Mualla Aylin Arıcı, Elif Barış, Emre Hamurtekin

The Role of Nicotinic Anti-Inflammatory Pathway in Prostaglandin Mediated Inflammatory Response in Sepsis: A Short Review

Sepsis is a severe and multifaceted condition of body in response to an infection, which affects multiple organs systems that makes it difficult to treat and enhances the mortality rates. Release of inflammatory cytokines can initiate an inflammatory response during sepsis. However, the response can be modified by the control mechanism inside the body that are essential for the keeping the balance and survival. The cholinergic anti-inflammatory pathway is defined as a comprehensive neurohumoral pathway that diminishes pro-inflammatory cytokine release through the vagus nerve and cholinergic receptors, predominantly α7 nicotinic acetylcholine receptors (α7nAChR) that expressed on inflammatory mononuclear cells. Thus, cholinergic agonists might be a part of prospective treatment approach in inflammatory diseases such as sepsis. This review covers the role of cholinergic system in prostaglandin mediated inflammatory response.

Keywords:

Cholinergic Anti-Inflammatory Pathway, α7nAChR Inflammation, Sepsis, Prostaglandin,

PDF

___

REFERENCES1. Rice TW, Bernard GR. Therapeutic Intervention and Targets for Sepsis. Annu Rev Med 2005;56(1):225-248.
2. Redwine JM, Buchmeier MJ, Evans CF. In vivo expression of major histocompatibility complex molecules on oligodendrocytes and neurons during viral infection. Am J Pathol 2001;159(4):1219-1224.
3. Katzung BG, Kruidering-Hall M, Trevor AJ. Katzung & Trevor’s Pharmacology: Examination & Board Review 12e. Immunopharmacology. New York; 2019.
4. Ulloa L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov. 2005;4:673.
5. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol 2011;6:19-48.
6. Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management BMJ 2016;353.
7. Remick DG. Pathophysiology of sepsis Am J Pathol 2007;170(5):1435-1444.
8. Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation Mol Med 2003;9(5-8):125-134.
9. Fujii T, Mashimo M, Moriwaki Y, Misawa H, Ono S et al. Expression and Function of the Cholinergic System in Immune Cells Front Immunol 2017; Vol 8.
10. Snider SA, Margison KD, Ghorbani P, LeBlond ND, O'Dwyer C et al. Choline transport links macrophage phospholipid metabolism and inflammation J Biol Chem 2018;293(29):11600-11611.
11. Borovikova L V, Ivanova S, Zhang M, Yang H, Botchkina GI et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin Nature 2000;405:458.
12. Tarnawski L, Reardon C, Caravaca AS, Rosas-Ballina M, Tusche MW et al. Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex Front Immunol 2018;9(November):1-8.
13. De Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation Br J Pharmacol 2007;151(7):915-929. 14. Banks W, J. Kastin A, D. Broadwell R. Passage of Cytokines across the Blood-Brain Barrier. Neuroimmunomodulation 1995;Vol 2.
15. Buller K. Role of Circumventricular Organs in pro-Inflammatory Cytokine-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis Clinical and experimental pharmacology & physiology 2001; Vol 28.
16. Tassorelli C, Greco R, Armentero MT, Blandini F, Sandrini G et al. A Role for Brain Cyclooxygenase‐2 and Prostaglandin‐E2 in Migraine: Effects of Nitroglycerin Neuroinflammation in Neuronal Death and Repair 2007; Vol 82:373-382.
17. Elmquist JK, Scammell homas E, Saper CB. Mechanisms of CNS response to systemic immune challenge: the febrile response. Trends Neurosci. 1997;20(12):565-570.
18. Rivest S. How circulating cytokines trigger the neural circuits that control the hypothalamic–pituitary–adrenal axis. Psychoneuroendocrinology. 2001;26(8):761-788.
19. Kanashiro A, Sônego F, Ferreira R, et al. Therapeutic Potential and Limitations of Cholinergic Anti-Inflammatory Pathway in Sepsis.2017; Vol 117.
20. Guslandi M. Nicotine treatment for ulcerative colitis. Br J Clin Pharmacol. 1999;48(4):481-484.
21. Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EX. Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices J Neurosci 1999;19(7):2693-2705.
22. McGrath J, McDonald JWD, MacDonald JK. Transdermal Nicotine for Induction of Remission in Ulcerative Colitis. The Cochrane Library 2004.
23. Aldhous M, Prescott R, Roberts S, Samuel K, Waterfall M, Satsangi J. Does Nicotine Influence Cytokine Profile and Subsequent Cell Cycling/Apoptotic Responses in Inflammatory Bowel Disease? Inflammatory Bowel Diseases 2008; Vol 14:1469-82.
24. Sagami S, Ueno Y, Tanaka S, Fujita A, Niitsu H et al. Choline Deficiency Causes Colonic Type II Natural Killer T (NKT) Cell Loss and Alleviates Murine Colitis under Type I NKT Cell Deficiency PLoS One 2017;12(1):e0169681-e0169681.
25. Ozawa K, Kitamura O, Uchida K, Honjo I. Clinical Trial of CDP Choline as a Medicament for Acute Pancreatitis and Its Relation to Pancreas and Liver Damage in Acute Pancreatitis Bulletin de la Société internationale de chirurgie1974; Vol 33.
26. Gorelick F, Lerch M. Do Animal Models of Acute Pancreatitis Reproduce Human Disease? Cellular and Molecular Gastroenterology and Hepatology 2017;Vol 4.
27. Treede I, Braun A, Sparla R, Kühnel M, Giese T et al. Anti-inflammatory effects of phosphatidylcholine J Biol Chem 2007;282(37):27155-27164.
28. Hartmann P, Szabó A, Eros G, Gurabi D, Horváth G et al. Anti-Inflammatory Effects of Phosphatidylcholine in Neutrophil Leukocyte-Dependent Acute Arthritis in Rats.Eur J Pharmacol 2009; Vol 622 (1-3):58-64
29. Wang H, Yu M, Ochani M, Amella CA, Tanovic M et al. Nicotinic Acetylcholine Receptor alpha7 Subunit Is an Essential Regulator of Inflammation Nature 2003;Vol 421 (6921):384-8
30. Zhao YX, He W, Jing XH,Liu JL, Rong PJ et al. Transcutaneous auricular vagus nerve stimulation protects endotoxemic rat from lipopolysaccharide-induced inflammation Evid Based Complement Alternat Med 2012;627023.
31. Bernik TR, Friedman SG, Ochani M,DiRamiro R, Ulloa L et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway J Exp Med 2002;195(6):781-788.
32. Huston J, Ochani M, Rosas-Ballina M,Liao H, Ochani K et al. Splenectomy Inactivates the Cholinergic Antiinflammatory Pathway during Lethal Endotoxemia and Polymicrobial Sepsis.2006; Vol 25.
33. Ulus IH, Cansev M. Kolin’in Merkezi ve Periferik Kolinerjik Nöronlarda ve Kolinerjik İletimdeki İşlevi Acıbadem Üniversitesi Sağlık Bilim Derg 2010;1(7).
34. B. Weiss G. Metabolism and Actions of CDP-Choline as an Endogenous Compound and Administered Exogenously as Citicoline Life Sci. 1995;56(9):637-60.
35. Köppen A, Klein J, Holler T, Löffelholz K. Synergistic effect of nicotinamide and choline administration on extracellular choline levels in the brain J Pharmacol Exp Ther 1993;266(2):720.
36. Ilcol Y, Cansev M, Yilmaz S, Hamurtekin E, H Ulus I. Intraperitoneal Administration of CDP-Choline and Its Cholinergic and Pyrimidinergic Metabolites Induce Hyperglycemia in Rats: Involvement of the Sympathoadrenal System Arch Physiol Biochem 2007;Vol 113(4-5):186-201
37. Savci V, Goktalay G, Cansev M, Cavun S, Yilmaz S et al. Intravenously Injected CDP-Choline Increases Blood Pressure and Reverses Hypotension in Haemorrhagic Shock: Effect Is Mediated by Central Cholinergic Activation Eur J Pharmacol 2003;Vol 468(2):129-39.
38. Cermak J, Holler T, Jackson D, Krzysztof Blusztajn J. Prenatal Availability of Choline Modifies Development of Hippocampal Cholinergic System FASEB J. 1998; Vol 12(3) 349-57.
39. H. Ulus I, J. Hirsch M, Wurtman J. TransSynaptic Induction of Adrenomedullary Tyrosine Hydroxylase Activity by Choline: Evidence That Choline Administration Can Increase Cholinergic Transmission Proc Natl Acad Sci U S A. 1977;74(2):798-800. 40. H Ulus I, C Scally M, Wurtman J. Enhancement by Choline of the Induction of Adrenal Tyrosine Hydroxylase by Phenoxybenzamine, 6-Hydroxydopamine, Insulin or Exposure to Cold J Pharmacol Exp Ther. 1978;204(3):676-82.
41. Savci V, Cavun S, Goktalay G, Ulus IH. Cardiovascular effects of intracerebroventricularly injected CDP-choline in normotensive and hypotensive animals: the involvement of cholinergic system Naunyn Schmiedebergs Arch Pharmacol 2002;365(5):388-398.
42. McDaniel MA, Maier SF, Einstein GO. “Brain-specific” nutrients: a memory cure? Nutrition 2003;19(11):957-975.
43. V. Dorman R, Dabrowiecki Z, A. Horrocks L. Effects of CDPcholine and CDPethanolamine on the Alterations in Rat Brain Lipid Metabolism Induced by Global Ischemia J Neurochem 1983;40(1):276-9.
44. Dıxon Ce, Ma X, Marıon Dw. Effects of CDP-Choline Treatment on Neurobehavioral Deficits after TBI and on Hippocampal and Neocortical Acetlycholine Release J Neurotrauma 1997;14(3):161-169.
45. K. Başkaya M, Dogan A, Adibhatla R, J. Dempsey R. Neuroprotective Effects of Citicoline on Brain Edema and Blood-Brain Barrier Breakdown after Traumatic Brain Injury J Neurosurg. 2000 Mar;92(3):448-52.
46. Adibhatla R, Hatcher J, J Dempsey R. Lipid Alterations in Transient Forebrain Ischemia: Possible New Mechanisms of CDP-Choline Neuroprotection J Neurochem. 2000 Dec;75(6):2528-35.
47. Qian K, Gu Y, Zhao Y, Li Z, Sun M. Citicoline Protects Brain Against Closed Head Injury in Rats Through Suppressing Oxidative Stress and Calpain Over-Activation Neurochem Res. 2014 Jul;39(7):1206-18.
48. Hamurtekin E, Gurun M. The Antinociceptive Effects of Centrally Administered CDP-Choline on Acute Brain Res. 2006 Oct 30;1117(1):92-100.
49. Gurun M, Parker R, C Eisenach J, Vincler M. The Effect of Peripherally Administered CDP-Choline in an Acute Inflammatory Pain Model: The Role of α7 Nicotinic Acetylcholine Receptor Anesth Analg. 2009 May;108(5):1680-7.
50. Yilmaz Z, Ilcol Y, Cansev M, Eralp Inan O, Kocatürk M, H Ulus I. Choline or CDP-Choline Attenuates Coagulation Abnormalities and Prevents the Development of Acute Disseminated Intravascular Coagulation in Dogs during Endotoxemia Blood Coagul Fibrinolysis. 2010 Jun;21(4):339-48.
51. Papke R, Bencherif M, Lippiello P. An Evaluation of Neuronal Nicotinic Acetylcholine Receptor Activation by Quaternary Nitrogen Compounds Indicates That Choline Is Selective for the α7 Subtype Neurosci Lett. 1996 Aug 9;213(3):201-4.
52. Ilcol YO, Yilmaz Z, Ulus IH. Endotoxin alters serum-free choline and phospholipid-bound choline concentrations, and choline administration attenuates endotoxin-induced organ injury in dogs Shock 2005;24(3):288-293.
53. Eastin CE, McClain CJ, Lee EY, Bagby GJ, Chawla RK. Choline deficiency augments and antibody to tumor necrosis factor-α attenuates endotoxin-induced hepatic injury Alcohol Clin Exp Res 1997;21(6):1037-1041.
54. Pavlov VA, Ochani M, Yang LH, et al. Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis Crit Care Med 2007;35(4):1139-1144.
55. Yeboah MM, Xue X, Javdan M, Susin M, Metz CN. Nicotinic acetylcholine receptor expression and regulation in the rat kidney after ischemia-reperfusion injury Am J Physiol Renal Physiol 2008;295(3):F654-F661.
56. van Westerloo DJ, Giebelen IA, Florquin S, et al. The Vagus Nerve and Nicotinic Receptors Modulate Experimental Pancreatitis Severity in Mice Gastroenterology 2006;130(6):1822-1830.
57. Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, et al. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling Mol Med 2008;14(9-10):567-574.
58. Ilcol YO, Yilmaz Z, Cansev M, Ulus IH. Choline or CDP-choline alters serum lipid responses to endotoxin in dogs and rats: Involvement of the peripheral nicotinic acetylcholine receptors Shock 2009;32(3):286-294.
59. Pan Z-Y, Wang H. Synergistic Interaction between Choline and Aspirin against Acute Inflammation Induced by Carrageenan and Lipopolysaccharide Int Immunopharmacol. 2014 May;20(1):229-37.
60. Li XD, Buccafusco JJ. Role of α7 Nicotinic Acetylcholine Receptors in the Pressor Response to Intracerebroventricular Injection of Choline: Blockade by Amyloid Peptide Aβ1-42 J Pharmacol Exp Ther. 2004;309(3):1206 LP-1212.
61. Yilmaz Z, Eralp Inan O, Kocaturk M, et al. Changes in serum proteins after endotoxin administration in healthy and choline-treated calves BMC Vet Res. 2016;12:210.
62. Yilmaz S, Coskun C, Yalcin M, Savci V. CDP-Choline Prevents Cardiac Arrhythmias and Lethality Induced by Short-Term Myocardial Ischemia-Reperfusion Injury in the Rat: Involvement of Central Muscarinic Cholinergic Mechanisms Naunyn Schmiedebergs Arch Pharmacol. 2008 Sep;378(3):293-301.
63. Coskun C, Avci B, Yalcin M, Yermezler A, Yilmaz S, Savci V. Protective Effect of CDP-Choline on Ischemia-Reperfusion-Induced Myocardial Tissue Injury in Rats Ir J Med Sci. 2014 Dec;183(4):539-48.
64. Schmidt K, Frederick Hernekamp J, Doerr M, Zivkovic AR, Brenner T et al. Cytidine-5-Diphosphocholine Reduces Microvascular Permeability during Experimental Endotoxemia BMC Anesthesiol. 2015;15:114.
65. Sevim Ç, Altinbas B, Yalcin M, İnan S, Özyiğit MÖ et al. Protective Effect of CDP-Choline on Hypotension and Tissue Injury in Septic Shock Model Ankara Üniv Vet Fak Derg 2017; 64, 103-110
66. Pereira MR, Leite PEC. The Involvement of Parasympathetic and Sympathetic Nerve in the Inflammatory Reflex J Cell Physiol. 2016;231(9):1862-1869.
67. Singh PM, Reid K, Gaddam R, Bhatia M, Smith S et al. Effect of choline chloride premedication on xylazine-induced hypoxaemia in sheep. Vet Anaesth Analg. 2017;44(5):1149-1155.
68. Thomsen MS, Mikkelsen JD. The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia J Neuroimmunol. 2012;251(1):65-72.
69. Wang H, Yu M, Ochani M, Amella CA, Tanovic M et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature. 2002;421:384.
70. Skok M, Grailhe R, Agenes F, Changeux J-P. The Role of Nicotinic Receptors in B-Lymphocyte Development and Activation Life Sci. 2007 May 30;80(24-25):2334-6.
71. De Rosa M, Esandi M, Garelli A, Rayes D, Bouzat C. Relationship between α7 nAChR and Apoptosis in Human Lymphocytes J Neuroimmunol. 2005 Mar;160(1-2):154-61.
72. Aicher A, Heeschen C, Mohaupt M, Cooke J, M Zeiher A et al. Nicotine Strongly Activates Dendritic Cell-Mediated Adaptive Immunity: Potential Role for Progression of Atherosclerotic Lesions Circulation. 2003 Feb 4;107(4):604-11.
73. Guinet E, Yoshida K, Nouri-Shirazi M. Nicotinic environment affects the differentiation and functional maturation of monocytes derived dendritic cells (DCs) Immunol Lett. 2004;95(1):45-55. 74. Venkatesan T, Choi Y-W, Lee J, Kim Y-K. Falcarindiol inhibits LPS-induced inflammation via attenuating MAPK and JAK-STAT signaling pathways in murine macrophage RAW 264.7 cells Mol Cell Biochem. 2018;445(1-2):169-178.
75. De Simone R, Ajmone-Cat M, Carnevale D, Minghetti L. Activation of alpha7 Nicotinic Acetylcholine Receptor by Nicotine Selectively up-Regulates Cyclooxygenase-2 and Prostaglandin E2 in Rat Microglial Cultures J Neuroinflammation. 2005 Jan 25;2(1):4.
76. Sopori ML, Kozak W, Savage SM, Geng Y, Soszynski D et al. Effect of nicotine on the immune system: Possible regulation of immune responses by central and peripheral mechanisms. Psychoneuroendocrinology. 1998;23(2):189-204.
77. Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function Physiol Rev. 2009;89(1):73-120.
78. Shen J, Yakel JL. Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system. Acta Pharmacol Sin. 2009;30(6):673-680.
79. Bagdas D, Wilkerson JL, Kulkarni A, Toma W, AlSharari S et al. The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain. Br J Pharmacol. 2016:2506-2520.
80. Resende RR, Adhikari A. Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation Cell Commun Signal 2009;7(1):20.
81. Báez-Pagán CA, Delgado-Vélez M, Lasalde-Dominicci JA. Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation J Neuroimmune Pharmacol. 2015;10(3):468-476.
82. Horenstein NA, Papke RL. Anti-inflammatory Silent Agonists ACS Med Chem Lett. 2017;8(10):989-991.
83. Skok M. Editorial: To Channel or Not to Channel? Functioning of Nicotinic Acetylcholine Receptors in Leukocytes J Leukoc Biol. 2009 Jul;86(1):1-3.
84. Villiger Y, Szanto I, Jaconi S, Blanchet C, Buisson B, et al. Expression of an α7 Duplicate Nicotinic Acetylcholine Receptor-Related Protein in Human Leukocytes J Neuroimmunol. 2002 May;126(1-2):86-98.
85. Panchal JL. Dual Signaling Modes of Alpha7 Nicotinic Acetylcholine Receptors ( α7 nAChRs ) Annals of Experimental and Molecular Biology 2018:7-8.
86. Kabbani N, Nichols RA. Beyond the Channel: Metabotropic Signaling by Nicotinic Receptors Trends Pharmacol Sci. 2018;39(4):354-366.
87. Kwon DH, Cha HJ, Choi EO, Leem SH, Kim GY et al. Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-κB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling. Int J Mol Med. 2018;41(1):264-274.
88. Li X, Su J, Cui X, Li Y, Barochia A et al. Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate Expert Opin Investig Drugs. 2009;18(8):1047-1060.
89. B Marrero M, Bencherif M. Convergence of Alpha 7 Nicotinic Acetylcholine Receptor-Activated Pathways for Anti-Apoptosis and Anti-Inflammation: Central Role for JAK2 Activation of STAT3 and NF-κB. Brain Res. 2009 Feb 23;1256:1-7.
90. Zhang C, Granville CA, Sayyah J, Granville CA, Zhang C et al. Tobacco components stimulate Akt-dependent proliferation and NFκB-dependent survival in lung cancer cells Carcinogenesis 2005;26(7):1182-1195.
91. Wang H, Liao H, Ochani M, Justiniani M, Lin X et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis Nat Med. 2004;10:1216.
92. Chatterjee PK, Al-Abed Y, Sherry B, Metz CN. Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation Am J Physiol Physiol. 2009;297(5):C1294-C1306.
93. M Williams L, Ricchetti G, Sarma U, Smallie T, M J Foxwell B. Interleukin-10 Suppression of Myeloid Cell Activation - A Continuing Puzzle Immunology. 2004 Nov;113(3):281-92.
94. Levy DE, Lee C. What does Stat3 do? J Clin Invest. 2002;109(9):1143-1148.
95. Peña G, Cai B, Deitch EA, Ulloa L. JAK2 inhibition prevents innate immune responses and rescues animals from sepsis J Mol Med (Berl). 2010;88(8):851-859.
96. Lee S Bin, Lee WS, Shin JS, Jang DS, Lee KT. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages Int Immunopharmacol. 2017;49(May):21-29.
97. Engblom D, Saha S, Engström L, Westman M, Audoly LP et al. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis Nat Neurosci. 2003;6:1137.
98. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: Multiple roles in inflammation and immune modulation Pharmacol Ther. 2004;103(2):147-166.
99. Mardini I, Fitzgerald G. Selective Inhibitors of Cyclooxygenase-2: A Growing Class of Anti-Inflammatory Drugs Mol Interv. 2001 Apr;1(1):30-8.
100. Noda M, Kariura Y, Pannasch U, Nishikawa K, Wang L et al. Neuroprotective Role of Bradykinin because of the Attenuation of pro-Inflammatory Cytokine Release from Activated Microglia J Neurochem. 2007 Apr;101(2):397-410.
101. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation Arterioscler Thromb Vasc Biol. 2011;31(5):986-1000.
102. Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA. Prostanoids in health and disease J Lipid Res. 2009;50 Suppl(Suppl):S423-S428.
103. Langenbach R, Loftin C, Lee C, Tiano H. Cyclooxygenase knockout mice: Models for elucidating isoform-specific functions Biochem Pharmacol. 1999;58(8):1237-1246.
104. Choi JS, Nurul Islam M, Yousof Ali M, Kim EJ, Kim YM et al. Effects of C-glycosylation on anti-diabetic, anti-Alzheimer’s disease and anti-inflammatory potential of apigenin Food Chem Toxicol. 2014;64:27-33.
105. Tajima T, Murata T, Aritake K, Urade Y, Michishita M et al. EP2 and EP4 receptors on muscularis resident macrophages mediate LPS-induced intestinal dysmotility via iNOS upregulation through cAMP/ERK signals AJP Gastrointest Liver Physiol. 2012;302(5):G524-G534.
106. Arrigoni E, Avéret N, Cohadon F. Effects of CDP-Choline on Phospholipase A2 and Cholinephosphotransferase Activities Following a Cryogenic Brain Injury in the Rabbit. Biochem Pharmacol. 1987 Nov 1;36(21):3697-700.
107. Ezoulin MJM, Liu Z, Dutertre-Catella H, Wu G, Dong CZ et al. A New Acetylcholinesterase Inhibitor with Anti-PAF Activity Modulates Oxidative Stress and pro-Inflammatory Mediators Release in Stimulated RAW 264.7 Macrophage Cells. Comparison with Tacrine. Int Immunopharmacol. 2007 Dec 15;7(13):1685-94.
108. Zhang J, Rivest S. Anti-Inflammatory Effects of Prostaglandin E2 in the Central Nervous System in Response to Brain Injury and Circulating Lipopolysaccharide J Neurochem. 2001 Feb;76(3):855-64.