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The vagus nerve and the nicotinic anti-inflammatory pathway

Key Points

  • Inflammation is a fundamental physiological process that is crucial for survival, but at the same time it is one of the major causes of human morbidity and mortality. The production of pro-inflammatory cytokines is beneficial and protects the organism against infections and injury. However, excessive production of these cytokines can be more dangerous than the original infection, resulting in lethal systemic inflammation. These cytokines are successful pharmacological targets for the treatment of a variety of clinical disorders.

  • Severe sepsis, the leading cause of death in intensive care units, is one of the most dramatic examples of the pathological potential of inflammation is sepsis. Severe sepsis is the third leading cause of death in developed societies, equals the number of fatalities from acute myocardial infarction, and accounts for 9.3% of overall deaths in the United States annually.

  • Vagus-nerve stimulation, acetylcholine and nicotine inhibit the production of pro-inflammatory cytokines from macrophages through a 'nicotinic anti-inflammatory pathway' that is dependent on the α7 nicotinic acetylcholine receptor (α7nAChR).

  • Similar to the development of α- and β-agonists for adrenergic receptors, the design of selective nicotinic agonists for the α(α7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases.

  • The therapeutic potential of nicotinic agonists has been limited by the characterization of the specific receptors for drug development. The recent characterization of the α7nAChR in macrophages supports the design of selective nicotine agonists that can overcome the toxic effect of nicotine mediated by other receptors.

Abstract

Physiological anti-inflammatory mechanisms are selected by evolution to effectively control the immune system and can be exploited for the treatment of inflammatory disorders. Recent studies indicate that the vagus nerve (which is the longest of the cranial nerves and innervates most of the peripheral organs) can modulate the immune response and control inflammation through a 'nicotinic anti-inflammatory pathway' dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Nicotine has been used in clinical trials for the treatment of ulcerative colitis, but its clinical applications are limited by its unspecific effects and subsequent toxicity. This article reviews recent advances supporting the therapeutic potential of selective nicotinic agonists in several diseases. Similar to the development of α- and β-agonists for adrenoceptors, selective agonists for α7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases.

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Figure 1: Inflammation contributes to the pathological progression of a variety of disorders.
Figure 2: Pharmacological activator of the vagus nerve.
Figure 3: The 'nicotinic anti-inflammatory pathway'.
Figure 4: Chemical structure of selective cholinergic agonists and antagonists.
Figure 5: Human nicotinic acetylcholine subunits.
Figure 6: Nicotinic regulation of pro-inflammatory cytokines.
Figure 7: Clinical implications of the vagus nerve and the 'nicotinic anti-inflammatory pathway'.

References

  1. 1

    Sands, K. E. et al. Epidemiology of sepsis syndrome in 8 academic medical centers. Academic Medical Center Consortium Sepsis Project Working Group. JAMA 278, 234–240 (1997).

    CAS  PubMed  Google Scholar 

  2. 2

    Angus, D. C. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29, 1303–1310 (2001).

    CAS  Google Scholar 

  3. 3

    Martin, G. S. et al. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003).

    PubMed  Google Scholar 

  4. 4

    Friedman, G., Silva, E. & Vincent, J. L. Has the mortality of septic shock changed with time. Crit. Care Med. 26, 2078–2086 (1998). References 1–4 are epidemiological studies of the clinical relevance for severe sepsis, one of the most dramatic examples of the pathological potential of pro-inflammatory cytokines.

    CAS  PubMed  Google Scholar 

  5. 5

    Abraham, E. et al. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: a reevaluation. Crit. Care Med. 28, 232–235 (2000).

    CAS  PubMed  Google Scholar 

  6. 6

    Matot, I. & Sprung, C. L. Definition of sepsis. Intensive Care Med. 27, 3–9 (2001).

    Google Scholar 

  7. 7

    Ulloa, L. & Tracey, K. J. The 'cytokine profile': a code for sepsis. Trends Mol. Med. 11, 56–63 (2005).

    CAS  PubMed  Google Scholar 

  8. 8

    Riedemann, N. C. et al. Novel strategies for the treatment of sepsis. Nature Med. 9, 517–524 (2003). References 7 and 8 are recent and comprehensive reviews on potential pharmacological targets to control systemic inflammation and the treatment of severe sepsis.

    CAS  Google Scholar 

  9. 9

    Hotkiss, R. S. & Karl, I. E. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348, 138–150 (2003).

    Google Scholar 

  10. 10

    Tracey, K. J. & Cerami, A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu. Rev. Med. 45, 491–503 (1994).

    CAS  PubMed  Google Scholar 

  11. 11

    Tracey, K. J. & Cerami, A. Tumor necrosis factor, other cytokines and disease. Annu. Rev. Cell Biol. 9, 317–343 (1993).

    CAS  PubMed  Google Scholar 

  12. 12

    Ulloa, L., Doody, J. & Massague, J. Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710–713 (1999).

    CAS  Google Scholar 

  13. 13

    Monteleone, G., Pallone, F. & MacDonald, T. T. Smad7 in TGF- β-mediated negative regulation of gut inflammation. Trends Immunol. 25, 513–517 (2004).

    CAS  PubMed  Google Scholar 

  14. 14

    Van der Poll, T. & Lowry, S. F. Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense? Shock 3, 1–12 (1995).

    CAS  PubMed  Google Scholar 

  15. 15

    Feldmann, M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Rev. Immunol. 2, 364–371 (2002).

    CAS  Google Scholar 

  16. 16

    Van Assche, G. & Rutgeerts, P. Anti-TNF agents in Crohn's disease. Expert Opin. Investig. Drugs 9, 103–111 (2000).

    CAS  PubMed  Google Scholar 

  17. 17

    Dinarello, C. A. The interleukin-1 family: 10 years of discovery. FASEB J. 8, 1314–1325 (1994). References 15–17 report succesful clinical trials targeting pro-inflammatory cytokines for the treatment of diverse inflammatory disorders.

    CAS  PubMed  Google Scholar 

  18. 18

    Abraham, E. et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Norasept ii study group. Lancet 351, 929–933 (1998).

    CAS  PubMed  Google Scholar 

  19. 19

    Abraham, E. et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase iii trial with 1, 342 patients. Crit. Care Med. 29, 503–510 (2001).

    CAS  PubMed  Google Scholar 

  20. 20

    Fisher, C. J. et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1RA sepsis syndrome study group. JAMA 271, 1836–1843 (1994).

    Google Scholar 

  21. 21

    Van der, P. T., Coyle, S. M., Barbosa, K., Braxton, C. C. & Lowry, S. F. Epinephrine inhibits tumor necrosis factor-α and potentiates interleukin 10 production during human endotoxemia. J. Clin. Invest. 97, 713–719 (1996).

    Google Scholar 

  22. 22

    Scheinman, R. I., Cogswell, P. C., Lofquist, A. K. & Baldwin, A. S. Jr. Role of transcriptional activation of IκBκ in mediation of immunosuppression by glucocorticoids. Science 270, 283–286 (1995).

    CAS  PubMed  Google Scholar 

  23. 23

    Madden, K. S., Sanders, V. M. & Felten, D. L. Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu. Rev. Pharmacol. Toxicol. 35, 417–448 (1995).

    CAS  PubMed  Google Scholar 

  24. 24

    Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    CAS  Google Scholar 

  25. 25

    Wang, H. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Med. 10, 1216–1221 (2004).

    CAS  Google Scholar 

  26. 26

    Matthay, M. A. & Ware, L. B. Can nicotine treat sepsis? Nature Med. 10, 1161–1162 (2004).

    CAS  PubMed  Google Scholar 

  27. 27

    Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003). References 25 and 27 present a characterization of α7 nicotinic acetylcholine receptor in human macrophages and its contribution to control the production of pro-inflammatory cytokines.

    CAS  Google Scholar 

  28. 28

    Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).

    CAS  Google Scholar 

  29. 29

    Bernik, T. R. et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J. Exp. Med. 195, 781–788 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Borovikova, L. V. et al. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton. Neurosci. 85, 141–147 (2000). References 29 and 30 present evidence of a previously unrecognized role of the vagus nerve in mediating the action of a pharmacological anti-inflammatory compound.

    CAS  PubMed  Google Scholar 

  31. 31

    Sitaraman, S. V., Hoteit, M. & Gewirtz, A. T. Semapimod. Cytokine. Curr. Opin. Investig. Drugs 4, 1363–1368 (2003).

    CAS  PubMed  Google Scholar 

  32. 32

    Ben Menachem, E. Vagus nerve stimulation, side effects, and long-term safety. J. Clin. Neurophysiol. 18, 415–418 (2001).

    CAS  PubMed  Google Scholar 

  33. 33

    Wucherpfennig, K. W. Infectious triggers for inflammatory neurological diseases. Nature Med. 8, 455–457 (2002).

    CAS  PubMed  Google Scholar 

  34. 34

    Aarli, J. A. Role of cytokines in neurological disorders. Curr. Med. Chem. 10, 1931–1937 (2003). References 33 and 34 are comprehensive reviews of the pathological contribution of pro-inflammatory cytokines to neurological disorders.

    CAS  PubMed  Google Scholar 

  35. 35

    Guarini, S. et al. Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway. Cardiovasc. Res. 63, 357–365 (2004).

    CAS  PubMed  Google Scholar 

  36. 36

    Larsson, E. et al. CNI-1493, an inhibitor of pro-inflammatory cytokines, retards cartilage destruction in rats with collagen induced arthritis. Ann. Rheum. Dis. 64, 494–496 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    D'Haens, G. Anti-TNF therapy for Crohn's disease. Curr. Pharm. Des. 9, 289–294 (2003).

    CAS  PubMed  Google Scholar 

  38. 38

    Ulloa, L., Batliwalla, F. M., Andersson, U., Gregersen, P. K. & Tracey, K. J. High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis. Arthritis Rheum. 48, 876–881 (2003).

    CAS  PubMed  Google Scholar 

  39. 39

    Gault, J. et al. Genomic organization and partial duplication of the human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics 52, 173–185 (1998).

    CAS  PubMed  Google Scholar 

  40. 40

    Villiger, Y. et al. Expression of an α7 duplicate nicotinic acetylcholine receptor–related protein in human leukocytes. J. Neuroimmunol. 126, 86–98 (2002).

    CAS  PubMed  Google Scholar 

  41. 41

    Miyazawa, A., Fujiyoshi, Y. & Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423, 949–955 (2003).

    CAS  Google Scholar 

  42. 42

    Marubio, L. M. & Changeux, J. -P. Nicotinic acetylcholine receptor knockout mice as animal models for studying receptor function. Eur. J. Pharmacol. 393, 113–121 (2000).

    CAS  PubMed  Google Scholar 

  43. 43

    Hogg, R. C., Raggenbass, M. & Bertrand, D. Nicotinic acetylcholine receptors: from structure to brain function. Rev. Physiol. Biochem. Pharmacol. 147, 1–46 (2003).

    CAS  PubMed  Google Scholar 

  44. 44

    Peng, X. et al. Human α7 acetylcholine receptor: cloning of the α7 subunit from the SH-SY5Y cell line and determination of pharmacological properties of native receptors and functional α7 homomers expressed in Xenopus oocytes. Mol. Pharmacol. 45, 546–554 (1994).

    CAS  PubMed  Google Scholar 

  45. 45

    Drisdel, R. C. & Green, W. N. Neuronal α-bungarotoxin receptors are α7 subunit homomers. J. Neurosci. 20, 133–139 (2000). References 43–45 present the original characterization and structure of the α7 nicotinic acetylcholine receptor.

    CAS  Google Scholar 

  46. 46

    Andersson, U. et al. High mobility group 1 protein (HMG-1) stimulates pro-inflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Orr-Urtreger, A. et al. Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents. J. Neurosci. 17, 9165–9171 (1997).

    CAS  PubMed  Google Scholar 

  48. 48

    Franceschini, D. et al. Altered baroreflex responses in α7 deficient mice. Behav. Brain Res. 113, 3–10 (2000).

    CAS  PubMed  Google Scholar 

  49. 49

    Wang, H. et al. Hmg-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Ulloa, L. et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc. Natl Acad. Sci. USA 99, 12351–12356 (2002).

    CAS  PubMed  Google Scholar 

  51. 51

    Ulloa, L. et al. Ethyl pyruvate protects against lethal systemic inflammation by preventing HMGB1 release. Ann. NY Acad. Sci. 987, 319–321 (2003).

    CAS  Google Scholar 

  52. 52

    Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296–301 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Calogero, S. et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nature Genet. 22, 276–280 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Bustin, M. At the crossroads of necrosis and apoptosis, signaling to multiple cellular targets by HMGB1. Sci STKE 151 (2002).

  55. 55

    Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl Acad. Sci. USA 101, 296–301 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Bonaldi, T. et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551–5560 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Stemmer, C., Schwander, A., Bauw, G., Fojan, P. & Grasser, K. D. Protein kinase CK2 differentially phosphorylates maize chromosomal high mobility group B (HMGB) proteins modulating their stability and DNA interactions. J. Biol. Chem. 277, 1092–1098 (2002).

    CAS  PubMed  Google Scholar 

  59. 59

    Lee, J. C. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Derijard, B. et al. Independent human Map kinase signal transduction pathways defined by mek and mkk isoforms. Science 267, 682–685 (1995).

    CAS  PubMed  Google Scholar 

  61. 61

    Baeuerle, P. A. & Henkel, T. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12, 141–179 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002).

    CAS  Google Scholar 

  63. 63

    Ando, Y. Transdermal nicotine for ulcerative colitis. Ann. Intern. Med. 127, 491–492 (1997).

    CAS  PubMed  Google Scholar 

  64. 64

    Guarini, S. et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation 107, 1189–1194 (2003).

    PubMed  Google Scholar 

  65. 65

    Motley, R. J., Rhodes, J., Kay, S. & Morris, T. J. Late presentation of ulcerative colitis in ex-smokers. Int. J. Colorectal Dis. 3, 171–175 (1988).

    CAS  PubMed  Google Scholar 

  66. 66

    Roberts, C. J. & Diggle, R. Non-smoking: a feature of ulcerative colitis. BMJ 285, 440–440 (1982).

    Google Scholar 

  67. 67

    Harries, A. D., Baird, A. & Rhodes, J. Non-smoking: a feature of ulcerative colitis. BMJ 284, 706–706 (1982).

    CAS  PubMed  Google Scholar 

  68. 68

    Logan, R. F. A., Edmond, M., Somerville, K. W., Langman, M. J. Smoking and ulcerative colitis. BMJ 288, 751–753 (1984).

    CAS  PubMed  Google Scholar 

  69. 69

    Motley, R. J. et al. Time relationships between cessation of smoking and onset of ulcerative colitis. Digestion 37, 125–127 (1987).

    CAS  PubMed  Google Scholar 

  70. 70

    de Castella, H. Non-smoking: a feature of ulcerative colitis. BMJ 284, 1706–1706 (1982). References 65–70 are epidemiological studies relating ulcerative colitis with non-smoking and suggesting nicotine as a potential therapeutic agent.

    CAS  PubMed  Google Scholar 

  71. 71

    Srivastava, E. D. et al. Transdermal nicotine in active ulcerative colitis. Eur. J. Gastroenterol. 3, 815–818 (1991).

    Google Scholar 

  72. 72

    Pullan, R. D. et al. Transdermal nicotine for active ulcerative colitis. N. Engl. J. Med. 330, 811–815 (1994).

    CAS  PubMed  Google Scholar 

  73. 73

    Benoni, C, Nilsson A. Smoking habits in patients with inflammatory bowel disease. Scand. J. 19, 824–830 (1984).

    CAS  Google Scholar 

  74. 74

    Tapper, A. R. et al. Nicotine activation of α4 receptors: sufficient for reward, tolerance, and sensitization. Science 306, 1029–1032 (2004).

    CAS  PubMed  Google Scholar 

  75. 75

    Avila, J. & Diaz-Nido, J. Tangling with hypothermia. Nature Med. 10, 460–461 (2004).

    CAS  PubMed  Google Scholar 

  76. 76

    Zijlstra, F. J. et al. Effect of nicotine on rectal mucus and mucosal eicosanoids. Gut 35, 247–251 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Thomas, G. A. et al. Transdermal nicotine as maintenance therapy for ulcerative colitis. N. Engl. J. Med. 332, 988–992 (1995). References 71, 72 and 77 describe clinical trials using nicotine for the treatment of ulcerative colitis.

    CAS  PubMed  Google Scholar 

  78. 78

    Cope, G. F., Heatley, R. V., Kelleher, J. & Axon, A. T. R. In vitro mucus glycoprotein production by colonic tissue from patients with ulcerative colitis. Gut 29, 229–234 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Calandra, T. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nature Med. 6, 164–170 (2000).

    CAS  Google Scholar 

  80. 80

    Martin, T. R. Mif mediation of sepsis. Nature Med. 6, 140–142 (2000).

    CAS  PubMed  Google Scholar 

  81. 81

    Mandavilli, A. Nicotine fix. Nature Med. 10, 660–661 (2004).

    CAS  PubMed  Google Scholar 

  82. 82

    Libert, C. Inflammation: A nervous connection. Nature 421, 328–329 (2003).

    CAS  PubMed  Google Scholar 

  83. 83

    Gotti, C. & Clementi, F. Neuronal nicotinic receptors: from structure to pathology. Prog. Neurobiol. 74, 363–396 (2004).

    CAS  PubMed  Google Scholar 

  84. 84

    Kitagawa, H. et al. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 28, 542–551 (2003).

    CAS  PubMed  Google Scholar 

  85. 85

    Nanri, M., Kasahara, N., Yamamoto, J., Miyake, H. & Watanabe, H. A comparative study on the effects of nicotine and GTS-21, a new nicotinic agonist, on the locomotor activity and brain monoamine level. Jpn J. Pharmacol. 78, 385–389 (1998).

    CAS  PubMed  Google Scholar 

  86. 86

    Crespi, F. Nefiracetam. Daiichi Seiyaku. Curr. Opin. Investig. Drugs 3, 788–793 (2002).

    CAS  PubMed  Google Scholar 

  87. 87

    Meyer, E. M., Kuryatov, A., Gerzanich, V., Lindstrom, J. & Papke, R. L. Analysis of 3-(4-hydroxy, 2-Methoxybenzylidene)anabaseine selectivity and activity at human and rat α-7 nicotinic receptors. J. Pharmacol. Exp. Ther. 287, 918–925 (1998).

    CAS  PubMed  Google Scholar 

  88. 88

    Lang, P. M., Burgstahler, R., Haberberger, R. V., Sippel, W. & Grafe, P. A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves. Neuroreport 16, 479–483 (2005).

    CAS  PubMed  Google Scholar 

  89. 89

    Dussor, G. O. et al. Potentiation of evoked calcitonin gene-related peptide release from oral mucosa: a potential basis for the pro-inflammatory effects of nicotine. Eur. J. Neurosci. 18, 2515–2526 (2003).

    PubMed  PubMed Central  Google Scholar 

  90. 90

    Vincler, M. & Eisenach, J. C. Plasticity of spinal nicotinic acetylcholine receptors following spinal nerve ligation. Neurosci. Res. 48, 139–145 (2004).

    CAS  PubMed  Google Scholar 

  91. 91

    Vincler, M. A. & Eisenach, J. C. Knock down of the α5 nicotinic acetylcholine receptor in spinal nerve-ligated rats alleviates mechanical allodynia. Pharmacol. Biochem. Behav. 80, 135–143 (2005).

    CAS  PubMed  Google Scholar 

  92. 92

    Sixma, T. K. & Smit, A. B. Acetylcholine binding protein (AChBP): a secreted glial protein that provides a high-resolution model for the extracellular domain of pentameric ligand-gated ion channels. Annu. Rev. Biophys. Biomol. Struct. 32, 311–334 (2003).

    CAS  PubMed  Google Scholar 

  93. 93

    Brejc, K. et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269–276 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Smit, A. B. et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature 411, 261–268 (2001).

    CAS  PubMed  Google Scholar 

  95. 95

    Karlin, A. Emerging structure of the nicotinic acetylcholine receptors. Nature Rev. Neurosci. 3, 102–114 (2002).

    CAS  Google Scholar 

  96. 96

    Celie, P. H. et al. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41, 907–914 (2004).

    CAS  Google Scholar 

  97. 97

    Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).

    CAS  PubMed  Google Scholar 

  98. 98

    Pasti, L., Volterra, A., Pozzan, T. & Carmignoto, G. Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817–7830 (1997).

    CAS  PubMed  Google Scholar 

  99. 99

    Akk, G. & Steinbach, J. H. Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site. J. Neurosci. 25, 1992–2001 (2005).

    CAS  PubMed  Google Scholar 

  100. 100

    Pereira, E. F. et al. Unconventional ligands and modulators of nicotinic receptors. J. Neurobiol. 53, 479–500 (2002).

    CAS  PubMed  Google Scholar 

  101. 101

    Cooper, J. C., Gutbrod, O., Witzemann, V. & Methfessel, C. Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus oocytes. Eur. J. Pharmacol. 309, 287–298 (1996).

    CAS  PubMed  Google Scholar 

  102. 102

    Fayuk, D. & Yakel, J. L. Regulation of nicotinic acetylcholine receptor channel function by acetylcholinesterase inhibitors in rat hippocampal CA1 interneurons. Mol. Pharmacol. 66, 658–666 (2004).

    CAS  PubMed  Google Scholar 

  103. 103

    Ueno, S., Bracamontes, J., Zorumski, C., Weiss, D. S. & Steinbach, J. H. Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor. J. Neurosci. 17, 625–634 (1997).

    CAS  PubMed  Google Scholar 

  104. 104

    Sugano, N., Shimada, K., Ito, K. & Murai, S. Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-κB activation. Biochem. Biophys. Res. Commun. 252, 25–28 (1998).

    CAS  PubMed  Google Scholar 

  105. 105

    Saeed, R. W. et al. Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J. Exp. Med. 201, 1113–1123 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Westerloo, D. J. et al. The Cholinergic Anti-Inflammatory Pathway Regulates the Host Response during Septic Peritonitis. J. Infect. Dis. 191, 2138–2148 (2005).

    PubMed  Google Scholar 

  107. 107

    Han, Y., Englert, J. A., Yang, R., Delude, R. L. & Fink, M. P. Ethyl pyruvate inhibits nuclear factor-κB-dependent signaling by directly targeting p65. J. Pharmacol. Exp. Ther. 312, 1097–1105 (2005).

    CAS  PubMed  Google Scholar 

  108. 108

    Critical Therapeutics, Inc. Critical Therapeutics initiates Phase II clinical study of CT1-01 [online], <http://phx.corporate-ir.net/phoenix.zhtml?c=177530&p=irol-newsArticle&ID=675157&highlight=> (15 Feb 2005).

Download references

Acknowledgements

The author is supported by the Faculty Award Program of the North Shore Health System and the North Shore-LIJ GCRC. The author is grateful for the critical reading and thoughtful suggestions from K. J. Tracey, E.Tuomanen. E. J. Miller, P. Morcillo, and P. Wang.

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DATABASES

Entrez Gene

α7nAChR

α-MSH

ACTH

HMGB1

IL-1

TNF

OMIM

Ankylosing spondylitis

Chrohn's disease

depression

Parkinson's disease

psoriasis

rheumatoid arthritis

Tourette's syndrome

ulcerative colitis

FURTHER INFORMATION

Chemistry Of Drugs And The Brain

Cholinomimetic Drugs

Neuronal Nicotinic Receptors

Pharmacological Research University of Toledo

Glossary

SEPSIS

The clinical signs of a systemic inflammatory response to infection; 'severe sepsis' refers to organ dysfunction observed during systemic inflammation even in the absence of confirmed infection.

SHOCK

Bodily collapse or near collapse caused by inadequate oxygen delivery to the cells; characterized by reduced cardiac output, rapid heartbeat, circulatory insufficiency and pallor. Loss of blood is an important cause of shock.

ISCHAEMIA

A decrease in the blood supply to a bodily organ, tissue or body part caused by constriction or obstruction of the blood vessels.

ACETYLCHOLINE

A crystalline derivative of choline that is released at the ends of nerve fibres in the somatic and parasympathetic nervous systems and is involved in the transmission of nerve impulses in the body.

NICOTINIC ACETYLECHOLINE RECEPTORS

One of the two classes of cholinergic receptors. Nicotinic receptors are defined by their preference for binding nicotine over muscarine.

NICOTINIC AGONISTS

Chemical analogues of nicotine that can bind to a specific subset of nicotine acetylcholine receptors.

ENDOTOXIN

A toxin produced by Gram-negative bacteria and released from the bacterial cell.

VAGOTOMY

Surgical sectioning of fibres of the vagus nerve, previously used to diminish acid secretion of the stomach and control a duodenal ulcer.

MUSCARINIC RECEPTORS

One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for muscarine over nicotine.

MUSCARINE

A highly toxic alkaloid related to the cholines, derived from the red form of the mushroom Amanita muscaria and found in decaying animal tissue.

ALLODYNIA

Pain originating from a non-injurious stimulus to the skin.

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Ulloa, L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 4, 673–684 (2005). https://doi.org/10.1038/nrd1797

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