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Melanocortins and the Cholinergic Anti-Inflammatory Pathway

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Melanocortins: Multiple Actions and Therapeutic Potential

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 681))

Abstract

Experimental evidence indicates that small concentrations of inflammatory molecules produced by damaged tissues activate afferent signals through ascending vagus nerve fibers, that act as the sensory arm of an “inflammatory reflex”. The subsequent activation of vagal efferent fibers, which represent the motor arm of the inflammatory reflex, rapidly leads to acetylcholine release in organs of the reticuloendothelial system. Acetylcholine interacts with α7 subunit-containing nicotinic receptors in tissue macrophages and other immune cells and rapidly inhibits the synthesis/release of tumor necrosis factor-α and other inflammatory cytokines. This neural anti-inflammatory response called “cholinergic anti-inflammatory pathway” is fast and integrated through the central nervous system. Preclinical studies are in progress, with the aim to develop therapeutic agents able to activate the cholinergic anti-inflammatory pathway. Melanocortin peptides bearing the adrenocorticotropin/α-melanocyte-stimulating hormone sequences exert a protective and life-saving effect in animals and humans in conditions of circulatory shock. These neuropeptides are likewise protective in other severe hypoxic conditions, such as prolonged respiratory arrest, myocardial ischemia, renal ischemia and ischemic stroke, as well as in experimental heart transplantation. Moreover, experimental evidence indicates that melanocortins reverse circulatory shock, prevent myocardial ischemia/reperfusion damage and exert neuroprotection against ischemic stroke through activation of the cholinergic anti-inflammatory pathway. This action occurs via stimulation of brain melanocortin MC3/MC4 receptors. Investigations that determine the molecular mechanisms of the cholinergic anti-inflammatory pathway activation could help design of superselective activators of this pathway.

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References

  1. Ferrari W, Floris E, Paulesu F. Eosinopenic effect of ACTH injected into the cisterna magna. Boll Soc It Biol Sper 1955; 31:859–862.

    CAS  Google Scholar 

  2. Ferrari W. Behavioural changes in animals after intracisternal injection with adrenocorticotrophic hormone and melanocyte-stimulating hormone. Nature 1958; 181:925–926.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrari W, Gessa GL, Vargiu L. Behavioral effects induced by intracisternally injected ACTH and MSH. Ann NY Acad Sci 1963; 104:330–345.

    Article  CAS  PubMed  Google Scholar 

  4. De Wied D. Effect of peptide hormones on behavior. In: Ganon WF, Martini L, eds. Frontiers in Neuroendocrinology, London/New York: Oxford University Press, 1969; 1:97–140.

    Google Scholar 

  5. Catania A. Neuroprotective action of melanocortins: a therapeutic opportunity. Trends Neurosci 2008; 31:353–360.

    Article  CAS  PubMed  Google Scholar 

  6. Eberle AN. The melanotropins: chemistry, physiology and mechanisms of action. Basel: Karger, 1988.

    Google Scholar 

  7. Getting SJ. Targeting melanocortin receptors as potential novel therapeutics. Pharmacol Ther 2006; 111:1–15.

    Article  CAS  PubMed  Google Scholar 

  8. O’Donohue TI, Dorsa DM. The opiomelanotropinergic neuronal and endocrine systems. Peptides 1982; 3:353–395.

    Article  PubMed  Google Scholar 

  9. Smith AI, Funder JW. Proopiomelanocortin processing in the pituitary, central nervous system and peripheral tissues. Endocrinol Rev 1988; 9:159–179.

    Article  CAS  Google Scholar 

  10. Versteeg DHG, Van Bergen P, Adan RAH et al. Melanocortins and cardiovascular regulation. Eur J Pharmacol 1998; 360:1–14.

    Article  CAS  PubMed  Google Scholar 

  11. Catania A, Gatti S, Colombo G et al. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev 2004; 56:1–29.

    Article  CAS  PubMed  Google Scholar 

  12. Getting SJ, Di Filippo C, D’Amico M et al. The melanocortin peptide HP228 displays protective effects in acute models of inflammation and organ damage. Eur J Pharmacol 2006; 532:138–144.

    Article  CAS  PubMed  Google Scholar 

  13. Wikberg JE, Mutulis F. Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov 2008; 7:307–323.

    Article  CAS  PubMed  Google Scholar 

  14. Mountjoy KG, Robbins LS, Mortrud MT et al. The cloning of a family of genes that encode the melanocortin receptors. Science 1992; 257:1248–1251.

    Article  CAS  PubMed  Google Scholar 

  15. Mountjoy KG, Wu C-SJ, Dumont LM et al. Melanocortin-4 receptor messenger ribonucleic acid expression in rat cardiorespiratory, musculoskeletal and in tegumentary systems. Endocrinology 2003; 144:5488–5496.

    Article  CAS  PubMed  Google Scholar 

  16. Schiöth HB. The physiological role of melanocortin receptors. Vitam Horm 2001; 63:195–232.

    Article  PubMed  Google Scholar 

  17. Schiöth HB, Haitina T, Ling MK et al. Evolutionary conservation of the structural, pharmacological and genomic characteristics of the melanocortin receptor subtypes. Peptides 2005; 26:1886–1900.

    Article  PubMed  CAS  Google Scholar 

  18. Tatro JB. Melanotropin receptors in the brain are differentially distributed and recognize both corticotrophin and alpha-melanocyte stimulating hormone. Brain Res 1990; 536:124–132.

    Article  CAS  PubMed  Google Scholar 

  19. Tatro JB, Entwistle ML. Distribution of melanocortin receptors in the lower brainstem of the rat. Ann NY Acad Sci 1994; 739:311–314.

    Article  CAS  PubMed  Google Scholar 

  20. Tatro JB. Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides. Neuroimmunomodulation 1996; 3:259–284.

    Article  CAS  PubMed  Google Scholar 

  21. Wikberg JES, Muceniece R, Mandrika I et al. New aspects on the melanocortins and their receptors. Pharmacol Res 2000; 42:393–420.

    Article  CAS  PubMed  Google Scholar 

  22. Brzoska T, Luger TA, Maser C et al. α-Melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in Vitro and in Vivo and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocr Rev 2008; 29:581–602.

    Article  CAS  PubMed  Google Scholar 

  23. Lasaga M, Debeljuk L, Durand D et al. Role of alpha-melanocyte stimulating hormone and melanocortin 4 receptor in brain inflammation. Peptides 2008; 29:1825–1835.

    Article  CAS  PubMed  Google Scholar 

  24. Martin WJ, MacIntyre DE. Melanocortin receptors and erectile function. Eur Urol 2004; 45:706–713.

    Article  CAS  PubMed  Google Scholar 

  25. Tatro JB. Melanocortins defend their territory: multifaceted neuroprotection in cerebral ischemia. Endocrinology 2006; 147:1122–1125.

    Article  CAS  PubMed  Google Scholar 

  26. Bertolini A, Guarini S, Ferrari W. Adrenal-independent, anti-shock effect of ACTH-(1–24) in rats. Eur J Pharmacol 1986; 122:387–388.

    Article  CAS  PubMed  Google Scholar 

  27. Bertolini A, Guarini S, Rompianesi E et al. α-MSH and other ACTH fragments improve cardiovascular function and survival in experimental hemorrhagic shock. Eur J Pharmacol 1986; 130:19–26.

    Article  CAS  PubMed  Google Scholar 

  28. Guarini S, Ferrari W, Mottillo G et al. Anti-shock effect of ACTH: haematological changes and influence of splenectomy. Arch In Pharmacodyn 1987; 289:311–318.

    CAS  Google Scholar 

  29. Guarini S, Tagliavini S, Bazzani C et al. Early treatment with ACTH-(1–24) in a rat model of hemorrhagic shock prolongs survival and extends the time-limit for blood reinfusion to be effective. Crit Care Med 1990; 18:862–865.

    Article  CAS  PubMed  Google Scholar 

  30. Guarini S, Bazzani C, Cainazzo MM et al. Evidence that melanocortin 4 receptor mediates hemorrhagic shock reversal caused by melanocortin peptides. J Pharmacol Exp Ther 1999; 291:1023–1027.

    CAS  PubMed  Google Scholar 

  31. Guarini S, Cainazzo MM, Giuliani D et al. Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway. Cardiovasc Res 2004; 63:357–365.

    Article  CAS  PubMed  Google Scholar 

  32. Giuliani D, Mioni C, Bazzani C et al. Selective melanocortin MC4 receptor agonists reverse haemorrhagic shock and prevent multiple organ damage. Br J Pharmacol 2007; 150:595–603.

    Article  CAS  PubMed  Google Scholar 

  33. Noera G, Lamarra M, Guarini S et al. Survival rate after early treatment for acute type-A aortic dissection with ACTH-(1–24). Lancet 2001; 358:469–470.

    Article  CAS  PubMed  Google Scholar 

  34. Squadrito F, Guarini S, Altavilla D et al. Adrenocorticotropin reverses vascular dysfunction and protects against splanchnic artery occlusion shock. Br J Pharmacol 1999; 128:816–822.

    Article  CAS  PubMed  Google Scholar 

  35. Guarini S, Bazzani C, Bertolini A. Resuscitating effect of melanocortin peptides after prolonged respiratory arrest. Br J Pharmacol 1997; 121:1454–1460.

    Article  CAS  PubMed  Google Scholar 

  36. Bazzani C, Guarini S, Botticelli AR et al. Protective effect of melanocortin peptides in rat myocardial ischemia. J Pharmacol Exp Ther 2001; 297:1082–1087.

    CAS  PubMed  Google Scholar 

  37. Guarini S, Schiöth HB, Mioni C et al. MC3 receptors are involved in the protective effect of melanocortins in myocardial ischaemia/reperfusion-induced arrhythmias. Naunyn-Schmiedeberg’s Arch Pharmacol 2002; 366:177–182.

    Article  CAS  Google Scholar 

  38. Getting SJ, Di Filippo C, Christian HC et al. MC-3 receptor and the inflammatory mechanisms activated in acute myocardial infarct. J Leukoc Biol 2004; 76:845–853.

    Article  CAS  PubMed  Google Scholar 

  39. Mioni C, Giuliani D, Cainazzo MM et al. Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors. Eur J Pharmacol 2003; 477:227–234.

    Article  CAS  PubMed  Google Scholar 

  40. Mioni C, Bazzani C, Giuliani D et al. Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats. Crit Care Med 2005; 33:2621–2628.

    Article  CAS  PubMed  Google Scholar 

  41. Vecsernyes M, Juhasz B, Der P et al. The administration of α-melanocyte-stimulating hormone protects the ischemic/reperfused myocardium. Eur J Pharmacol 2003; 470:177–183.

    Article  CAS  PubMed  Google Scholar 

  42. Chiao H, Kohda Y, McLeroy P et al. Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest 1997; 99:1165–1172.

    Article  CAS  PubMed  Google Scholar 

  43. Lee YS, Park JJ, Chung KY. Change of melanocortin receptor expression in rat kidney ischemia-reperfusion injury. Transplant Proc 2008; 40:2142–2144.

    Article  CAS  PubMed  Google Scholar 

  44. Jo SK, Yun SY, Chang KH et al. α-MSH decreases apoptosis in ischaemic acute renal failure in rats: possibile mechanism of this beneficial effect. Nephrol Dial Transplant 2001; 16:1583–1591.

    Article  CAS  PubMed  Google Scholar 

  45. Giuliani D, Mioni C, Altavilla D et al. Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia. Endocrinology 2006; 147:1126–1135.

    Article  CAS  PubMed  Google Scholar 

  46. Giuliani D, Leone S, Mioni C et al. Broad therapeutic treatment window of the [Nle4, D-Phe7] α-melanocyte-stimulating hormone for long-lasting protection against ischemic stroke, in Mongolian gerbils. Eur J Pharmacol 2006; 538:48–56.

    Article  CAS  PubMed  Google Scholar 

  47. Giuliani D, Ottani A, Mioni C et al. Neuroprotection in focal cerebral ischemia owing to delayed treatment with melanocortins. Eur J Pharmacol 2007; 570:57–65.

    Article  CAS  PubMed  Google Scholar 

  48. Chen G, Frøkiær J, Pedersen M et al. Reduction of ischemic stroke in rat brain by alpha melanocyte stimulating hormone. Neuropeptides 2008; 42:331–338.

    Article  CAS  PubMed  Google Scholar 

  49. Ottani A, Giuliani D, Mioni C et al. Vagus nerve mediates the protective effects of melanocortins against cerebral and systemic damage after ischemic stroke. J Cereb Blood Flow Metab 2008; doi:10.1038/ jcbfm.2008.140.

    Google Scholar 

  50. Gatti S, Colombo G, Buffa R et al. α-Melanocyte-stimulating hormone protects the allograft in experimental heart transplantation. Transplantation 2002; 74:1678–1684.

    Article  CAS  PubMed  Google Scholar 

  51. Borovikova LV, Ivanova S, Zhang M et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405:458–462.

    Article  CAS  PubMed  Google Scholar 

  52. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853–859.

    Article  CAS  PubMed  Google Scholar 

  53. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007; 117:289–296.

    Article  CAS  PubMed  Google Scholar 

  54. Hatton KW, McLarney JT, Pittman T et al. Vagal nerve stimulation: overview and implications for anesthesiologists. Anesth Analg 2006; 103:1241–1249.

    Article  PubMed  Google Scholar 

  55. Wheless JW, Baumgartner J. Vagus nerve stimulation therapy. Drugs Today 2004; 40:501–515.

    Article  PubMed  Google Scholar 

  56. Basedovsky H, Rey DA, Sorkin E et al. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986; 233:652–654.

    Article  Google Scholar 

  57. Hu XX, Goldmuntz EA, Brosnan CF. The effect of norepinephrine on endotoxin-mediated macrophage activation. J Neuroimmunol 1991; 31:35–42.

    Article  CAS  PubMed  Google Scholar 

  58. Lipton JM, Catania A. Antiinflammatory action of neuroimmunomodulator α-MSH. Immunol Today 1997; 18:140–145.

    Article  CAS  PubMed  Google Scholar 

  59. Goehler LE, Gaykema RP, Hansen MK et al. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci 2000; 85:49–59.

    Article  CAS  PubMed  Google Scholar 

  60. Herman GE, Emch GS, Tovar CA et al. c-Fos generation in the dorsal vagal complex after systemic endotoxin is not dependent on the vagus nerve. Am J Physiol Regul Integr Comp Physiol 2001; 208:289–299.

    Google Scholar 

  61. Emch GS, Herman GE, Rogers RC. TNF-α activates solitary nucleus neurons responsive to gastric distension. Am J Physiol Gastrointest Liver Physiol 2000; 279:G582–G586.

    CAS  PubMed  Google Scholar 

  62. Watkins LR, Maier SF. Implications of immune-to-brain communication for sickness and pain. Proc Natl Acad Sci USA 1999; 96:7710–7713.

    Article  CAS  PubMed  Google Scholar 

  63. Stenberg EM. Neural-immune interactions in health and disease. J Clin Invest 1997; 100:2641–2647.

    Article  Google Scholar 

  64. Scheimann RI, Cogswell PC, Lofquist AK et al. Role of trancriptional activation of IkB α in mediation of immunosuppression by glucocorticoids. Science 1995; 270:283–286.

    Article  Google Scholar 

  65. Guarini S, Altavilla D, Cainazzo MM et al. Efferent vagal fibre stimulation blunts nuclear factor-kB activation and protects against hypovolemic hemorrhagic shock. Circulation 2003, 107:1189–119.

    Article  PubMed  Google Scholar 

  66. Guarini S, Tagliavini S, Bazzani C et al. Nicotine reverses hemorrhagic shock in rats. Naunyn-Schmiedeberg’s Arch Pharmacol 1991; 343:427–430.

    CAS  Google Scholar 

  67. Guarini S, Bazzani C, Tagliavini S et al. Reversal of experimental hemorrhagic shock by dimethylphenylpiperazinium (DMPP). Experientia 1992; 48:663–667.

    Article  CAS  PubMed  Google Scholar 

  68. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005; 19:493–499.

    Article  CAS  PubMed  Google Scholar 

  69. Oke SL, Tracey KJ. From CNI-1493 to the immunological homonculus: physiology of the inflammatory reflex. J Leukoc Biol 2008; 83:512–517.

    Article  CAS  PubMed  Google Scholar 

  70. Parrish WR, Gallowitsch-Puerta M, Czura CJ et al. Experimental therapeutic strategies for severe sepsis: mediators and mechanisms. Ann N Y Acad Sci 2008; 1144:210–236.

    Article  CAS  PubMed  Google Scholar 

  71. Van der Zanden EP, Boeckxstaens Ge, de Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterol Motil 2009; 21:6–17.

    Article  Google Scholar 

  72. Loewy AD. Central autonomic pathways. In: Loewy AD, Spyer KM, eds. Central Regulation of Autonomic Functions. Oxford: Oxford University Press, 1990:88–104.

    Google Scholar 

  73. Baue AE. Multiple organ failure, multiple organ dysfunction syndrome and systemic inflammatory response syndrome. Why no magic bullets? Arch Surg 1997; 132:703–707.

    CAS  Google Scholar 

  74. Le Tulzo Y, Shenkar R, Kaneko D et al. Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kB regulation and cytokine expression. J Clin Invest 1997; 99:1516–1524.

    Article  PubMed  Google Scholar 

  75. Guarini S, Bazzani C, Mattera Ricigliano G et al. Influence of ACTH-(1–24) on free radical levels in the blood of haemorrhage-shocked rats: direct ex vivo detection by electron spin resonance spectrometry. Br J Pharmacol 1996; 119:29–34.

    CAS  PubMed  Google Scholar 

  76. Guarini S, Bini A, Bazzani C et al. Adrenocorticotropin normalizes the blood levels of nitric oxide in haemorrhage-shocked rats. Eur J Pharmacol 1997; 336:15–21.

    Article  CAS  PubMed  Google Scholar 

  77. Altavilla D, Guarini S, Bitto A et al. Activation of the cholinergic anti-infiammatory pathway reduces NF-kB activation, blunts TNF-α production and protects against splanchnic artery occlusion shock. Shock 2006; 25:500–506.

    Article  CAS  PubMed  Google Scholar 

  78. McDonald MC, Mota-Filipe H, Paul A et al. Calpain inhibitor I reduces the activation of nuclear factor-kB and organ injury/dysfunction in hemorrhagic shock. FASEB J 2001; 15:171–186.

    Article  CAS  PubMed  Google Scholar 

  79. Cui X, Wu R, Zhou M et al. Adrenomedullin and its binding protein attenuate the proinflammatory response after hemorrhage. Crit Care Med 2005; 33:391–398.

    Article  CAS  PubMed  Google Scholar 

  80. Jarrar D, Chaudry IH, Wang P. Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches. Int J Mol Med 1999; 4:575–583.

    CAS  PubMed  Google Scholar 

  81. Bertolini A, Guarini S, Ferrari W et al. Adrenocorticotropin reversal of experimental hemorrhagic shock is antagonized by morphine. Life Sci 1986; 39:1271–1280.

    Article  CAS  PubMed  Google Scholar 

  82. Guarini S, Vergoni AV, Bertolini A. Anti-shock effect of ACTH-(1–24): comparison between intracerebroventricular and intravenous route of administration. Pharmacol Res Commun 1987; 19:255–260.

    Article  CAS  PubMed  Google Scholar 

  83. Guarini S, Tagliavini S, Bazzani C et al. Effect of ACTH-(1–24) on the volume of circulating blood and on regional blood flow in rats bled to hypovolemic shock. Resuscitation 1989; 18:133–134.

    Article  CAS  PubMed  Google Scholar 

  84. Bazzani C, Tagliavini S, Bertolini E et al. Influence of ACTH-(1–24) on metabolic acidosis and hypoxemia induced by massive hemorrhage in rats. Resuscitation 1992; 23:113–120.

    Article  CAS  PubMed  Google Scholar 

  85. Guarini S, Ferrari W, Bertolini A. Anti-shock effect of ACTH-(1–24): influence of subtotal hepatectomy. Pharmacol Res Commun 1988; 20:395–403.

    Article  CAS  PubMed  Google Scholar 

  86. Jochem J. Involvement of proopiomelanocortin-derived peptides in endogenous central istamine-induced reversal of critical haemorrhagic hypotension in rats. J Physiol Pharmacol 2004; 55:57–71.

    CAS  PubMed  Google Scholar 

  87. Bertuglia S, Giusti A. Influence of ACTH-(1–24) and plasma hyperviscosity on free radical production and capillary perfusion after hemorrhagic shock. Microcirculation 2004; 11:227–238.

    Article  CAS  PubMed  Google Scholar 

  88. Ludbrook J, Ventura S. ACTH-(1–24) blocks the decompensatory phase of the haemodynamic response to acute hypovolaemia in conscious rabbits. Eur J Pharmacol 1995; 275:267–275.

    Article  CAS  PubMed  Google Scholar 

  89. Bertolini A, Guarini S, Ferrari W et al. ACTH-(1–24) restores blood pressure in acute hypovolaemia and haemorrhagic shock in humans. Eur J Clin Pharmacol 1987; 32:537–538.

    Article  CAS  PubMed  Google Scholar 

  90. Noera G, Pensa P, Guelfi P et al. ACTH-(1–24) and hemorrhagic shock: preliminary clinical results. Resuscitation 1989; 18:145–147.

    Article  CAS  PubMed  Google Scholar 

  91. Noera G, Angiello L, Biagi B et al. Haemorrhagic shock in cardiac surgery. Pharmacological treatment with ACTH (1–24). Resuscitation 1991; 22:123–127.

    Article  CAS  PubMed  Google Scholar 

  92. Pinelli G, Chesi G, Di Donato C et al. Preliminary data on the use of ACTH-(1–24) in human shock conditions. Resuscitation 1989; 18:149–150.

    Article  CAS  PubMed  Google Scholar 

  93. Altavilla D, Cainazzo MM, Squadrito F et al. Tumour necrosis factor-α as a target of melanocortins in haemorrhagic shock, in the anaesthetized rat. Br J Pharmacol 1998; 124:1587–1590.

    Article  CAS  PubMed  Google Scholar 

  94. Guarini S, Tagliavini S, Bazzani C et al. Intracerebroventricular injection of hemicolinium-3 prevents the ACTH-induced, but not the physostigmine-induced, reversal of hemorrhagic shock in rats. Pharmacology 1990; 40:85–89.

    Article  CAS  PubMed  Google Scholar 

  95. Guarini S, Rompianesi E, Ferrari W et al. Influence of vagotomy and of atropine on the anti-shock effect of adrenocorticotropin. Neuropeptides 1986; 8:19–24.

    Article  CAS  PubMed  Google Scholar 

  96. Guarini S, Tagliavini S, Ferrari W et al. Reversal of haemorrhagic shock in rats by cholinomimetic drugs. Br J Pharmacol 1989; 98:218–824.

    CAS  PubMed  Google Scholar 

  97. Savić J, Varagić VM, Prokić DJ et al. The life-saving effect of physostigmine in haemorrhagic shock. Resuscitation 1991; 21:57–60.

    Article  PubMed  Google Scholar 

  98. Onat F, Aslan N, Gören Z et al. Reversal of hemorrhagic shock in rats by oxotremorine: the role of muscarinic and nicotinic receptors and AV3V region. Brain Res 1994; 660:261–266.

    Article  CAS  PubMed  Google Scholar 

  99. Bazzani C, Balugani A, Bertolini A et al. Comparison of the effects of ACTH-(1–24), methylprednisolone, aprotinin and norepinephrine in a model of hemorrhagic shock in rats. Resuscitation 1993; 25:219–226.

    Article  CAS  PubMed  Google Scholar 

  100. Gonindard C, Goigoux C, Hollande E et al. The administration of an α-MSH analogue reduces the serum release of IL-1 α and TNF α induced by the injection of a sublethal dose of lipopolysaccharides in the BALB/c mouse. Pigment Cell Res 1996; 9:148–153.

    Article  CAS  PubMed  Google Scholar 

  101. Lipton JM, Ceriani G, Macaluso A et al. Antiinflammatory effects of the neuropeptide α-MSH in acute, chronic and systemic inflammation. Ann NY Acad Sci 1994; 741:137–148.

    Article  CAS  PubMed  Google Scholar 

  102. Pavlov VA, Ochani M, Gallowitsch-Puerta M et al. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci USA 2006; 103:5219–5223.

    Article  CAS  PubMed  Google Scholar 

  103. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res 2004; 61:481–497.

    Article  CAS  PubMed  Google Scholar 

  104. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res 2002; 53:31–47.

    Article  CAS  PubMed  Google Scholar 

  105. Eefting F, Rensing B, Wigman J et al. Role of apoptosis in reperfusion injury. Cardiovasc Res 2004; 61:414–426.

    Article  CAS  PubMed  Google Scholar 

  106. O’Neill CA, Fu LW, Halliwell B et al. Hydroxyl radical production during myocardial ischemia and reperfusion in cats. Am J Physiol Heart Circ Physiol 1996; 271:H660–H667.

    Google Scholar 

  107. Bolli R, Marban E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 1999; 79:609–634.

    CAS  PubMed  Google Scholar 

  108. Ramasamy R, Hwang YC, Liu Y et al. Metabolic and functional protection by selective inhibition of nitric oxide synthase 2 during ischemia-reperfusion in isolated perfused hearts. Circulation 2004; 109:1668–1673.

    Article  CAS  PubMed  Google Scholar 

  109. Li C, Browder W, Kao RL. Early activation of transcription factor NF-kB during ischemia in perfused rat heart. Am J Physiol Heart Circ Physiol 1999; 276:H543–H552.

    CAS  Google Scholar 

  110. Shimizu N, Yoshiyama M, Omura T et al. Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats. Cardiovasc Res 1998; 38:116–124.

    Article  CAS  PubMed  Google Scholar 

  111. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res 2004; 61:448–460.

    Article  CAS  PubMed  Google Scholar 

  112. Moukarbel GV, Ayoub CM, Abchee AB. Pharmacological therapy for myocardial reperfusion injury. Curr Opin Pharmacol 2004; 4:147–153.

    Article  CAS  PubMed  Google Scholar 

  113. Monassier JP. Reperfusion injury in acute myocardial infarction: from bench to cath lab. Part II: Clinical issues and therapeutic options. Arch Cardiovasc Dis 2008; 101:565–575.

    Article  PubMed  Google Scholar 

  114. Landmesser U, Wollert KC, Drexler H. Potential novel pharmacological therapies for myocardial remodelling. Cardiovasc Res 2009; 81:519–527.

    Article  CAS  PubMed  Google Scholar 

  115. Bazzani C, Mioni C, Ferrazza G et al. Involvement of the central nervous system in the protective effect of melanocortins in myocardial ischaemia/reperfusion injury. Resuscitation 2002; 52:109–115.

    Article  CAS  PubMed  Google Scholar 

  116. Juhasz B, Der P, Szodoray P et al. Adrenocorticotrope hormone fragment (4–10) attenuates the ischemia/ reperfusion-induced cardiac injury in isolated rat hearts. Antioxid Redox Signal 2007; 9:1851–1861.

    Article  CAS  PubMed  Google Scholar 

  117. Colombo G, Gatti S, Turcatti F et al. Gene expression profiling reveals multiple protective influences of the peptide α-melanocyte-stimulating hormone in experimental heart transplantation. J Immunol 2005; 175:3391–3401.

    CAS  PubMed  Google Scholar 

  118. Zuanetti G, De Ferrari GM, Priori SG et al. Protective effect of vagal stimulation on reperfusion arrhythmias in cats. Circ Res 1987; 61:429–435.

    CAS  PubMed  Google Scholar 

  119. Vanoli E, De Ferrari GM, Stramba-Badiale M et al. Vagal stimulation and prevention of sudden death in conscious dog with a healed myocardial infarction. Circ Res 1991; 68:1471–1481.

    CAS  PubMed  Google Scholar 

  120. Li M, Zheng C, Sato T et al. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 2004; 109:120–124.

    Article  PubMed  Google Scholar 

  121. Cheng Z, Zhang H, Guo SZ et al. Differential control over postganglionic neurons in rat cardiac ganglia by NA and DmnX neurons: anatomical evidence. Am J Physiol Regul Integr Comp Physiol 2004; 286:R625–R633.

    CAS  PubMed  Google Scholar 

  122. Cheng Z, Guo SZ, Lipton AJ et al. Domoic acid lesions in nucleus of the solitary tract: time-dependent recovery of hypoxic ventilatory response and peripheral afferent axonal plasticity. J Neurosci 2002; 22:3215–26.

    CAS  PubMed  Google Scholar 

  123. Zhang H, Gozal D, Yu J et al. Attenuation of baroreflex control of the heart rate following domoic acid (DA) lesions in the nucleus ambiguus (NA) of the rat. Soc Neurosci Abstr 2002; 29.

    Google Scholar 

  124. Anderson MR. The systemic inflammatory response in heart failure. Prog Ped Card 2000; 11:219–230.

    Article  Google Scholar 

  125. Katare RG, Ando M, Kakinuma Y et al. Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mithocondrial permeability transition pore independent of the bradycardiac effect. J Thorac Cardiovasc Surg 2009; 137:223–231.

    Article  CAS  PubMed  Google Scholar 

  126. Krishnamurthy P, Rajasingh J, Lambers E et al. IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res 2009; 104:e9–e18.

    Article  CAS  PubMed  Google Scholar 

  127. Leker RR, Shohami E. Cerebral ischemia and trauma—different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Rev 2002; 39:55–73.

    Article  PubMed  Google Scholar 

  128. Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 2002; 33:2123–2136.

    Article  PubMed  Google Scholar 

  129. Wise PM, Dubal DB, Rau SW et al. Are estrogens protective or risk factors in brain injury and neurodegeneration? Re-evaluation after the women’s health initiative. Endocr Rev 2005; 26:308–312.

    Article  CAS  PubMed  Google Scholar 

  130. Rogalewski A, Schneider A, Ringelstein EB et al. Toward a multimodal neuroprotective treatment of stroke. Stroke 2006; 37:1129–1136.

    Article  PubMed  Google Scholar 

  131. Adams HP, Del Zoppo G, Alberts MJ et al. Guidelines for the early management of adults with ischemic stroke. Stroke 2007; 38:1655–711.

    Article  PubMed  Google Scholar 

  132. Yepes M, Roussel BD, Ali C et al. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci 2009; 32:48–55.

    Article  CAS  PubMed  Google Scholar 

  133. Huh SK, Lipton JM, Batjer HH. The protective effects of α-melanocyte stimulating hormone on canine brain ischemia. Neurosurgery 1997; 40:132–140.

    Article  CAS  PubMed  Google Scholar 

  134. Huang Q, Tatro JB. α-Melanocyte stimulating hormone suppresses intracerebral tumor necrosis factor-α and interleukin-1 β gene expression following transient cerebral ischemia in mice. Neurosci Lett 2002; 334:186–190.

    Article  CAS  PubMed  Google Scholar 

  135. Forslin Aronsson S, Spulber S, Popescu LM et al. α-Melanocyte-stimulating hormone is neuroprotective in rat global cerebral ischemia. Neuropeptides 2006; 40:65–75.

    Article  CAS  PubMed  Google Scholar 

  136. Tatro JB, Sinha PS. The central melanocortin system and fever. Ann N Y Acad Sci 2003; 994:246–257.

    Article  CAS  PubMed  Google Scholar 

  137. Spulber S, Moldovan M, Oprica M et al. α-MSH decreases core and brain temperature during global cerebral ischemia in rats. Neuroreport 2005; 16:69–72.

    Article  CAS  PubMed  Google Scholar 

  138. Gendron A, Teitelbaum J, Cossette C et al. Temporal effects of left versus right middle cerebral artery occlusion on spleen lymphocyte subsets and mitogenic response in Wistar rats. Brain Res 2002; 955:85–97.

    Article  CAS  PubMed  Google Scholar 

  139. Prass K, Meisel C, Hoflich C et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med 2003; 198:725–736.

    Article  CAS  PubMed  Google Scholar 

  140. Emsley HCA, Smith CJ, Gavin CM et al. An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. J Neuroimmunol 2003; 139:93–101.

    Article  CAS  PubMed  Google Scholar 

  141. Smith CJ, Emsley HCA, Gavin CM et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004; 4:2.

    Article  PubMed  Google Scholar 

  142. Offner H, Subramanian S, Parker SM et al. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab 2006; 26:654–665.

    Article  CAS  PubMed  Google Scholar 

  143. Zhang G, Zhang L, Logan R et al. Decreased expression and impaired function of muscarinic acetylcholine receptors in the rat hippocampus following transient forebrain ischemia. Neurobiol Dis 2005; 20:805–813.

    Article  CAS  PubMed  Google Scholar 

  144. Spencer SJ, Mouihate A, Pittman QJ. Peripheral inflammation exacerbates damage after global ischemia independently of temperature and acute brain inflammation. Stroke 2007; 38:1570–1577.

    Article  CAS  PubMed  Google Scholar 

  145. Vila N, Castillo J, Dávalos A et al. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke 2003; 34:671–675.

    Article  CAS  PubMed  Google Scholar 

  146. Mountjoy KG, Mortrud MT, Low MJ et al. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 1994; 8:1298–1308.

    Article  CAS  PubMed  Google Scholar 

  147. Li SJ, Varga K, Archer P et al. Melanocortin antagonists define two distinct pathways of cardiovascular control by α-and γ-melanocyte-stimulating hormones. J Neurosci 1996; 16:5182–5188.

    CAS  PubMed  Google Scholar 

  148. Rosas-Ballina M, Ochani M, Parrish WR et al. Splenic nerve is required for cholinergic anti-inflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci USA 2008; 105:11008–11013.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy

    Daniela Giuliani, Alessandra Ottani, Carla Bazzani & Salvatore Guarini

  2. Department of Clinical and Experimental Medicine and Pharmacology Section of Pharmacology, University of Messina, Messina, Italy

    Domenica Altavilla & Francesco Squadrito

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  1. Daniela Giuliani
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  2. Alessandra Ottani
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  3. Domenica Altavilla
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  4. Carla Bazzani
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  5. Francesco Squadrito
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  6. Salvatore Guarini
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Correspondence to Salvatore Guarini .

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  1. Fondazione IRCCS, Center for Preclinical Investigation, Ca Granda, Ospedale Maggiore Policlinico, Milano, Italy

    Anna Catania MD

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Giuliani, D., Ottani, A., Altavilla, D., Bazzani, C., Squadrito, F., Guarini, S. (2010). Melanocortins and the Cholinergic Anti-Inflammatory Pathway. In: Catania, A. (eds) Melanocortins: Multiple Actions and Therapeutic Potential. Advances in Experimental Medicine and Biology, vol 681. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6354-3_6

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