Acta Biologica Hungarica

, Volume 53, Issue 1–2, pp 229–244 | Cite as

Nonsynaptic Noradrenaline Release in Neuro-Immune Responses

  • E. S. ViziEmail author
  • I. J. Elenkov


Evidence has recently been obtained that the branches of the autonomic nervous system, mainly, the sympathetic [25], regulate cytokine production. Not only the primary (thymus, bone marrow) and secondary (spleen, tonsils, and lymph nodes) lymphoid organs, but also many other tissues are involved in immune responses and are heavily influenced by noradrenaline (NA) derived from varicose axon terminals of the sympathetic nervous system [25, 100]. Besides NA released from nonsynaptic varicosities of noradrenergic terminals [92], circulating catecholamines (adrenaline, dopamine, NA) are also able to influence immune responses, the production of pro- and anti-inflammatory cytokines by different immune cells. The sympathetic nervous system (catecholamines) and the hypothalamic-pituitary-adrenal (HPA) axis (cortisol) are the major integrative and regulatory components of different immune responses. In our laboratory convincing evidence has been obtained that NA released non-synaptically [90, 92] from sympathetic axon terminals and enhanced in concentration in the close proximity of immune cells is able to inhibit production of proinflammatory (TNF-α, IFN-γ, IL-12, IL-1) and increase antiinflammatory cytokines (IL-10) in response to LPS [25, 91], indicating a fine-tuning control of the production of TNF-α and other cytokines by sympathetic innervation under stressful conditions. This effects are mediated via β2-adrenoceptors expressed on immune cells and coupled to cAMP levels.


Immune response sympathetic outflow cytokines nonsynaptic 


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  1. 1.
    Abraham, E., Wunderink, R., Silverman, H., Perl, T. M., Nasraway, S., Levy, H., Bone, R., Wenzel, R. P., Balk, R., Allred, R. (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 273, 934–941.PubMedGoogle Scholar
  2. 2.
    Amano, F., Akamatsu, Y. (1991) A lipopolysaccharide (LPS)-resistant mutant isolated from a macrophagelike cell line, J774. 1, exhibits an altered activated-macrophage phenotype in response to LPS. Infect Immun. 59, 2166–2174.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Bal-Price, A., Brown, G. C. (2001) Inflammatory neurodegeneration mediated by nitric oxide fromactivated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J. Neurosci. 21, 6480–6491.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., 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, 620–624.Google Scholar
  5. 5.
    Beckman, J. S., Chen, J., Crow, J. P., Ye, Y. Z. (1994) Reactions of nitric oxide, superoxide and peroxynitrite with superoxide dismutase in neurodegeneration. Prog. Brain. Res. 103, 371–380.PubMedGoogle Scholar
  6. 6.
    Bencsics, Á., Sershen, H., Baranyi, M., Audrey H., Lajtha, Á., Vizi, E. S. (1997) Dopamine, as well as norepinephrine, is a link between noradrenergic nerve terminals and splenocytes. Brain Research 761, 236–243.PubMedGoogle Scholar
  7. 7.
    Benveniste, E. N., Nguyen, V. T., O’Keefe, G. M. (2001) Immunological aspects of microglia: relevance to Alzheimer’s disease. Neurochem. Int. 39, 381–391.PubMedGoogle Scholar
  8. 8.
    Besedovsky, H. O., Del Rey, A. (1996) Immune-neuro-endocrine interactions: facts and hypothesis. Endocrine Rev. 17, 64–102.Google Scholar
  9. 9.
    Bone, R. C. (1991) The pathogenesis of sepsis. Ann. Intern. Med. 115, 457–469.PubMedGoogle Scholar
  10. 10.
    Bone, R. C., Balk, R. A., Cerra, F. B., Dellinger, R. P., Fein, A. M., Knaus, W. A., Schein, R. M., Sibbald, W. J. (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101, 1644–1655.PubMedGoogle Scholar
  11. 11.
    Borovikova, L. V., Ivanova, S., Nardi, D., Zhang, M., Yang, H., Ombrellino, M., Tracey, K. J. (2000) Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton. Neurosci. 85, 141–147.PubMedGoogle Scholar
  12. 12.
    Borovikova, L. V., Ivanova. S., Zhang, M., Yang, H., Botchkina, G. I., Watkins, L. R., Wang, H., Abumrad, N., Eaton, J. W., Tracey, K. J. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462.PubMedGoogle Scholar
  13. 13.
    Bourne, H. R., Lichtenstein, L. M., Melmon, K. L., Henney, C. S., Weinstein, Y., Shearer, G. M. (1974) Modulation of inflammation and immunity by cyclic AMP. Science 184, 19–28.PubMedGoogle Scholar
  14. 14.
    Carlson, S. L., Brooks, W. H., Roszman, T. L. (1989) Neurotransmitter-lymphocyte interactions: dual receptor modulation of lymphocyte proliferation and cAMP production. J Neuroimmunol. 24, 155–162.PubMedGoogle Scholar
  15. 15.
    Chang, R. C., Stadlin, A., Tsang, D. (2001) Effects of tumor necrosis factor alpha on taurine uptake in cultured rat astrocytes. Neurochem. Int. 38, 249–254.PubMedGoogle Scholar
  16. 16.
    Chrousos, G. P. (1995) The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351–1362.Google Scholar
  17. 17.
    Cohen, N., Ader, R., Felten, D. L. (1994) Psychoneuroimmunology. In: L. H. Sigal, Y. Ron (eds), Immunology and Inflammation: Basic Mechanisms and Clinical Consequences. McGraw-Hill, New York, pp. 465–494.Google Scholar
  18. 18.
    Cuzzocrea, S., Riley, D. P., Caputi, A. P., Salvemini, D. (2001) Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol. Rev. 53, 135–159.PubMedGoogle Scholar
  19. 19.
    de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G., de Vries, J. E. (1991) Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. Exp. Med. 174, 1209–1220.Google Scholar
  20. 20.
    Dunn, A. J. (2000) Effects of the IL-1 receptor antagonist on the IL-1- and endotoxin-induced activation of HPA axis and cerebral biogenic amines in mice. Neuroimmunomodulation 7, 36–45.PubMedGoogle Scholar
  21. 21.
    Elenkov, I. J., Haskó, G., Kovács, K., Vizi, E. S. (1995) Modulation of lipopolysaccharide-induced tumor necrosis factor-α production by selective α- and β-adrenergic drugs in mice. J. Neuroimmunol. 61, 123–131.PubMedGoogle Scholar
  22. 22.
    Elenkov, I. J., Kovács, K., Bertók, L., Vizi, E. S. (1992) Lipopolysaccharide is able to bypass corticotrophin- releasing factor in affecting plasma ACTH and corticosterone levels: evidence from rats with lesion of the paraventricular nucleus. J. Endocrinol. 133, 231–236.PubMedGoogle Scholar
  23. 23.
    Elenkov, I. J., Kovács, K., Duda, E., Stark, E., Vizi, E. S. (1992) Presynaptic inhibitory effect of TNF-α on the release of noradrenaline in isolated median eminence. J. Neuroimmunol. 41, 117–120.PubMedGoogle Scholar
  24. 24.
    Elenkov, I. J., Papanicolaou, D. A., Wilder, R. L., Chrousos, G. P. (1996) Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: Clinical implications. Proc. Ass. Am. Phys. 108, 1–8.Google Scholar
  25. 25.
    Elenkov, I. J., Wilder, R. L., Chrousos, G. P., Vizi, E. S. (2000) The sympathetic nerve–an integrative interface between two “supersystems”: the brain and the immune system. Pharmacol. Rev. 52, 595–638.PubMedGoogle Scholar
  26. 26.
    Fagni, L., Lafon-Cazal, M., Rondouin, G., Manzoni, O., Lerner-Natoli, M., Bockaert, J. (1994) The role of free radicals in NMDA-dependent neurotoxicity. Prog. Brain. Res. 103, 381–390.PubMedGoogle Scholar
  27. 27.
    Felten, D. L., Felten, S. Y., Bellinger, D. L. (1992) Noradrenergic and peptidergic innervation of lymphoid organs. In: J. E. Blalock (ed.), Chemical Immunology: Neuroimmunoendocrinology. Karger, Basel, pp. 25–48.Google Scholar
  28. 28.
    Felten, D. L., Felten, S. Y., Bellinger, D. L., Carlson, S. L., Ackerman, K. D., Madden, K. S., Olschowki, J. A., Livnat, S. (1987) Noradrenergic sympathetic neural interactions with the immune system: structure and function. Immunol. Rev. 100, 225–260.PubMedGoogle Scholar
  29. 29.
    Felten, D. L., Felten, S. Y., Carlson, S. L., Olschowka, J. A., Livnat, S. (1985) Noradrenergic and peptidergic innervation of lymphoid tissue. J. Immunol. 135, 755s–765s.PubMedGoogle Scholar
  30. 30.
    Fessler, H. E., Otterbein, L., Chung, H. S., Choi, A. M. (1996) Alpha-2 adrenoceptor blockade protects rats against lipopolysaccharide. Am. J. Respir. Crit. Care. Med. 154, 1689–1693.PubMedGoogle Scholar
  31. 31.
    Fleshner, M., Goehler, L. E., Schwartz, B. A., McGorry, M., Martin, D., Maier, S. F., Watkins, L. R. (1998) Thermogenic and corticosterone responses to intravenous cytokines (IL-1beta and TNFalpha) are attenuated by subdiaphragmatic vagotomy. J. Neuroimmunol. 86, 134–141.PubMedGoogle Scholar
  32. 32.
    Freund, T. F., Buzsaki, G. (1996) Interneurons of the hippocampus. Hippocampus. 6, 347–470.PubMedGoogle Scholar
  33. 33.
    Fuchs, A. C., Granowitz, E. V., Shapiro, L., Vannier, E., Lonnemann, G., Angel, J. B., Kennedy, J. S., Rabson, A. R., Radwanski, E., Affrime, M. B., Cutler, D. L., Grint, P. C., Dinarello, C. A. (1996) Clinical, hematologic, and immunologic effects of interleukin-10 in humans. J. Clin. Immunol. 16, 291–303.PubMedGoogle Scholar
  34. 34.
    Green, S. J., Nacy, C. A. (1993) Antimicrobial and immunopathological effects of cytokine-induced nitric oxide synthesis. Curr. Opin. Infect. Dis. 6, 384.Google Scholar
  35. 35.
    Hámori, J. (1990) Morphological plasticity of postsynaptic neurones in reactive synaptogenesis. J. Exp. Biol. 153: 251–260.PubMedGoogle Scholar
  36. 36.
    Hámori, J., Pasik, P., Pasik, T. (1991) Different types of synaptic triads in the monkey dorsal lateral geniculate nucleus. J. Hirnforsch. 32, 369–379.PubMedGoogle Scholar
  37. 37.
    Hámori, J., Takács, J., Verley, R., Petrusz, P., Farkas-Bargeton, E. (1990) Plasticity of GABA- and glutamate-containing terminals in the mouse thalamic ventrobasal complex deprived of vibrissal afferents: an immunogold-electron microscopic study. J. Comp. Neurol. 302, 739–748.PubMedGoogle Scholar
  38. 38.
    Haskó, G., Elenkov, I. J., Kvetan, V., Vizi, E. S. (1995) Differential effect of selective block of α2- adrenoceptors on plasma levels of tumor necrosis factor-α, interleukin-6 and corticosterone induced by bacterial lipopolysaccharide in mice. J. Endocrinol. 144, 457–462.Google Scholar
  39. 39.
    Haskó, G., Szabó, C., Merkel, K., Bencsics, A., Zingarelli, B., Kvetan, V., Vizi, E. S. (1996) Modulation of lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide production by dopamine receptor agonists and antagonists in mice. Immunology Letters, 49, 143–147.PubMedGoogle Scholar
  40. 40.
    Haskó, G., Szabó, C., Németh, Z. H., Deitch, E. A. (2001) Sulphasalazine inhibits macrophage activation: inhibitory effects on inducible nitric oxide synthase expression, interleukin-12 production and major histocompatibility complex II expression. Immunology 103, 473–478.PubMedCentralGoogle Scholar
  41. 41.
    Hemmer, K., Fransen, L., Vanderstichele, H., Vanmechelen, E., Heuschling, P. (2001) An in vitro model for the study of microglia-induced neurodegeneration: involvement of nitric oxide and tumor necrosis factor-alpha. Neurochem. Int. 38, 557–565.PubMedGoogle Scholar
  42. 42.
    Hertz, L., Yu, A. C., Kala, G., Schousboe, A. (2000) Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation, hyperammonemia and energy deprivation. Neurochem. Int. 37, 83–102.PubMedGoogle Scholar
  43. 43.
    Hoffman, M., Weinberg, J. B. (1987) Tumor necrosis factor-alpha induces increased hydrogen peroxide production and Fc receptor expression, but not increased Ia antigen expression by peritoneal macrophages. J. Leukoc. Biol, 42, 704–707.PubMedGoogle Scholar
  44. 44.
    Huang, B. R., Gu, J. J., Ming H., Lai, D. B., Zhou, X. F. (2000) Differential actions of neurotrophins on apoptosis mediated by the low affinity neurotrophin receptor p75NTR in immortalised neuronal cell lines. Neurochem. Int. 36, 55–65.PubMedGoogle Scholar
  45. 45.
    James, E. G., Kendal, D. D., Kendal, M. D. (1996) Peripheral and central neural mechanisms for immune regulation through the innervation of immune effector sites. In: J. A. Marsh, M. D. Kendal (eds), The Physiology of Immunity. CRC Press, pp. 103–127.Google Scholar
  46. 46.
    Kammer, G. M. (1988) The adenylate cyclase-cAMP-protein kinase a pathway and regulation of the immune response. Immunol. Today 9, 222–229.PubMedGoogle Scholar
  47. 47.
    Kim, H., Kim, Y. S., Kim, S. Y., Suk, K. (2001) The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci. Lett. 309, 67–71.PubMedGoogle Scholar
  48. 48.
    Kiss, J. P., Vizi, E. S. (2001) Nitric oxide: A novel link between synaptic and nonsynaptic transmission. Trends Neurosci. 24, 211–215.PubMedGoogle Scholar
  49. 49.
    Klein, B. D., White, H. S., Callahan, K. S. (2000) Cytokine and intracellular signaling regulation of tissue factor expression in astrocytes. Neurochem. Int. 36, 441–449.PubMedGoogle Scholar
  50. 50.
    Kobilka, B. (1992) Adrenergic receptors as models for G protein-coupled receptors. Annu. Rev. Neurosci. 15, 87–114.PubMedGoogle Scholar
  51. 51.
    Landmann, R. (1992) Beta-adrenergic receptors in human leukocyte subpopulations. Eur. J. Clin. Invest. 1, 30–36.Google Scholar
  52. 52.
    Le, Y. L., Shih, K., Bao, P., Ghirnikar, R. S., Eng, L. F. (2000) Cytokine chemokine expression in contused rat spinal cord. Neurochem. Int. 36, 417–425.Google Scholar
  53. 53.
    Linder, M. E., Gilman A. G. (1992) G proteins. Sci. Am. 267, 56–61, 64–65.PubMedGoogle Scholar
  54. 54.
    Madden, K. S., Felten, S. Y., Felten, D. L., Hardy, C. A., Livnat, S. (1994) Sympathetic nervous system modulation of the immune system. II. Induction of lymphocyte proliferation and migration in vivo by chemical sympathectomy. J. Neuroimmunol. 49, 67–75.PubMedGoogle Scholar
  55. 55.
    Madden, K. S., Sanders, V. M., Felten, D. L. (1995) Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu. Rev. Pharmacol. Toxicol. 35, 417–448.PubMedGoogle Scholar
  56. 56.
    Maekawa, M., Murayama, T., Nomura, Y. (2001) Involvement of noradrenaline transporters in Snitrosocysteine- stimulated noradrenaline release from rat brain slices: existence of functional Na(+)-independent transporter activity. Neurochem. Int. 38, 323–331.PubMedGoogle Scholar
  57. 57.
    Maier, S. F., Goehler, L. E., Fleshner, M., Watkins, L. R. (1998) The role of the vagus nerve in cytokine-to-brain communication. Ann. NY Acad. Sci. 840, 289–300.PubMedGoogle Scholar
  58. 58.
    McCarthy, Pastores, S., Haskó, G., Vizi, E. S., Kvetan, V. (1996) Cytokine production and its manipulation by vasoactive drugs. New Horizons, 4, 252–264.Google Scholar
  59. 59.
    Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., Hill, A. M. (2000) M-1/M-2 Macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166–6173.Google Scholar
  60. 60.
    Mire-Sluis, A., Thorpe, R. (eds), (1998) Cytokines. Academic Press.Google Scholar
  61. 61.
    Molina-Holgado, F., Grencis, R., Rothwell, N. J. (2001) Actions of exogenous and endogenous IL- 10 on glial responses to bacterial LPS/cytokines. Glia 33, 97–106.PubMedGoogle Scholar
  62. 62.
    Mossmer, R., Daniel, S., Albert, D., Heils, A., Okladnova, O., Schmitt, A., Lesch, K. P. (2000) Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF). Neurochem. Int. 36, 197–202.Google Scholar
  63. 63.
    Nathan, C. (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J. 6, 3051–3064.PubMedGoogle Scholar
  64. 64.
    Nicholson, C., Sykova, E. (1998) Extracellular space structure revealed by diffusion analysis. Trends Neurosci. 27, 207–215.Google Scholar
  65. 65.
    Nickoloff, B. J., Karabin, G. D., Barker, J. N., Griffiths, C. E., Sarma, V., Mitra, R. S., Elder, J. T., Kunkel, S. L., Dixit, V. M. (1991) Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am. J. Pathol. 138, 129–140.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Nilsson, L. N., Das, S., Potter, H. (2001) Effect of cytokines, dexamethazone and the A/T-signal peptide polymorphism on the expression of alpha(1)-antichymotrypsin in astrocytes: significance for Alzheimer’s disease. Neurochem. Int. 39, 361–370.PubMedGoogle Scholar
  67. 67.
    Paton, W. D. M., Vizi, E. S. (1969) The inhibitory action of noradrenaline and adrenaline on acetylcholine output by guinea-pig ileum longitudinal muscle strip. Br. J. Pharmac. 35, 10–28.Google Scholar
  68. 68.
    Pryor, W. A., Squadrito, G. L. (1995) The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am. J. Physiol. 268, 699–722.Google Scholar
  69. 69.
    Reichlin, S. (1993) Neuroendocrine-immune interactions. N. Engl. J. Med, 329, 1246–1253.Google Scholar
  70. 70.
    Rothwell, N. J. (1998) Cytokines–killers in the brain? J. Physiol. 514, 3–17.Google Scholar
  71. 71.
    Rothwell, N. J. (2000) Show them how it’s really done. Nature, 405, 621.PubMedGoogle Scholar
  72. 72.
    Savage, D. D., Galindo, R., Queen, S. A., Paxton, L. L., Allan, A. M. (2001) Characterization of electrically evoked [3H]-D-aspartate release from hippocampal slices. Neurochem. Int. 38, 255–267.PubMedGoogle Scholar
  73. 73.
    Schulz, J. B., Matthews, R. T., Jenkins, B. G., Ferrante, R. J., Siwek, D., Henshaw, D. R., Cipolloni, P. B., Mecocci, P., Kowall, N. W., Rosen, B. R. (1995) Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J. Neurosci. 15, 8419–8429.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Selmaj, K., Raine, C. S., Cannella, B., Brosnan, C. F. (1991) Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J. Clin. Invest. 87, 949–954.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Selmaj, K. W., Raine, C. S. (1988) Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann. Neurol. 23, 339–346.PubMedGoogle Scholar
  76. 76.
    Severn, A., Rapson, N. T., Hunter, C. A., Liew, F. Y. (1992) Regulation of tumor necrosis factor production by adrenaline and beta-adrenergic agonists. J. Immunol. 148, 3441–3445.PubMedGoogle Scholar
  77. 77.
    Sheng, J. G., Jones, R. A., Zhou, X. Q., McGinness, J. M., Van Eldik, L. J., Mrak, R. E., Griffin, W. S. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer’s disease: potential significance for tau protein phosphorylation. Neurochem. Int. 39, 341–348.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Shimizu, N., Hori, T., Nakane, H. (1994) An interleukin-1 beta-induced noradrenaline release in the spleen is mediated by brain corticotropin-releasing factor: an in vivo microdialysis study in conscious rats. Brain Behav. Immun. 8, 14–23.PubMedGoogle Scholar
  79. 79.
    Spengler, R. N., Chensue, S. W., Giacherio, D. A., Blenk, N., Kunkel, S. L. (1994) Endogenous norepinephrine regulates tumor necrosis factor-alpha production from macrophages in vitro. J. Immunol. 152, 3024–3031.PubMedGoogle Scholar
  80. 80.
    Sternberg, E. M., Hill, J. M., Chrousos, G. P., Kamilaris, T., Listwak, S. J., Gold, P. W., Wilder, R. L. (1989) Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc. Natl. Acad. Sci. USA 86, 2374–2378.PubMedGoogle Scholar
  81. 81.
    Suberville, S., Bellocq, A., Fouqueray, B., Philippe, C., Lantz, O., Perez, J., Baud, L. (1996) Regulation of interleukin-10 production by beta-adrenergic agonists. Eur. J. Immunol. 26, 2601–2605.PubMedGoogle Scholar
  82. 82.
    Szabó, C., Haskó, G., Zingarrelli, B., Németh, Z., Salzman, A. L., Kvetan, V., McCarthy, Pastores, S., Vizi, E. S. (1997) Isoproterenol regulates tumour necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxaemia. Immunology, 90, 95–100.PubMedCentralGoogle Scholar
  83. 83.
    Szabo, C., Salzman, A. L. (1995) Endogenous peroxynitrite is involved in the inhibition of mitochondrial respiration in immuno-stimulated J774. 2 macrophages. Biochem. Biophys. Res. Commun. 209, 739–743.PubMedGoogle Scholar
  84. 84.
    Szabó, C., Salzman, A. L., Ischiropoulos, H. (1995) Peroxynitrite-mediated oxidation of dihydrorhodamine 123 occurs in early stages of endotoxic and hemorrhagic shock and ischemia-reperfusion injury. FEBS Lett. 372, 229–232.PubMedGoogle Scholar
  85. 85.
    Szabó, C., Zingarelli, B., O’Connor, M., Salzman, A. L. (1996) DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc. Natl. Acad. Sci. USA 93, 1753–1758.PubMedGoogle Scholar
  86. 86.
    Szelényi, J., Kiss, J. P., Vizi, E. S. (2000) Differential involvement of sympathetic nervous system in the modulation of TNF-α production by α2- and β-adrenoceptors in mice. J. Neuroimmunol. 103, 34–40.Google Scholar
  87. 87.
    Tracey, K. J., Czura, C. J., Ivanova, S. (2001) Mind over immunity. FASEB J. 15, 1575–1576.PubMedGoogle Scholar
  88. 88.
    Uchigata, Y., Yamamoto, H., Kawamura, A., Okamoto, H. (1982) Protection by superoxide dismutase, catalase, and poly(ADP-ribose) synthetase inhibitors against alloxan- and streptozotocininduced islet DNA strand breaks and against the inhibition of proinsulin synthesis. J. Biol. Chem. 257, 6084–6088.PubMedGoogle Scholar
  89. 89.
    Vizi, E. S. (1980) Non-synaptic modulation of transmitter release: pharmacological implication. TIPS 172–175.Google Scholar
  90. 90.
    Vizi, E. S. (1984) Non-synaptic Interactions Between Neurons: Modulation of Neurochemical Transmission. Pharmacological and Clinical Aspects. John Wiley and Sons, Chichester, New York.Google Scholar
  91. 91.
    Vizi, E. S. (1998) Receptor-mediated local fine-tuning by noradrenergic innervation of neuroendocrine and immune systems. Ann. NY Acad. Sci. 851, 388–396.PubMedGoogle Scholar
  92. 92.
    Vizi, E. S. (2000) Role of high-affinity receptors and membrane transporters in nonsynaptic communication and drug action in the CNS. Pharm. Rev. 52, 63–89.PubMedGoogle Scholar
  93. 93.
    Vizi, E. S., Kiss, J. P. (1998) Neurochemistry and pharmacology of the major hippocampal transmitter systems: Synaptic and non-synaptic interactions. Hippocampus 8: 566–607.Google Scholar
  94. 94.
    Vizi, E. S., Lábos, E. (1991) Non-synaptic interactions at presynaptic level. Progr. Neurobiol. 37, 145–163.Google Scholar
  95. 95.
    Vizi, E. S., Mike, Á., Tarnawa, I. (1996) 2,3-Benzodiazepines (GYKI 52466 and analogs): negative allosteric modulators of AMPA receptors. CNS Drug Reviews 2, 91–126.Google Scholar
  96. 96.
    Vizi, E. S., Szelényi, J., Selmeczy, Z., Papp, Z., Németh, Z. H., Haskó, G. (2001) Enhanced TNFand decreased IL-10-specific immune responses to LPS during the third trimester of pregnancy in mice. J. Endocrinol. 171, 355–361.PubMedGoogle Scholar
  97. 97.
    Vizi, E. S., Tóth, I. E., Orsó, E,. Szalay, K. S., Szabó, D., Baranyi, M., Vinson, G. P. (1993) Dopamine is taken up from the circulation by, and released from, local noradrenergic varicose axon terminals in zona glomerulosa of the rat: a neurochemical and immunocytochemical study. J. Endocrinol. 139, 213–226.PubMedGoogle Scholar
  98. 98.
    Vizi, E. S., Tóth, I. E., Szalay, K. S., Windisch, K., Orsó, E., Szabó, D., Vinson, G. P. (1992) Catecholamines released from local adrenergic axon terminals are possibly involved in fine tuning of steroid secretion from zona glomerulosa cells: functional and morphological evidence. J. Endocrinol. 135, 551–561.PubMedGoogle Scholar
  99. 99.
    Watkins, L. R., Goehler, L. E., Relton, J. K., Tartaglia, N., Silbert, L., Martin, D., Maier, S. F. (1995) Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci. Lett. 183, 27–31.PubMedGoogle Scholar
  100. 100.
    Wekerle, H. (1998) The viral triggering of autoimmune disease. Nature Med. 4, 770–771.PubMedGoogle Scholar
  101. 101.
    Woiciechowsky, C., Asadullah, K., Nestler, D., Eberhardt, B., Platzer, C., Schoning, B., Glockner, F., Lanksch, W. R., Volk, H. D., Docke, W. D. (1998) Sympathetic activation triggers systemic interleukin- 10 release in immunodepression induced by brain injury. Nature Med. 4, 808–813.PubMedGoogle Scholar
  102. 102.
    Yu, A. C., Lau, L. T. (2000) Expression of interleukin-1 alpha, tumor necrosis factor alpha and interleukin- 6 genes in astrocytes under ischemic injury. Neurochem. Int. 36, 369–377.PubMedGoogle Scholar
  103. 103.
    Zhang, J., Dawson, V. L., Dawson, T. M., Snyder, S. H. (1994) Nitric oxide activation of poly(ADPribose) synthetase in neurotoxicity. Science 263, 687–689.PubMedGoogle Scholar
  104. 104.
    Zhang, J., Terreni, L., De Simoni, M. G., Dunn, A. J. (2001) Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum. Neurochem. Int. 38, 303–308.PubMedGoogle Scholar
  105. 105.
    Zhu, Y., Ahlemeyer, B., Bauerbach, E., Krieglstein, J. (2001) TGF-beta1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures. Neurochem. Int. 38, 227–235.Google Scholar
  106. 106.
    Zingarelli, B., O’Connor, M., Wong, H., Salzman, A. L., Szabo, C. (1996) Peroxynitrite-mediated DNA strand breakage activates poly-adenosine diphosphate ribosyl synthetase and causes cellular energy depletion in macrophages stimulated with bacterial lipopolysaccharide. J. Immunol. 156, 350–358.PubMedGoogle Scholar

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© Akadémiai Kiadó, Budapest 2002

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Department of Pharmacology and PharmacotherapySemmelweis UniversityBudapestHungary
  2. 2.Division of Rheumatology, Immunology and AllergyGeorgetown University Medical CenterWashington, D.C.Hungary

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