Molecular Neurobiology

, Volume 27, Issue 3, pp 325–355

Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria



In inflammatory, infectious, ischemic, and neurodegenerative pathologies of th central nervous system (CNS) glia become “activated” by inflammatory mediators, and express new proteins such as the inducible isoform of nitric oxide synthase (iNOS). Although these activated glia have beneficial roles, in vitro they potently kill cocultured neurons, and there is increasing evidence that they contribute to pathology in vivo. Nitric oxide (NO) from iNOS appears to be a key mediator of such glial-induced neuronal death. The high sensitivity of neurons to NO is partly due to NO causing inhibition of respiration, rapid glutamate release from both astrocytes and neurons, and subsequent excitotoxic death of the neurons. NO is a potent inhibitor of mitochondrial respiration, due to reversible binding of NO to cytochrome oxidase in competition with oxygen, resulting in inhibition of energy production and sensitization to hypoxia. Activated astrocytes or microglia cause a potent inhibition of respiration in cocultured neurons due to glial NO inhibiting cytochrome oxidase within the neurons, resulting in ATP depletion and glutamate release. In some conditions, glutamate-induced neuronal death can itself be mediated by N-methyl-d-aspartate (NMDA)-receptor activation of the neuronal isoform of NO synthase (nNOS) causing mitochondrial damage. In addition NO can be converted to a number of reactive derivatives such as peroxynitrite, NO2, N2O3, and S-nitrosothiols that can kill cells in part by inhibiting mitochondrial respiration or activation of mitochondrial permeability transition, triggering neuronal apoptosis or necrosis.

Index Entries

Inflammation neurons microglia astrocytes nitric oxide brain excitotoxicity cell death Alzheimer’s disease 


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  1. 1.
    Eddleston M. and Mucke L. (1993) Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neurosci. 54, 15–36.Google Scholar
  2. 2.
    Kreutzberg G. W. (1996) Microglia: a sensor for pathological events in the CNS. TINS 19, 312–318.PubMedGoogle Scholar
  3. 3.
    Kyrkanides S., O’Banion M. K., Whiteley P. E., Daeschner J. C., and Olschowka J. A. (2001) Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury. J. Neuroimmunol. 119, 269–277.PubMedGoogle Scholar
  4. 4.
    Piehl F. and Lidman O. (2001) Neuroinflammation in the rat CNS cells and their role in the regulation of immune reactions. Immunol. Rev. 184, 212–225.PubMedGoogle Scholar
  5. 5.
    Dong Y., Benveniste E. N. (2001) Immune function of astrocytes. Glia 36, 180–190.PubMedGoogle Scholar
  6. 6.
    Acarin L., Gonzalez B., and Castellano B. (2001) Glial activation in the immature rat brain: implication of inflammatory transcription factors and cytokine expression. Prog. Brain. Res. 132, 375–89.PubMedGoogle Scholar
  7. 7.
    Banati R. B., Gehramann J., Schubert P., and Kreutzberg G. W. (1993) Cytotoxicity of microglia. Glia 7, 111–118.PubMedGoogle Scholar
  8. 8.
    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, 487–494.PubMedGoogle Scholar
  9. 9.
    Bolanos J. P., Almeida A., Stewart V., Peuchen S., Land J. M., Clark J. B., and Heales S.J.R. (1997) Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J. Neurochem. 68, 2227–2240.PubMedGoogle Scholar
  10. 10.
    Chao C. C. (1996) Cytokine-stimulated astrocytes damage human neurons via a NO mechanism. Glia 16, 276–284.PubMedGoogle Scholar
  11. 11.
    Hu J., Ferreira A., and Van Eldik L. J. (1997) S100 beta induces neuronal cell death through nitric oxide release from astrocytes. J. Neurochem. 69, 2294–2301.PubMedGoogle Scholar
  12. 12.
    Kingham P. J., Cuzner M. L., and Pocock J. M. (1999) Apoptotic pathways mobilized in microglia and neurons as a consequence of chromogranin A-induced microglial activation. J. Neurochem. 73, 538–547.PubMedGoogle Scholar
  13. 13.
    Tanabe K., Akanishi H., Maeda H., Nishioku T., Hashimoto K., Liou S. Y., Akamines A., and Yamamoto K. (1999) A predominant apoptotic death pathway of neuronal PC12 cells induced by activated microglia is displaced by a nonapoptotic death pathway following blocakage of caspase-3-dependent cascade. J. Biol. Chem. 274, 15,725–15,731.Google Scholar
  14. 14.
    Loihl A. K. and Murphy S. (1998) Expression of NOS-2 in glia associated with CNS pathology. Prog. Brain Res. 118, 253–267.PubMedGoogle Scholar
  15. 15.
    Bolanos J. P. and Almeida A. (1999) Role of nitric oxide in brain hypoxia-ischaemia. Biochim. Biophys. Acta 1411, 415–436.PubMedGoogle Scholar
  16. 16.
    Liberatore G. T., Jackson-Lewis V., Vukosavic S., et al. (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nature Medicine 5, 1403–1409.PubMedGoogle Scholar
  17. 17.
    Itagaki S., McGeer P. L., Akiyama H., Zhu S., and Selkoe D. (1989) Relationship of microglia and astrocytes to amyloid deposits of Alzheimer Disease. J. Neuroimmunol. 24, 173–182.PubMedGoogle Scholar
  18. 18.
    Miyazono M., Iwaki T., Kitamoto T., Kaneko Y., Doh-ura K., and Tateishi J. (1991) A comparative immunohistochemical study of Kuru and senile plaques with aspecial reference to glial reactions at various stages of amyloid plaque formation. Am. J. Pathol. 139, 589–598.PubMedGoogle Scholar
  19. 19.
    McGeer P. L. and Rogers J. (1992) Antiinflammatory agents as a therapeutic approach to Alzheimer’s disease. Neurology 42, 447–449.PubMedGoogle Scholar
  20. 20.
    Wa J., Food M. R, Gabathuler R., Rothenberger S., Yamada T., Yasuhara O., and McGeer P. L. (1996) Reactive microglia specifically associated with amyloid plaques in Alzheimer’s disease brain tissue express melanotransferrin. Brain Res. 712, 122–126.Google Scholar
  21. 21.
    Wallace M. N., Geddes J. G., Farquhar D. A., and Masson M. R. (1997) Nitic oxide synthase in reactive astrocytes adjacent to beta-amyloid plaques. Exp. Neurol. 144, 266–272.PubMedGoogle Scholar
  22. 22.
    Lee S. C., Zhao M. L., Hirano A., and Dickson D. W. (1999) Inducible nitric oxide synthase immunoreactivity in the Alzheimer disease hippocampus: association with Hirano bodies, neurofibrillary tangles, and senile plaques. J. Neuropathol. Exp. Neurol. 58, 1163–1169.PubMedGoogle Scholar
  23. 23.
    Meda L., Cassatella M. A., Szendrei G. I., et al. (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374, 647–650.PubMedGoogle Scholar
  24. 24.
    Goodwin J., 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, 207–214.PubMedGoogle Scholar
  25. 25.
    Ishii K., Muelhauser F., Liebl U., et al. (2000) Subacute NO generation induced by Alzheimer’s beta-amyloid in the living brain: reversal by inhibition of the inducible NO synthase. FASEB J. 14, 1485–1489.PubMedGoogle Scholar
  26. 26.
    McGeer E. G. and McGeer P. L. (1995) Brain inflammation in Alzheimer disease and the therapeutic implications. Curr. Pharm. Des. 10, 821–836.Google Scholar
  27. 27.
    McGeer P. L., Schulzer M., and McGeer E. G. (1996) Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47, 425–432.PubMedGoogle Scholar
  28. 28.
    Lim G. P, Yang F., Chu T., et al. (2000) Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J. Neurosci. 20, 5709–5714.PubMedGoogle Scholar
  29. 29.
    Ruffolo R. R., Feuerstein G. Z., Hunter A. J., Poste G., and Metcalf B. W., Eds. (1999) Inflammatory cells and mediators in CNS diseases. Eds., Harwood Academic Publishers.Google Scholar
  30. 30.
    Hart M. N. and Fabry Z. (1995) CNS antigen presentation. Trends Neurosci. 11, 475–481.Google Scholar
  31. 31.
    Hickey W. F., Hsu B. L., and Kimura H. (1991) T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 28, 254–260.PubMedGoogle Scholar
  32. 32.
    Allan S. M. and Rothwell N. J. (2001) Cytokines and acute neurodegeneration. Nat. Rev. Neurosci. 2, 734–744.PubMedGoogle Scholar
  33. 33.
    Beckman J. S., Chen J., Crow J. P., and Ye Y. Z. (1994) Reactions of nitric oxide, superoxide and peroxynitrite with superoxide dismutase in neurodegeration. Progress in Brain. Res. 103, 371–380.Google Scholar
  34. 34.
    Chao C. C., Hu S., and Peterson P. K. (1995) Modulation of human microglial cell superoxide production by cytokines. J. Leukoc. Biol. 58, 65–70.PubMedGoogle Scholar
  35. 35.
    Chao C. C., Hu S., Sheng W. S., Kravitz F. H., and Peterson P. P. (1999) Inflammation-mediated neuronal cell injury. In: Inflammatory Cells and Mediators in CNS diseases (Ruffolo R. R., Feuerstein G. Z., Hunter A. J., Poste G., and Metcalf B. W., eds.) Harwood Academic Publishers, pp. 483–495.Google Scholar
  36. 36.
    Piani D., Frei K., Do K. Q., Cuenod M., and Fontana A. (1991) Murine brain macrophages induced NMDA receptor mediated neurotoxicity in vitro by secreting glutamate. Neurosci. Lett. 133, 159–162.PubMedGoogle Scholar
  37. 37.
    Piani D., Spranger M., Frei K., Schaffner A., and Fontana A. (1992) Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur. J. Immunol. 22, 2429–2436.PubMedGoogle Scholar
  38. 38.
    Barger S. W. and Basile A. S. (2001) Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J. Neurochem. 76, 846–854.PubMedGoogle Scholar
  39. 39.
    Chao C. C., Hu S., 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. Behav. Immun. 9, 355–365.PubMedGoogle Scholar
  40. 40.
    Viviani B., Corsini E., Galli C. L., and Marinovich M. (1998) Glia increase degeneration of hippocampal neurons through release of tumor necrosis factor-alpha. Toxicol. Appl. Pharmacol. 150, 271–276.PubMedGoogle Scholar
  41. 41.
    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
  42. 42.
    Brown G. C., Bolanos J. P., Heals S. J., and Clark J. B. (1995) Nitric-oxide produced by activated astrocytes rapidly and reversibly inhibits cellular respiration. Neurosci. Lett. 193, 201–204.PubMedGoogle Scholar
  43. 43.
    Murphy S. (2000) Production of nitric oxide by glial cells: regulation and potential roles in the CNS. Glia 29, 1–14.PubMedGoogle Scholar
  44. 44.
    McNaught K.S.P. and Brown G. C. (1998) Nitric oxide causes glutamate release from brain synaptosomes following inhibition of mitochondrial function. J. Neurochem. 70, 1541–1546.PubMedGoogle Scholar
  45. 45.
    Bal-Price A. and Brown G. C. (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal repiration, causing glutamate release and excitotoxicity. J. Neurosci. 21, 6480–6491.PubMedGoogle Scholar
  46. 46.
    Trabace L. and Kendrick K. M. (2000) Nitric oxide can differentially modulate striatal neurotransmitter concentrations via soluble guanylate cyclase and peroxynitrite formation. J. Neurochem. 75, 1664–1674.PubMedGoogle Scholar
  47. 47.
    Bal-Price A., Moneer Z., and Brown G. C. (2002) Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. Glia 40, 312–323.PubMedGoogle Scholar
  48. 48.
    Bal-Price A., Matthias A., and Brown G. C. (2002) Stimulation of the NADPH oxidase in activated rat microglia removes nitric oxide but induces peroxynitrite production. J. Neurochem. 80, 73–80.PubMedGoogle Scholar
  49. 49.
    Torreilles F., Salman-Tabcheh S., Guerin M., and Torreilles H. (1999) Neurodegenerative disorders: the role of peroxynitrite. Brain. Res. Rev. 30, 153–163.PubMedGoogle Scholar
  50. 50.
    Dawson V. L., and Dawson T. M. (1996) Nitric oxide neurotoxicity. J. Chem. Neuroanat. 10, 179–190.PubMedGoogle Scholar
  51. 51.
    Radi R., Cassina A., and Hodara R. (2002) Nitric oxide and peroxynitrite interactions with mitochondria. Biol. Chem. 383, 401–409.PubMedGoogle Scholar
  52. 52.
    Gunasekar P. G., Kanthasamy A. G, Borowitz J. L., and Isom G. E. (1995) NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implication for cell death. J. Neurochem. 65, 2016–2021.PubMedGoogle Scholar
  53. 53.
    Stewart V. C., Heslegrave A. J., Brown G. C., Clark J. B., and Heales S. J. (2002) Nitric oxide-dependent damage to neuronal mitochondria involves the NMDA receptor. Eur. J. Neurosci. 15, 458–464.PubMedGoogle Scholar
  54. 54.
    Prast K. and Philippu A. (2000) Nitric oxide as modulator of neuronal function. Progress in Neurobiol. 64, 51–68.Google Scholar
  55. 55.
    Serou M. J., DeCoster M. A., and Bazan N. G. (1999) Interleukin-1 beta activates expression of cyclooxygenase-2 and inducible nitric oxide synthase in primary hippocampal neuronal culture: platelet-activating factor as a preferential mediator of cyclooxygenase-2 expression. J. Neurosci. Res. 58, 593–598.PubMedGoogle Scholar
  56. 56.
    Possel H., Noack H., Putzke J., Wolf G., and Sies H. (2000) Selective upregulation of inducible nitric oxide synthase (iNOS by lipopolysaccharide (LPS) and cytokines in microglia: in vitro and in vivo studies. Glia 32, 51–59.PubMedGoogle Scholar
  57. 57.
    Simmons M. L. and Murphy S. (1992) Induction of nitric oxide synthase in glial cells. J. Neurochem. 59, 897–905.PubMedGoogle Scholar
  58. 58.
    Tran M. H., Yamada K., Olariu A., Mizuno M., Ren X. H., and Nabeshima T. (2001) Amyloid β-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. FASEB 15, 1407–1409.Google Scholar
  59. 59.
    Taylor B. S. and Geller D. A. (2000) Molecular regulation of the human inducible nitric oxide synthase (iNOS) gene. Shock 13, 413–424.PubMedGoogle Scholar
  60. 60.
    Lee S. C. and Brosnan C. F. (1996) Cytokine Regulation of iNOS Expression in Human. Glial Cells Methods 10, 31–37.Google Scholar
  61. 61.
    Merrill J. E., Murphy S. P., Mitrovic B., et al. (1997) Inducible nitric oxide synthase and nitric oxide production by oligodendrocytes. J. Neurosci. Res. 48, 372–384.PubMedGoogle Scholar
  62. 62.
    Wagner A. H., Schwabe O., and Hecker M. (2002) Atorvastatin inhibition of cytokine-inducible nitric oxide synthase expression in native endothelial cells in situ. Br. J. Pharmacol. 136, 143–149.PubMedGoogle Scholar
  63. 63.
    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, 266–276.PubMedGoogle Scholar
  64. 64.
    Fukuto J. M., Cho J. Y., and Switzer C. H. (2000) The chemical properties of nitric oxide and related nitrogen oxides. In: Nitric Oxide Biology and Pathology (Ignarro L., ed.) Academic Press, USA, pp. 23–40.Google Scholar
  65. 65.
    Nicholls D. G. and Budd S. L. (2000) Mitochondria and neuronal survival. Physiol. Rev. 80, 315–360.PubMedGoogle Scholar
  66. 66.
    Manfredi G. and Beal M. F. (2000) The role of mitochondria in the pathogenesis of neurodegenerative diseases. Brain. Pathol. 10, 462–472.PubMedGoogle Scholar
  67. 67.
    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, 910–916.PubMedGoogle Scholar
  68. 68.
    Bolanos J. P., Heales S. J., Land J. M., and Clark J. B. (1995) Effect of peroxy-nitrite on the mitochondrial respiratory chain: differential susceptibility of neurones and astrocytes in primary culture. J. Neurochem. 64, 1965–1972.PubMedGoogle Scholar
  69. 69.
    Brown G. C. and Borutaite V. (2002) Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Rad. Biol. Med. 33, 1440–1450.PubMedGoogle Scholar
  70. 70.
    Brown G. C. (2001) Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim. Biophys. Acta. 1504, 46–57.PubMedGoogle Scholar
  71. 71.
    Stewart V. C., Land J. M., Clark J. B., and Heales S. J. (1998) Pretreatment of astrocytes with interferon-alpha/beta prevents neuronal mitochondrial respiratory chain damage. J. Neurochem. 70, 432–434.PubMedGoogle Scholar
  72. 72.
    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
  73. 73.
    Brown G. C. and Cooper C. E. (1994) Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett. 345, 50–54.Google Scholar
  74. 74.
    Cleeter M. W. J., Cooper J. M., Darley-Usmar V. M., Moncada S., and Schapira A.H.V. (1994) Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respirator chain, by nitric oxide. Implications for neurodegenerative diseases. FEBS Lett. 345, 50–54.PubMedGoogle Scholar
  75. 75.
    Cooper C. E. (2002) Nitric oxide and cytochrome oxidase: substrate, inhibitor or effector? Trends Biochem Sci. 27, 33–39.PubMedGoogle Scholar
  76. 76.
    Brorson J. R., Schumacker P. T., and Zhang H. (1999) Nitric oxide acutely inhibits neuronal energy production. J. Neurosci. 19, 147–158.PubMedGoogle Scholar
  77. 77.
    Almeida A., Almeida J., Bolanos J. P., and Moncada S. (2001) Different responses of astrocytes and neurons to nitric oxide. The role of glycolytically generated ATP in astrocyte protection. Proc. Natl. Acad. Sci. 98, 15,294–15,249.Google Scholar
  78. 78.
    Lee V. Y., McClintock D. S., Santore M. T., Budinger G.R.S., and Chandel N. S. (2002) Hypoxia sensitizes cells to nitric oxide-induced apoptosis. J. Biol. Chem. 277, 16,067–16,074.Google Scholar
  79. 79.
    Brown G. C., Foxwell N., and Moncada S. (1998) Transcellular regulation of cell respiration by NO generated by activated macrophages. FEBS Lett. 439, 321–324.PubMedGoogle Scholar
  80. 80.
    Borutaite V., Matthias A., Harris H., Moncada S., and Brown G. C. (2001) Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation. Am. J. Physiol. 24, 2256–2260.Google Scholar
  81. 81.
    Cassina A. and Radi R. (1996) Different inhibitory actions of NO and peroxy-nitrite on mitochondrial electron transport. Arch. Biophys. Biochem. 328, 309–316.Google Scholar
  82. 82.
    Clementi E., Brown G. C., Feelisch M., and Moncada S. (1998) Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective role of glutathione. Proc. Natl. Acad. Sci. USA 95, 7631–7636.PubMedGoogle Scholar
  83. 83.
    Ribo N. A., Clementi E., Melani M., Boveris A., Cadenas E., Moncada S., and Poderoso J. I. (2001) Nitric oxide inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem. J. 359, 139–145.Google Scholar
  84. 84.
    Borutaite V., Budriunaite A., and Brown G. C. (2000) Reversal of nitric oxide-, peroxynitrite- and S-nitrosothiol-induced inhibition of mitochondrial respiration or complex I activity by light and thiols. Biochim. Biophys. Acta. 1459, 405–412.PubMedGoogle Scholar
  85. 85.
    Drapier J. C. and Hibbs J. B., Jr. (1988) Differentiation of murine macrophages to express non-specific cytotoxicity for tumour cells results in l-arginine-dependent inhibition of mitochondrial iron-sulphur in the macrophage effector cells. J. Immunol. 140, 2829–2838.PubMedGoogle Scholar
  86. 86.
    Stuehr D. J. and Nathan C. F. (1989) NO: a macrophage product responsible for cytostasis and respiratory inhibition in tumour target cells. J. Exp. Med. 169, 1543–1555.PubMedGoogle Scholar
  87. 87.
    Yamamoto T., Maruyama W., Kato Y., Yi H., Shamoto-Nagai M., Tanaka M., Sato Y., and Naoi M. (2002) Selective nitration of mitochondrial complex I by peroxynitrite: involvement in mitochondria dysfunction and cell death of dopaminergic SH-SY5Y cells. J. Neural. Transm. 109, 1–13.PubMedGoogle Scholar
  88. 88.
    Henry Y., Lepoivre M., Drapier J. C., Ducrocq C., Boucher J. L., and Guissani A. (1993) EPR characterization of molecular targets for NO in mammalian cells and organelles. FASEB J. 7, 1124–1134.PubMedGoogle Scholar
  89. 89.
    Welter R., Yu L., and Yu C. A. (1996) The effects of nitric oxide on electron transport complexes. Arch. Biochem. Biophys. 331, 9–14.PubMedGoogle Scholar
  90. 90.
    Stachowiak O., Dolder M., Wallimann T., and Richter C. (1998) Mitochondrial creatine kinase is a prime target of peroxynitrite-induced modification and inactivation. J. Biol. Chem. 273, 16,694–16,699.Google Scholar
  91. 91.
    Gadelha F. R., Thomson L., Fagian M. M., Costa A.D.T., Radi R., and Vercesi A. E. (1997) Calcium-independent permeabilization of the inner mitochondrial membrane by peroxynitrite is mediated by membrane protein thiol cross-linking and lipid peroxidation. Arch. Biochem. Biophys. 345, 243–250.PubMedGoogle Scholar
  92. 92.
    Liu Z. and Martin L. J. (2001) Motor neurons rapidly accumulate DNA single-strand breaks after in vitro exposure to nitric oxide and peroxynitrite and in vivo axotomy. J. Comp. Neurol. 432, 35–60.PubMedGoogle Scholar
  93. 93.
    Sharpe M. A. and Cooper C. E. (1998) Interaction of peroxynitrite with mitochondrial cytochrome oxidase: catalytic production of nitric oxide and irreversible inhibition of enzyme activity. J. Biol. Chem. 273, 30,961–30,972.Google Scholar
  94. 94.
    Cooper C. E. and Davies N. A. (2000) Effects of nitric oxide on the cytochrome oxidase Km for oxygen: implications for mitochondrial pathology. Biochim. Biophys. Acta. 1459, 390–396.PubMedGoogle Scholar
  95. 95.
    Packer M. A. and Murphy M. P. (1994) Peroxynitrite causes calcium efflux from mitochondria which is prevented by cyclosporin A. FEBS Lett. 345, 237–240.PubMedGoogle Scholar
  96. 96.
    Borutaite V., Morkuniene R., and Brown G. C. (1999) Release of cytochrome c from heart mitochondria is induced by high calcium and peroxynitrite and is responsible for calciuminduced inhibition of substrate oxidation. Biochim. Biophys. Acta. 1453, 41–48.PubMedGoogle Scholar
  97. 97.
    Borutaite V., Morkuniene R., and Brown G. C. (2000) Nitric oxide donors, nitrosothiols and mitochondrial respiration inhibitors induce caspase activation by different mechanisms. FEBS Lett. 467, 155–159.PubMedGoogle Scholar
  98. 98.
    Bernardi P., Petronilli V., Di Lisa F., and Forte M. (2001) A mitochondrial perspective on cell death. Trends Biochem. Sci. 26, 112–117.PubMedGoogle Scholar
  99. 99.
    Crompton M. (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem. J. 341, 233–249.PubMedGoogle Scholar
  100. 100.
    Brookes P. S., Salinas E. P., Darley-Usmar K., Eiserich J. P., Freeman B. A., Darley-Usmar V. D., and Anderson P. G. (2000) Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release. J. Biol. Chem. 275, 20,474–20,479.Google Scholar
  101. 101.
    Viveira H. L., Belzacq A. S., Haouzi D., et al. (2001) The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal. Oncogene 20, 4305–4316.Google Scholar
  102. 102.
    Piantadosi C. A., Tatro L. G., and Whorton A. R. (2002) NO and differential effects of ATP on mitochondrial permeability transition. Nitric Oxide 6, 45–60.PubMedGoogle Scholar
  103. 103.
    Daugas E., Nochy D., Ravagnan L., Loeffler M., Susin S. A., Zamzami N., and Kroemer G. (2000) Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett. 476, 181–123.Google Scholar
  104. 104.
    Chai J., Du C., Wu J. W., Kyin S., Wang X., and Shi Y. (2000) Structural and biochemical basis of apoptotic activation by Smac/Diablo. Nature 406, 855–862.PubMedGoogle Scholar
  105. 105.
    Petronilli V., Penzo D., Scorrano L., Bernardi P., and Di Lisa F. (2001) The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J. Biol. Chem. 276, 12,030–12,034.Google Scholar
  106. 106.
    Folbergrova J., Li P. A., Uchino H., Smith M. L., and Siesjo B. K. (1997) Changes in the bioenergetic state of rat hippocampus during 2.5 min of ischemia, and prevention of cell damage by cyclosporin A in hyperglycemic subjects. Exp. Brain. Res. 114, 44–50.PubMedGoogle Scholar
  107. 107.
    Zhu S., Stavrovskaya I. G., Drozda M., et al. (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417, 74–78.PubMedGoogle Scholar
  108. 108.
    Sankarapandi S., Zweier J. L., Mukherjee G., Quinn M. T., and Huso D. L. (1998) Measurement and characterization of superoxide generation in microglial cells: evidence for an NADPH oxidase-dependent pathway. Arch. Biochem. Biophys. 353, 312–321.PubMedGoogle Scholar
  109. 109.
    McBride A. and Brown G. C. (1997) Activated human neutrophils rapidly break down nitric oxide. FEBS Lett. 417, 231–234.PubMedGoogle Scholar
  110. 110.
    Do K. Q., Grima G., Benz B., and Salt T. E. (2002) Glial-neuronal transfer of arginine and s-nitrosothiols in NO transmission. Ann. NY Acad. Sci. 962, 81–92.PubMedGoogle Scholar
  111. 111.
    Yoneyama H., Yamamoto A., and Kosaka H. (2001) Neuronal nitric oxide synthase generates superoxide from the oxygenase domain. Biochem. J. 360, 247–253.PubMedGoogle Scholar
  112. 112.
    Xia Y. and Zweier J. L. (1997) Superoxide and peroxynitrite generation from inducible NO synthase in macrophages. Proc. Natl. Acad. Sci. USA 94, 6954–6958.PubMedGoogle Scholar
  113. 113.
    McBride A., Borutaite V., and Brown G. C. (1999) Superoxide dismutase and hydrogen peroxide cause rapid nitric oxide breakdown, peroxynitrite production and subsequent cell death. Biochim. Biophys. Acta 1454, 275–288.PubMedGoogle Scholar
  114. 114.
    Bauer G. (2000) Reactive oxygen and nitrogen species: efficient, selective, and interactive signals during intercellular induction of apoptosis. Anticancer Res. 20, 4115–4139.PubMedGoogle Scholar
  115. 115.
    Brown G. C. (1995) Reversible binding and inhibition of catalase by nitric oxide. Eur. J. Biochem. 232, 188–191.PubMedGoogle Scholar
  116. 116.
    Boveris A. and Cadenas E. (2000) Mitochondrial production of hydrogen peroxide regulation by NO and the role of ubisemiquinone. IUBMB Life 50, 245–250.PubMedGoogle Scholar
  117. 117.
    Wei T., Chen C., Hou J., Xin W., and Mori A. (2000) Nitric oxide induces oxidative stress and apoptosis in neuronal cells. Biochim. Biophys. Acta. 1498, 72–79.PubMedGoogle Scholar
  118. 118.
    Eliasson M. J., Huang Z., Ferrante R. J., Sasamata M., Molliver M. E., Snyder S. H., and Moskowitz M. A. (1999) Neuronal NO synthase activation and peroxynitrite formation in bschemic stroke linked to neural damage. J. Neurosci. 19, 5910–5918.PubMedGoogle Scholar
  119. 119.
    Lipton S. A., Choi Y. B., Pan Z. H., et al. (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of NO and related nitroso-compounds. Nature 364, 626–632.PubMedGoogle Scholar
  120. 120.
    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, 266–276.PubMedGoogle Scholar
  121. 121.
    Xie Z., Wei M., Morgan T. E., Fabrizio P., Han D., Finch C. E., and Longo V. D. (2002) Peroxynitrite mediates neurotoxicity of amyloid beta-peptidel-42- and lipopolysaccharide-activated microglia. J. Neurosci. 22, 3484–3492.PubMedGoogle Scholar
  122. 122.
    Zhang J., Dawson V., Dawson T., and Synder S. (1994) Nitric oxide activation of poly(ADP-ribose)synthase and neurotoxicity. Science 263, 687–684.PubMedGoogle Scholar
  123. 123.
    Di Stasi A. M., Mallozzi C., Macchia G., Maura G., Petrucci T. C., and Minetti M. (2002) Peroxynitrite affects exocytosis and SNARE complex formation and induces tyrosine nitration of synaptic proteins. J. Neurochem. 82, 420–429.PubMedGoogle Scholar
  124. 124.
    Leist M., Fava E., Montecucco C., and Nicotera P. (1997) Peroxynitrite and nitric oxide donors induce neuronal apoptosis by eliciting autocrine excitotoxicity. Eur. J. Neurosci. 9, 1488–1498.PubMedGoogle Scholar
  125. 125.
    Zhang X., Chen J., Graham S. H., et al. (2002) Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J. Neurochem. 82, 181–191.PubMedGoogle Scholar
  126. 126.
    Cassina P., Peluffo H., Pehar M., et al. (2002) Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. J. Neurosci. Res. 67, 21–29.PubMedGoogle Scholar
  127. 127.
    Almedia A., Heales S. J., Bolanos J. P., and Medina J. M. (1998) Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial dysfunction and glutathione depletion. Brain Res. 790, 209–216.Google Scholar
  128. 128.
    Bolanos J. P., Heales S. J., Peuchen S., Barker J. E., Land J. M., and Clark J. B. (1996) Nitric oxide-mediated mitochondrial damage: a potential neuroprotective role for glutathione. Free Radic. Biol. Med. 21, 995–1001.PubMedGoogle Scholar
  129. 129.
    Jenner P., Dexter D. T., Sian J., Shapira A.H.V., and Marsden C. D. (1992) Oxidative stress as a cause of nigral cell death in Parkson’s disease and incidental Lewy body disease. Ann. Neurol. 32, 582–587.Google Scholar
  130. 130.
    Meldrum B. and Garthwaite J. (1990) Excitatory amino acid neurotoxicity and neurode-generative disease. Trends Pharmacol. Sci. 11, 379–387.PubMedGoogle Scholar
  131. 131.
    Murphy T. H., Schnaar R. L., and Coyle J. T. (1990) Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. FASEB J. 4, 1624–1633.PubMedGoogle Scholar
  132. 132.
    Schubert D. and Piasecki D. (2001) Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. J. Neurosci. 21, 7455–7462.PubMedGoogle Scholar
  133. 133.
    Sattler R. and Tymianski M. (2001) Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol. Neurobiol. 24, 107–129.PubMedGoogle Scholar
  134. 134.
    Schinder A. F., Olson E. C., Spitzer N. C., and Montal M. (1996) Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J. Neurosci. 16, 6125–6133.PubMedGoogle Scholar
  135. 135.
    Novelli A., Reilly J. A., Lysko P. G., and Henneberry R. C. (1988) Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when mintracellular energy levels are reduced. Brain Res. 451, 205–212.PubMedGoogle Scholar
  136. 136.
    Dawson V. L., Dawson T. M., London E. D., Bredt D. S., and Snyder S. H. (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA 88, 6368–6371.PubMedGoogle Scholar
  137. 137.
    Strijbos P.L.M., Leach M. J., and Garthwaite J. (1996) Vicious cycle involving Na+ channels, glutamate release, and NMDA receptors mediates delayed neurodegeneration through nitric oxide formation. J. Neuroscience. 16, 5004–5013.Google Scholar
  138. 138.
    Keelan J., Vergun O., and Duchen M. R. (1999) Excitotoxic mitochondrial depolarisation requires both calcium and nitric oxide in rat hippocampal neurons. J. Physiol. 520, 797–813.PubMedGoogle Scholar
  139. 139.
    Almeida A. and Bolanos J. P. (2001) A transient inhibition of mitochondrial ATP synthesis by nitric oxide synthase activation triggered apoptosis in primary cortical neurons. J. Neurochem. 77, 676–690.PubMedGoogle Scholar
  140. 140.
    Ruiz F., Alvarez G., Ramos M., Hernandez M., Bogonez E., and Satrustegui J. (2000) Cyclosporin A targets involved in protection against glutamate excitotoxicity. Eur. J. Pharmacol. 404, 29–39.PubMedGoogle Scholar
  141. 141.
    Dawson V. L., Kizushi V. M., Huang P. L., Snyder S. H., and Dawson T. M. (1996) Resitance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J. Neurosci. 16, 2479–2487.PubMedGoogle Scholar
  142. 142.
    Brustovetsky N. and Dubinsky J. M. (2000) Limitations of cyclosporin A inhibition of the permeability transition in CNS mitochondria. J. Neurosci. 20, 8229–8237.PubMedGoogle Scholar
  143. 143.
    Grima G., Benz B., and Do K. Q. (2001) Glialderived arginine, the NO precursor, protects neurons from NMDA-induced excitotoxicity. Eur. J. Neurosci. 14, 1762–1770.PubMedGoogle Scholar
  144. 144.
    Urushitani M., Nakamizo T., Inoue R., et al. (2001) N-methyl-d-aspartate receptor-mediated mitochondrial Ca(2+) overload in acute excitotoxic motor neuron death: a mechanism distinct from chronic neurotoxicity after Ca(2+) influx. J. Neurosci Res. 63, 377–387.PubMedGoogle Scholar
  145. 145.
    Meffert M. K., Premack B. A., and Schulman H. (1994) Nitric oxide stimulates Ca+2-independent synaptic vesicle release. Neuron 12, 1235–1244.PubMedGoogle Scholar
  146. 146.
    Sequeira S., Ambrosio A., Malva J. O., Carvalho A. P., and Carvalho C. M. (1997) Modulation of glutamate release from rat hippocampal synaptosomes by nitric oxide. Nitric Oxide 1, 315–329.PubMedGoogle Scholar
  147. 147.
    Meffert M. K., Calakos N. C., Scheller R. H., and Schulman H. (1996) Nitric oxide modulates synaptic vesicle docking fusion reactions. Neuron 16, 1229–1236.PubMedGoogle Scholar
  148. 148.
    Piani D. and Fontana A. (1994) Involvement of the cystine transport system xc-in the macrophage-induced glutamate-dependent cytotoxicity to neurons. J. Immunol. 152, 3578–3585.PubMedGoogle Scholar
  149. 149.
    Noda M., Nakanishi H., and Akaike N. (1999) Glutamate release from microglia via glutamate transporter is enhanced by amyloid-beta peptide. Neuroscience 92, 1465–1474.PubMedGoogle Scholar
  150. 148.
    Siesjo B. K. and Bengtsson F. (1989) Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J. Cereb. Blood Flow Metab. 9, 127–140.PubMedGoogle Scholar
  151. 149.
    Pocock J. M. and Nicholls D. G. (1998) Exocytotic and nonexocytotic modes of glutamate release from cultured cerebellar granule cells during chemical ischaemia. J. Neurochem. 70, 806–813.PubMedGoogle Scholar
  152. 150.
    Beal M. F., Brouillet E., Jenkins B. G., et al. (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci. 13, 4181–4192.PubMedGoogle Scholar
  153. 151.
    Lee W. T., Shen Y. Z., and Chang C. (2000) Neuroprotective effect of lamotrigine and MK-801 on rat brain lesions induced by 3-nitropropionic acid: evaluation by magnetic resonance imaging and in vivo proton magnetic resonance spectroscopy. Neuroscience 95, 89–95.PubMedGoogle Scholar
  154. 152.
    Betarbet R., Sherer T. B., and Greenamyre J. T. (2002) Animal models of Parkinson’s disease. Bioessays 24, 308–318.PubMedGoogle Scholar
  155. 153.
    Greene J. G. and Greenamyre J. T. (1995) Exacerbation of NMDA, AMPA, and L-glutamate excitotoxicity by the succinate dehydrogenase inhibitor malonate. J. Neurochem. 64, 2332–2338.PubMedGoogle Scholar
  156. 154.
    Greenamyre J. T., Sherer T. B., Betarbet R., and Panov A. V. (2001) Complex I and Parkinson’s disease. IUBMB Life 52, 135–141.PubMedGoogle Scholar
  157. 155.
    Kim W. K. and Ko K. H. (1998) Potentiation of N-methyl-d-aspartate-mediated neurotoxicity by immunostimulated murine microglia. J. Neurosci. Res. 54, 17–26.PubMedGoogle Scholar
  158. 156.
    Capano M., Virji S., and Crompton M. (2002) Cyclophilin-A is involved in excitotoxin-induced caspase activation in rat neuronal B50 cells. Biochem. J. 363, 29–36.PubMedGoogle Scholar
  159. 157.
    Withe B. C., Sullivan J. M., DeGracia D. J., et al. (2000) Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J. Neurol. Sci. 179, 1–33.Google Scholar
  160. 158.
    Leist M., Volbracht C., Kuhnle S., Fava E., Ferrandomay E., and Nicotera P. (1997) Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide. Molecular Medicine 11, 750–764.Google Scholar
  161. 159.
    Tamatami M., Ogawa S., Niitsu Y., and Tohyama M. (1998) Involvement of Bcl-2 family and caspase-3-like protease in NO-mediated neuronal apoptosis. J. Neurochem. 71, 1588–1596.Google Scholar
  162. 160.
    Uehara T., Kikuchi Y., and Nomura Y. (1999) Caspase activation accompanying cytochrome c release from mitochondria is possibly involved in nitric-oxide-induced neuronal apoptosis in SH-SY5Y cells. J. Neurochem. 72, 196–205.PubMedGoogle Scholar
  163. 161.
    Szabo C. and Dawson V. L. (1998) Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol. Sci. 19, 287–298.PubMedGoogle Scholar
  164. 162.
    Yu S. W., Wang H., Poitras M. F., et al. (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297, 259–263.PubMedGoogle Scholar
  165. 163.
    Molina y Vedia L., McDonald B., Reep B., Brune B., Di Silvio M., Billiar T. R., and Lapentina E. G. (1992) NO-induced S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits enzyme activity and increases endogenous ADP- ribosylation. J. Biol. Chem. 267, 24,929–24,932.Google Scholar
  166. 164.
    Albina J. E., Mastrofrancesco B., and Reichner J. S. (1999) Acyl phosphatase activity of NO-inhibited glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a potential mechanism for uncoupling glycolysis from ATP production in NO producing cells. Biochem. J. 341, 5–9.PubMedGoogle Scholar
  167. 165.
    Bal-Price A. and Brown G. C. (2000) Nitric oxide-induced necrosis and apoptosis in PC12 cells mediated by mitochondria. J. Neurochem. 75, 1455–1464.PubMedGoogle Scholar
  168. 166.
    Leist M. and Nicotera P. (1998) Apoptosis, excitotoxicity, and neuropathology. Exp. Cell Res. 239, 183–201.PubMedGoogle Scholar
  169. 167.
    Volbracht C., Fava E., Leist M., and Nicotera P. (2001) Calpain inhibitors prevent nitric oxide-triggered excitotoxic apoptosis. Neuroreport. 12, 3645–3648.PubMedGoogle Scholar
  170. 168.
    Leist M., Single B., Naumann H., Fava E., Simon B., Kuhnle S., and Nicotera P. (1999) Inhibition of mitochondrial ATP generation by nitric oxide switches apoptosis to necrosis. Exp. Cell Res. 249, 396–403.PubMedGoogle Scholar
  171. 169.
    Ghatan S., Larner S., Kinoshita Y., Hetman M., Patel L., Xia Z., Youle R. J., and Morrison R. S. (2000) p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons. J. Cell Biol. 150, 335–547.PubMedGoogle Scholar
  172. 170.
    Cheng A., Chan S. L., Milhavet O., Wang S., and Mattson M. P. (2001) p38 MAP kinase mediates nitric oxide-induced apoptosis of neural progenitor cells. J. Biol. Chem. 276, 43,320–43,327.Google Scholar
  173. 171.
    Vincent A. M., TenBroeke M., and Maiese K. (1999) Neuronal intracellular pH directly mediates NO-induced programmed cell death. J. Neurobiol. 40, 171–184.PubMedGoogle Scholar
  174. 172.
    Golde S., Chandran S., Brown G. C., and Compston A. (2002) Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J. Neurochem. 82, 269–282.PubMedGoogle Scholar
  175. 173.
    Lipton S. A. and Stamler J. S. (1994) Actions of redox-related congeners of nitric oxide at the NMDA receptor. Neuropharmacology 33, 1229–1233.PubMedGoogle Scholar
  176. 174.
    D’Emilia D. M. and Lipton S. A. (1999) Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures. Neurosci Lett. 265, 103–106.PubMedGoogle Scholar
  177. 175.
    Torok N. J., Higuchi H., Bronk S., and Gores G. J. (2002) Nitric oxide inhibits apoptosis down-stream of cytochrome C release by nitrosylating caspase 9. Cancer Res. 62, 1648–1653.PubMedGoogle Scholar
  178. 176.
    Thippeswamy T., McKay J. S., and Morris R. (2001) Bax and caspases are inhibited by endogenous nitric oxide in dorsal root ganglion neurons in vitro. Eur. J. Neurosci. 14, 1229–1236.PubMedGoogle Scholar
  179. 177.
    Lipton S. A. (1999) Neuronal protection and destruction by NO. Cell Death Differ. 6, 943–951.PubMedGoogle Scholar
  180. 178.
    Takuma K., Phuagphong P., Lee E., Mori K., Baba A., and Matsuda T. (2001) Anti-apoptotic effect of cGMP in cultured astrocytes: inhibition by cGMP-dependent protein kinase of mitochondrial permeable transition pore. J. Biol. Chem. 276, 48,093–48,099.Google Scholar
  181. 179.
    Boje K. M. and Arora P. K. (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res. 587, 250–256.PubMedGoogle Scholar
  182. 180.
    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. Immuno. 149, 2736–2741.Google Scholar
  183. 181.
    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
  184. 182.
    Jeohn G. H., Kim W. G., and Hong J. S. (2000) Time dependency of the action of nitric oxide in lipopolysaccharide-interferon-gamma-induced neuronal cell death in murine primary neuronglia co-cultures. Brain Res. 880, 173–177.PubMedGoogle Scholar
  185. 183.
    Le W., Rowe D., Xie W., Ortiz I., He Y., and Appel S. H. (2001) Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson’s disease. J. Neurosci. 21, 8447–8455.PubMedGoogle Scholar
  186. 184.
    McMillian M., Kong L. Y., Sawin S. M., Wilson B., Das K., Hudson P., Hong J. S., and Bing G. (1995) Selective killing of cholinergic neurons by microglial activation in basal forebrain mixed neuronal/glial cultures. Biochem. Biophys. Res. Commun. 215, 572–577.PubMedGoogle Scholar
  187. 185.
    Bauer J., Rauschka H., and Lassmann H. (2001) Inflammation in the nervous system: the human perspective. Glia 36, 235–243.PubMedGoogle Scholar
  188. 186.
    Chao C. C., Lokensgard J. R., Sheng W. S., Hu S., and Peterson P. K. (1997) IL-1-induced iNOS expression in human astrocytes via NF-kappaB. Neuroreport 8, 3163–3166.PubMedGoogle Scholar
  189. 187.
    Matsuoka Y., Kitamura Y., Takahashi H., Tooyama I., Kimura H., and Gebicke-Haerter P.J. (1999) Interferon-gamma plus lipopolysaccharide induction of delayed neuronal apoptosis in rat hippocampus. Neurochem. Int. 34, 91–99.PubMedGoogle Scholar
  190. 188.
    Iravani M. M., Kashefi K., Mander P., Rose S., and Jenner P. (2002) Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neuroscience 110, 49–58.PubMedGoogle Scholar
  191. 189.
    Park W. S., Chang Y. S., and Lee M. (2001) N(omega)-nitro-l-arginine methyl ester (L-NAME) attenuates the acute inflammatory responses and brain injury during the early phase of experimental Escherichia coli meningitis in the newborn piglet. Neurol. Res. 23, 862–886.PubMedGoogle Scholar
  192. 190.
    Morimoto K., Murasugi T., and Oda T. (2002) Acute neuroinflammation exacerbates excitotoxicity in rat hippocampus in vivo. Exp. Neurol. 177, 95–104.PubMedGoogle Scholar
  193. 191.
    Vodovotz Y., Lucia M. S., Flanders K. C., et al. (1996) Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer’s disease. J. Exp. Med. 184, 1425–1433.PubMedGoogle Scholar
  194. 192.
    Smith M. A., Richey P. L., Sayre L. M., Beckman J. S., and Perry G. (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J. Neurosci. 17, 2653–2657.PubMedGoogle Scholar
  195. 193.
    Duda J. E., Giasson B. I., Chen Q., et al. (2000) Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. Am. J. Pathol. 157, 1439–1445.PubMedGoogle Scholar
  196. 194.
    McGeer P. L. and McGeer E. G. (2001) Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 22, 799–809.PubMedGoogle Scholar
  197. 195.
    Tran M. H., Yamada K., Olariu A., Mizuno M., Ren X. H., and Nabeshima T. (2001) Amyloid β-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. FASEB J 15, 1407–1409.PubMedGoogle Scholar
  198. 196.
    Koistinaho M., Kettunen M. I., Goldsteins G., et al. (2002) Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc. Natl. Acad. Sci. USA 99, 1610–1615.PubMedGoogle Scholar
  199. 197.
    McGeer P. L., Yasojima K., and McGeer E. G. (2001) Inflammation in Parkinson’s disease. Adv. Neurol. 86, 83–9.PubMedGoogle Scholar
  200. 198.
    Knott C., Stern G., and Wilkin G. P. (2000) Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol. Cell Neurosci. 16, 724–739.PubMedGoogle Scholar
  201. 199.
    Hunot S., Boissiere F., Faucheux B., Brugg B., Mouatt-Prigent A., Agid Y., and Hirsch E. C. (1996) Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience 72, 355–363.PubMedGoogle Scholar
  202. 200.
    Good P. F., Hsu A., Werner P., Perl D. P., and Olanow C. W. (1998) Protein nitration in Parkinson’s disease. J. Neuropathol. Exp. Neurol. 57, 338–342.PubMedGoogle Scholar
  203. 201.
    Barthwal M. K., Srivastava N., and Dikshit M. (2001) Role of NO in a progressive neurodegeneration model of Parkinson’s disease in the rat. Redox Rep. 6, 297–302.PubMedGoogle Scholar
  204. 202.
    Du Y., Ma Z., Lin S., et al. (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc. Natl. Acad. Sci. USA 98, 14,669–14,674.Google Scholar
  205. 203.
    Schapira A. H., Mann V. M., Cooper J. M., et al. (1990) Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J. Neurochem. 55, 2142–2145.PubMedGoogle Scholar
  206. 204.
    Dehmer T., Lindenau J., Haid S., Dichgans J., and Schulz J. B. (2000) Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J. Neurochem. 74, 2213–2216.PubMedGoogle Scholar
  207. 205.
    Hantraye P., Brouillet E., Ferrante R., Palfi S., Dolan R., Matthews R. T., and Beal M. F. (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat. Med. 2, 1017–1021.PubMedGoogle Scholar
  208. 206.
    Przedborski S., Jackson-Lewis V., Yokoyama R., Shibata T., Dawson V. L., and Dawson T. M. (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine(MPTP)-induced dopaminergic neurotoxicity. Proc. Natl. Acad. Sci. 93, 4565–4571.PubMedGoogle Scholar
  209. 207.
    Estevez A. G., Spear N., Manuel S. M., Barbeito L., Radi R., and Beckman J. S. (1998) Role of endogenous nitric oxide and peroxynitrite formation in the survival and death of motor neurons in culture. Prog. Brain Res. 118, 269–280.PubMedGoogle Scholar
  210. 208.
    Sasaki S., Shibata N., Komori T., and Iwata M. (2000) iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis. Neurosci. Lett. 8, 44–48.Google Scholar
  211. 209.
    Phul R. K., Shaw P. J., Ince P. G., and Smith M. E. (2000) Expression of nitric oxide synthase isoforms in spinal cord in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1, 259–256.PubMedGoogle Scholar
  212. 210.
    Beckman J. S., Carson M., Smith C. D., and Koppenol W. H. (1993) ALS, SOD and peroxynitrite. Nature 364, 584–588.PubMedGoogle Scholar
  213. 211.
    Almer G., Vukosavic S., Romero N., and Przedborski S. (1999) Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. J. Neurochem. 72, 2415–2425.PubMedGoogle Scholar
  214. 212.
    Sasaki S., Warita H., Abe K., and Iwata M. (2001) Inducible nitric oxide synthase (iNOS) and nitrotyrosine immunoreactivity in the spinal cords of transgenic mice with a G93A mutant SOD1 gene. J. Neuropathol. Exp. Neurol. 60, 839–846.PubMedGoogle Scholar
  215. 213.
    Tohgi H., Abe T., Yamazaki K., Murata T., Ishizaki E., and Isobe C. (1999) Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis. Ann. Neurol. 46, 129–131.PubMedGoogle Scholar
  216. 214.
    Trapp B. D., Peterson J., Ransohoff R. M., Rudick R., Mork S., and Bo L. (1998) Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 323–325.Google Scholar
  217. 215.
    Liu J. S., Zhao M. L., Brosnan C. F., and Lee S. C. (2001) Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am. J. Pathol. 158, 2057–2066.PubMedGoogle Scholar
  218. 216.
    De Groot C. J., Ruuls S. R., Theeuwes J. W., Dijkstra C. D., and Van der Valk P. (1997) Immunocytochemical characterization of the expression of inducible and constitutive isoforms of nitric oxide synthase in demyelinating multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 56, 10–20.PubMedGoogle Scholar
  219. 217.
    Bagasra O., Michaels F. H., Zheng Y. M., et al. (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc. Natl. Acad. Sci. USA 92, 12,041–12,045.Google Scholar
  220. 218.
    Oleszak E. L., Zaczynska E., Bhattacharjee M., Butunoi C., Legido A., and Katsetos C. D. (1998) Inducible nitric oxide synthase and nitrotyrosine are found in monocytes/macrophages and/or astrocytes in acute, but not in chronic, multiple sclerosis. Clin. Diagn. Lab. Immunol. 5, 438–445.PubMedGoogle Scholar
  221. 219.
    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, 575–585.PubMedGoogle Scholar
  222. 220.
    Fenyk-Melody J. E., Garrison A. E., Brunnert S. R., Weidner J. R., Shen F., Shelton B. A., and Mudgett J. S. (1998) Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. J. Immunol. 160, 2940–2946.PubMedGoogle Scholar
  223. 221.
    Pozza M., Bettelli C., Aloe L., Giardino L., and Calza L. (2000) Further evidence for a role of nitric oxide in experimental allergic encephalomyelitis: aminoguanidine treatment modifies its clinical evolution. Brain Res. 855, 39–46.PubMedGoogle Scholar
  224. 222.
    Hooper D. C., Bagasra O., Marini J. C., et al. (1997) Prevention of experimental allergic encephalo-myelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis. Proc. Natl. Acad. Sci. USA 94, 2528–2533.PubMedGoogle Scholar
  225. 223.
    Malinski T., Bailey F., Zhang Z. G., and Chopp M. (1993) Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 13, 355–358.PubMedGoogle Scholar
  226. 224.
    Jiang K., Kim S., Murphy S., Song D., and Pastuszko A. (1996) Effect of hypoxia and reoxygenation on regional activity of nitric oxide synthase in brain of newborn piglets. Neurosci Lett. 206, 199–203.PubMedGoogle Scholar
  227. 225.
    Zhang Z. G., Chopp M., Gautam S., et al. (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, 85–95.PubMedGoogle Scholar
  228. 226.
    Guo Y., Ward M. E., Beasjours S., Mori M., and Hussain S. N. (1997) Regulation of cerebellar nitric oxide production in response to prolonged in vivo hypoxia. J. Neurosci. Res. 49, 89–97.PubMedGoogle Scholar
  229. 227.
    Huang Z., Huang PL., Panahian N., Dalkara T., Fishman M. C., and Moskowitz M. A. (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265, 1883–1885.PubMedGoogle Scholar
  230. 228.
    Hara H., Huang P. L., Panahian N., Fishman M. C., and Moskowitz M. A. (1996) Reduced brain edema and infarction volume in mice lacking the neuronal isoform of NO synthase after transient MCA occlusion. J. Cereb. Blood Flow Metab. 16, 605–611.PubMedGoogle Scholar
  231. 229.
    Ste-Marie L., Hazell A. S., Bemeur C., Butterworth R., and Montgomery J. (2001) Immunohistochemical detection of inducible nitric oxide synthase, nitrotyrosine and manganese superoxide dismutase following hyperglycemic focal cerebral ischemia. Brain Res. 918, 10–19.PubMedGoogle Scholar
  232. 230.
    Holtz M. L., Craddock S. D., and Pettigrew K. (2001) Rapid expression of neuronal and inducible nitric oxide synthases during post-ischemic reperfusion in rat brain. Brain Res. 898, 49–60.PubMedGoogle Scholar
  233. 231.
    Parmentier-Batteur S., Bohme G. A., Lerouet D., Zhou-Ding L., Beray V., Margaill I., and Plotkine M. (2001) Antisense oligodeoxynucleotide to inducible nitric oxide synthase protects against transient focal cerebral ischemia-induced brain injury. J. Cereb. Blood Flow Metab. 21, 15–21.PubMedGoogle Scholar
  234. 232.
    Parmentier S., Bohme G. A., Lerouet D., Damour D., Stutzmann J. M., Margaill I., and Plotkine M. (1999) Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury. Br. J. Pharmacol. 127, 546–552.PubMedGoogle Scholar
  235. 233.
    Samdani A. F., Dawson T. M., and Dawson V. L. (1997) Nitric oxide synthase in models of focal ischemia. Stroke 28, 1283–1288.PubMedGoogle Scholar
  236. 234.
    Wei G., Dawson V. L., and Zweier J. L. (1999) Role of neuronal and endothelial nitric oxide synthase in nitric oxide generation in the brain following cerebral ischemia. Biochim. Biophys. Acta. 1455, 23–34.PubMedGoogle Scholar
  237. 235.
    Grzybicki D., Moore S. A., Schelper R., Glabinski A. R., Murphy S., and Ransohoff R. M. (1998) Expression of monocyte chemoattractant protein (MCP-1) and nitric oxide synthase-2 following cerebral trauma. Acta. Neuropathol. 95, 98–103.PubMedGoogle Scholar
  238. 236.
    Wada K., Chatzipanteli K., Kraydieh S, Busto R., and Dietrich W. D. (1998) Inducible nitric oxide synthase expression after traumatic brain injury and neuroprotection with aminoguanidine treatment in rats. Neurosurgery 43, 1427–1436.PubMedGoogle Scholar
  239. 237.
    Satake K., Matsuyama Y., Kamiya M., Kawakami H., Iwata H., Adachi K., and Kiuchi K. (2000) Nitric oxide via macrophage iNOS induces apoptosis following traumatic spinal cord injury. Mol. Brain Res. 85, 114–122.PubMedGoogle Scholar
  240. 238.
    Kyrkanides S., O’Banion M. K., Whiteley P. E., Daeschner J. C., and Olschowka J. A. (2001) Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury. J. Neuroimmunol. 119, 269–277.PubMedGoogle Scholar
  241. 239.
    Payan H., Toga M., and Berard-Badier M. (1970) The pathology of post-traumatic epilepsies. Epilepsia 11, 390–392.Google Scholar
  242. 240.
    Bagetta G., Paoletti A. M., Leta A., Del Duca C., Nistico R., Rotiroti D., and Corasaniti M. T. (2002) Abnormal expression of neuronal nitric oxide synthase triggers limbic seizures and hippocampal damage in rat. Biochem. Biophys. Res. Commun. 291, 255–260.PubMedGoogle Scholar
  243. 241.
    Chavko M., Xing G., and Keyser D. O. (2001) Increased sensitivity to seizures in repeated exposures to hyperbaric oxygen: role of NOS activation. Brain Res. 900, 227–233.PubMedGoogle Scholar
  244. 242.
    Van Leeuwen R., De Vries R., and Dzoljic M. R. (1995) 7-Nitro indazole, an inhibitor of neuronal nitric oxide synthase, attenuates pilocarpine-induced seizures. Eur. J. Pharmacol. 287, 211–213.PubMedGoogle Scholar
  245. 243.
    Chung H. Y., Kim H. J., Kim J. W., and Yu B. P. (2001) The inflammation hypothesis of aging: molecular modulation by calorie restriction. Ann. NY Acad. Sci. 928, 327–335.PubMedGoogle Scholar
  246. 244.
    Hilbig H., Holler J., Dinse H. R., and Bidmon H. J. (2002) In contrast to neuronal NOS-I, the inducible NOS-II expression in aging brains is modifled by enriched environmental conditions. Exp. Toxicol. Pathol. 53, 427–431.PubMedGoogle Scholar
  247. 245.
    Shin C. M., Chung Y. H., Kim M. J., Lee E. Y., Kim E. G., and Cha C. I. (2002) Age-related changes in the distribution of nitrotyrosine in the cerebral cortex and hippocampus of rats. Brain Res. 931, 194–199.PubMedGoogle Scholar
  248. 246.
    Uttenthal L. O., Alonso D., Fernandez A. P., et al. (1998) Neuronal and inducible nitric oxide synthase and nitrotyrosine immunoreactivities in the cerebral cortex of the aging rat. Microsc. Res. Tech. 43, 75–88.PubMedGoogle Scholar
  249. 247.
    McCann S. M., Licinio J., Wong M. L., Yu W. H., Karanth S., and Rettorri V. (1998) The nitric oxide hypothesis of aging. Exp. Gerontol. 33, 813–826.PubMedGoogle Scholar
  250. 248.
    Adamson D. C., Wildemann B., Sasaki M., et al. (1996) Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 274, 1917–1921.PubMedGoogle Scholar
  251. 249.
    Rostasy K., Monti L., Yiannoutsos C., et al. (1999) Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activ-ation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. Ann. Neurol. 46, 207–216.PubMedGoogle Scholar
  252. 250.
    Hu S., Ali H., Sheng W. S., Ehrlich L. C., Peterson P. K., and Chao C. C. (1999) Gp-41-mediated astrocyte inducible nitric oxide synthase mRNA expression: involvement of interleukin-1beta production by microglia. J. Neurosci. 19, 6468–6474.PubMedGoogle Scholar
  253. 251.
    Zhao M. L., Kim M. O., Morgello S., and Lee S. C. (2001) Expression of inducible nitric oxide synthase, interleukin-1 and caspase-1 in HIV-1 encephalitis. J. Neuroimmunol. 115, 182–191.PubMedGoogle Scholar
  254. 252.
    Giovannoni G., Miller R. F., Heales S. J., Land J. M., Harrison M. J., and Thompson E. J. (1998) Elevated cerebrospinal fluid and serum nitrate and nitrite levels in patients with central nervous system complications of HIV-1 infection: a correlation with blood-brain-barrier dysfunction. J. Neurol. Sci. 156, 53–58.PubMedGoogle Scholar
  255. 253.
    Torre D., Ferrario G., Speranza F., Orani A., Fiori G. P., and Zeroli C. (1996) Serum concentrations of nitrite in patients with HIV-1 infection. J. Clin. Pathol. 49, 574–576.PubMedGoogle Scholar
  256. 254.
    Floyd R. A., Hensley K., Jaffery F., Maidt L., Robinson K., Pye Q., and Stewart C. (1999) Increased oxidative stress brought on by proinflammatory cytokines in neurodegenerative processes and the protective role of nitrone-based free radical traps. Life Sci. 65, 1893–1899.PubMedGoogle Scholar
  257. 255.
    Hori K., Burd P. R., Furuke K., Kutza J., Weih K. A., and Clouse L. (1999) Human immunodeficiency virus-1-infected macrophages induce inducible nitric oxide synthase and nitric oxide (NO) production in astrocytes: astrocytic NO as a possible mediator of neural damage in acquired immunodeficiency syndrome. Blood 93, 1843–1850.PubMedGoogle Scholar
  258. 256.
    Colton C. A. (1995) Induction of nitric oxide in cultured microglia: evidence for a cytoprotective role. Adv. Neuroimmunol. 5, 491–503.PubMedGoogle Scholar
  259. 257.
    Schoneboom B. A., Catlin K. M., Marty A. M., and Grieder F. B. (2000) Inflammation is a component of neurodegeneration in response to Venezuelan equine encephalitis virus infection in mice. J. Neuroimmunol. 109, 132–146.PubMedGoogle Scholar
  260. 258.
    Winkler F., Koedel U., Kastenbauer S., and Pfister H. W. (2001) Differential expression of nitric oxide synthases in bacterial meningitis: role of the inducible isoform for blood-brain barrier breakdown. J. Infect. Dis. 183, 1749–1759.PubMedGoogle Scholar
  261. 259.
    Leib S. L., Kim Y. S., Black S. M., Tureen J. H., and Tauber M. G. (1998) Inducible nitric oxide synthase and the effect of aminoguanidine in experimental neonatal meningitis. J. Infect. Dis. 177, 692–700.PubMedGoogle Scholar
  262. 260.
    Sugaya K., Chou S., Xu S. J., and McKinney M. (1998) Indicators of glial activation and brain oxidative stress after intraventricular infusion of endotoxin. Mol. Brain Res. 58, 1–9.PubMedGoogle Scholar
  263. 261.
    Wong B. S., Liu T., Paisley D., et al. (2001) Induction of HO-1 and NOS in doppel-expressing mice devoid of PrP: implications for doppel function. Mol. Cell. Neurosci. 17, 768–775.PubMedGoogle Scholar
  264. 262.
    Fabrizi C., Silei V., Menegazzi M., et al. (2001) The stimulation of inducible nitric-oxide synthase by the prion protein fragment 106–126 in human microglia is tumor necrosis factor-alpha-dependent and involves p38 mitogenactivated protein kinase. J. Biol. Chem. 276, 25,692–25,696.Google Scholar
  265. 263.
    Kim J. I., Ju W. K., Choi J. H., Choi E., Carp R. I., Wisniewski H. M., and Kim Y. S. (1999) Expression of cytokine genes and increased nuclear factor-kappa B activity in the brains of scrapieinfected mice. Mol. Brain Res. 73, 17–27.PubMedGoogle Scholar
  266. 264.
    Van Everbroeck B., Dewulf E., Pals P., Lubke U., Martin J. J., and Cras P. (2002) The role of cytokines, astrocytes, microglia and apoptosis in Creutzfeldt-Jakob disease. Neurobiol. Aging 23, 59–64.PubMedGoogle Scholar
  267. 265.
    Goyagi T., Goto S., Bhardwaj A., Dawson V. L., Hurn P. D., and Kirsch J. R. (2002) Neuroprotective effect of sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production. Stroke 32, 1613–1620.Google Scholar
  268. 266.
    Kastenbauer S., Klein M., Koedel U., and Pfister H. W. (2001) Reactive nitrogen species contribute to blood-labyrinth barrier disruption in suppurative labyrinthitis complicating experimental pneumococcal meningitis in the rat. Brain Res. 904, 208–217.PubMedGoogle Scholar
  269. 267.
    Corasaniti M. T., Melino G., Navarra M., Garaci E., Finazzi-Agro A., and Nistico G. (1995) Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase. Neurodegeneration 4, 315–321.PubMedGoogle Scholar
  270. 268.
    Clark R. S., Kochanek P. M., Obrist W. D., et al. (1996) Cerebrospinal fluid and plasma nitrite and nitrate concentrations after head injury in humans. Crit. Care Med. 24, 1243–1251.PubMedGoogle Scholar

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© Humana Press Inc 2003

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of CambridgeCambridgeUK

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