading: evidence of a neuro-modulatory role of nitric oxide in arginine vasopressin and oxytocin secretion. Endocrinology 134 (3), 1011–1017.PubMedCrossRefGoogle Scholar
  188. 188.
    Weiner, C. P., Lizasoain, I., Baylis, S. A., Knowles, R. G., Charles, I. G., and Moncada, S. (1994) Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc. Natl. Acad. Sci. USA 91 (11), 5212–5216.PubMedCrossRefGoogle Scholar
  189. 189.
    Hokfelt, T., Ceccatelli, S., Gustafsson, L., Hulting, A. L., Verge, V., Villar, M., Xu, X. J., Xu, Z. Q., Wiesenfeld-Hallin, Z., and Zhang, X. (1994) Plasticity of NO synthase expression in the nervous and endocrine systems. Neuropharmacology 33 (11), 1221–1227.PubMedCrossRefGoogle Scholar
  190. 190.
    Baltrons, M. A., Agullo, L., and Garcia, A. (1995) Dexamethasone upregulates a constitutive nitric oxide synthase in cerebellar astrocytes but not in granule cells in culture. J. Neurochem. 64 (1), 447–450.PubMedCrossRefGoogle Scholar
  191. 191.
    Tatro, J. B., Romero, L. I., Beasley, D., Steere, A. C., and Reichlin, S. (1994) Borrelia burgdorferi and Escherichia coli lipopolysaccharides induce nitric oxide and interleukin-6 production in cultured rat brain cells. J. Infect. Dis. 169 (5), 1014–1022.PubMedCrossRefGoogle Scholar
  192. 192.
    Sun, N., Grzybicki, D., Castro, R. F., Murphy, S., and Perlman, S. (1995) Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus. Virology 213 (2), 482–493.PubMedCrossRefGoogle Scholar
  193. 193.
    McElhaney, M. R., Chandler, L. J., and Streit, W. J. (1994) Astrocytes but not microglia express NADPH-diaphorase activity after motor neuron injury in the rat. Neurosci. Lett. 180 (1), 67–70.CrossRefGoogle Scholar
  194. 194.
    Hu, S. X., Sheng, W. S., Peterson, P. K., and Chao, C. C. (1995) Differential regulation by cytokines of human astrocyte nitric oxide production. Glia 15 (4), 491–494.PubMedCrossRefGoogle Scholar
  195. 195.
    Park, S. K., Grzybicki, G., Lin, H. L., and Murphy, S. (1994) Modulation of inducible nitric oxide synthase expression in astroglial cells. Neuropharmacology 33, 1419–1423.PubMedCrossRefGoogle Scholar
  196. 196.
    Hewett, S. J., Corbett, J. A., McDaniel, M. L., and Choi, D. W. (1993) Interferon-gamma and interleukin-1 beta induce nitric oxide formation from primary mouse astrocytes. Neurosci. Lett. 164 (1–2), 229–232.PubMedCrossRefGoogle Scholar
  197. 197.
    Minc-Golomb, D., Tsarfaty, I., and Schwartz, J. P. (1994) Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine. Br. J. Pharmacol. 112 (3), 720–722.PubMedCrossRefGoogle Scholar
  198. 198.
    Goureau, O., Hicks, D., Courtois, Y., and De Kozak, Y. (1994) Induction and regulation of nitric oxide synthase in retinal Muller glial cells. J. Neurochem. 63 (1), 310–317.PubMedCrossRefGoogle Scholar
  199. 199.
    Brenner, T., Yamin, A., and Gallily, R. (1994) Mycoplasma triggering of nitric oxide production by central nervous system glial cells and its inhibition by glucocorticoids. Brain Res. 641 (1), 51–56.PubMedCrossRefGoogle Scholar
  200. 200.
    Freyer, D., Weih, M., Weber, J. R., Burger, W., Scholz, P., Manz, R., Ziegenhorn, A., Angestwurm, K., and Dirnagl, U. (1996) Pneumococcal cell wall components induce nitric oxide synthase and TNF-alpha in astroglial-enriched cultures. Glia 16 (1), 1–6.PubMedCrossRefGoogle Scholar
  201. 201.
    Simmons, M. L. and Murphy, S. (1994) Roles for protein kinases in the induction of nitric oxide synthase in astrocytes. Glia 11 (3), 227–234.PubMedCrossRefGoogle Scholar
  202. 202.
    Hu, J. G., Castets, F., Guevara, J. L., and Vaneldik, L. J. (1996) S100–beta stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes. J. Biol. Chem. 271 (5), 2543–2547.PubMedCrossRefGoogle Scholar
  203. 203.
    Feinstein, D. L., Galea, E., and Reis, D. J. (1993) Norepinephrine suppresses inducible nitric oxide synthase activity in rat astroglial cultures. J. Neurochem. 60 (5), 1945–1948.PubMedCrossRefGoogle Scholar
  204. 204.
    Chandler, L. J., Kopnisky, K., Richards, E., Crews, F. T., and Sumners, C. (1995) Angiotensin II decreases inducible nitric oxide synthase expression in rat astroglial cultures. Am. J. Physiol. 268 (3 pt. 1), C700–C707.PubMedGoogle Scholar
  205. 205.
    Murphy, S., Lin, H. L., and Park, S. K. (1995) Cytokine-induced expression of type initric oxide synthase in astrocytes is downregulated by ATP and glutamate. Glia 15 (1), 77–82.PubMedCrossRefGoogle Scholar
  206. 206.
    Colasanti, M., Di Pucchio, T., Persichini, T., Sogos, V., Presta, M., and Lauro, G. M. (1995) Inhibition of inducible nitric oxide synthase mRNA expression by basic fibroblast growth factor in human microglial cells. Neurosci. Lett. 195 (1), 45–48.PubMedCrossRefGoogle Scholar
  207. 207.
    Bogdan, C., Werner, E., Stenger, S., Wachter, H., Rollinghoff, M., and WernerFelmayer, G. (1995) 2,4–Diamino-6–hydroxypyrimidine, an inhibitor of tetrahydrobiopterin synthesis, downregulates the expression of iNOS protein and mRNA in primary murine macrophages. FEBS Lett. 363(1–2),69–74.Google Scholar
  208. 208.
    Syapin, P. J. (1995) Ethanol inhibition of inducible nitric oxide synthase activity in C6 glioma cells. Alcohol Clin. Exp. Res. 9 (1), 262–267.CrossRefGoogle Scholar
  209. 209.
    Simmons, M. L. and Murphy, S. (1993) Cytokines regulate L-arginine-dependent cyclic GMP production in rat glial cells. Eur. J. Neurosci. 5 (7), 825–831.PubMedCrossRefGoogle Scholar
  210. 210.
    Bogdan, C., Vodovotz, Y., Paik, J., Xie, Q. W., and Nathan, C. (1994) Mechanism of suppression of nitric oxide synthase expression by interleukin-4 in primary mouse macrophages. J. Leukocyte Biol. 55 (2), 227–233.PubMedGoogle Scholar
  211. 211.
    Bogdan, C., Paik, J., Vodovotz, Y., and Nathan, C. (1992) Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J. Biol. Chem. 267(32), 23,301–23, 308.Google Scholar
  212. 212.
    Park, S. K., Lin, H. L., and Murphy, S. (1994) Nitric oxide limits transcriptional induction of nitric oxide synthase in CNS glial cells. Biochem. Biophys. Res. Commun. 201 (2), 762–768.PubMedCrossRefGoogle Scholar
  213. 213.
    Vodovotz, Y., Bogdan, C., Paik, J., Xie, Q. W., and Nathan, C. (1993) Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J. Exp. Med. 178 (2), 605–613.PubMedCrossRefGoogle Scholar
  214. 214.
    Forstermann, U., Schmidt, H. H., Kohlhaas, K. L., and Murad, F. (1992) Induced RAW 264.7 macrophages express soluble and particulate nitric oxide synthase• inhibition by transforming growth factor-beta. Eur. J. Pharmacol. 225 (2), 161–165.PubMedCrossRefGoogle Scholar
  215. 215.
    Feinstein, D. L., Galea, E., Cermak, J., Chugh, P., Lyandver, T. L., and Reis, D. J. (1994) Nitric oxide synthase expression in glial cells: suppression by tyrosine kinase inhibitors. J. Neurochem. 62 (2), 811–814.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Kathleen M. K. Boje

There are no affiliations available

Personalised recommendations