Immunomodulatory and neuroprotective effects of inosine.

Abstract Adenosine has been considered as a potential immunomodulatory and neuroprotective agent for 30 years. Inosine, a major degradation product of adenosine, was thought originally to have no biological effects. However, recent studies demonstrate that inosine has potent immunomodulatory and neuroprotective effects. Inosine enhances mast-cell degranulation, attenuates the production of pro-inflammatory mediators by macrophages, lymphocytes and neutrophils, and is protective in animal models of sepsis, ischemia–reperfusion and autoimmunity. Inosine preserves the viability of glial cells and neuronal cells during hypoxia, and stimulates axonal regrowth after injury. The biological actions of inosine might involve effects on adenosine receptors, poly(ADP-ribose) polymerase and cellular energy levels. In this article, we review recent observations indicating that it might be possible to exploit inosine therapeutically for the treatment of tissue damage caused by inflammation and ischemia.

[1]  B. Fredholm,et al.  Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors , 2002, Neuroscience.

[2]  A. Ohta,et al.  Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage , 2001, Nature.

[3]  A. Hamberger,et al.  Blockade of N-methyl-d-aspartate-sensitive acidic amino acid receptors inhibits ischemia-induced accumulation of purine catabolites in the rat striatum , 1986, Neuroscience Letters.

[4]  R. Kloner,et al.  Alterations in the distribution of high-energy phosphates during ischemia in a canine model of reperfusion-induced ventricular fibrillation. , 1985, American heart journal.

[5]  E. Deitch.  ANIMAL MODELS OF SEPSIS AND SHOCK: A REVIEW AND LESSONS LEARNED , 1998, Shock.

[6]  B. Cronstein,et al.  Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. , 2003, Arthritis and rheumatism.

[7]  J. Wang,et al.  Inosine attenuates tourniquet-induced skeletal muscle reperfusion injury. , 2001, The Journal of surgical research.

[8]  K. Herbaczyńska-Cedro,et al.  The influence of inosine on the size of myocardial ischaemia and myocardial metabolism in the pig. , 1982, Clinical physiology.

[9]  B. Fredholm,et al.  International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. , 2001, Pharmacological reviews.

[10]  H. Tian,et al.  The potential etiologic role of tumor necrosis factor in mediating multiple organ dysfunction in rats following intestinal ischemia-reperfusion injury. , 1995, Resuscitation.

[11]  M. Sitkovsky.  Use of the A(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo. , 2003, Biochemical pharmacology.

[12]  T. Stone.  Purines and neuroprotection. , 2002, Advances in experimental medicine and biology.

[13]  M. Aldrich,et al.  The importance of adenosine deaminase for lymphocyte development and function. , 2000, Biochemical and biophysical research communications.

[14]  T. Shanley,et al.  Suppression of macrophage inflammatory protein (MIP)‐1α production and collagen‐induced arthritis by adenosine receptor agonists , 1998, British journal of pharmacology.

[15]  M. Sitkovsky,et al.  Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo. , 2003, Blood.

[16]  P. J. Richardson,et al.  Role of Histidine Residues in the Adenosine A2a Receptor Ligand Binding Site , 1994, Journal of neurochemistry.

[17]  Beverly H. Koller,et al.  Disruption of the A3 Adenosine Receptor Gene in Mice and Its Effect on Stimulated Inflammatory Cells* , 2000, The Journal of Biological Chemistry.

[18]  D. Winter,et al.  Inosine modulates gut barrier dysfunction and end organ damage in a model of ischemia-reperfusion injury. , 2002, The Journal of surgical research.

[19]  D. Behrendt,et al.  Nucleotide Degradation and Functional Impairment During Cardioplegia: Amelioration by Inosine , 1983, Circulation.

[20]  H. Koprowski,et al.  Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Remick,et al.  Requirements for tumor necrosis factor-alpha and interleukin-1 in limb ischemia/reperfusion injury and associated lung injury. , 1993, The American journal of pathology.

[22]  R. Ulevitch.  New therapeutic targets revealed through investigations of innate immunity , 2001, Critical care medicine.

[23]  S. Holgate,et al.  The effect of methyltransferase inhibitors on histamine release from human dispersed lung mast cells activated with anti-human IgE and calcium ionophore A23187. , 1984, Biochemical pharmacology.

[24]  M. Verdys,et al.  Adenine nucleotide synthesis from inosine during normoxia and after ischaemia in the isolated perfused rat heart. , 1985, Canadian Journal of Physiology and Pharmacology.

[25]  C. Szabó,et al.  The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors , 2002, Pharmacological Reviews.

[26]  H. Koprowski,et al.  Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease , 2001, Multiple sclerosis.

[27]  K. Murthy,et al.  Anti-inflammatory effects of inosine in human monocytes, neutrophils and epithelial cells in vitro. , 2001, International journal of molecular medicine.

[28]  B. Fredholm,et al.  Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. , 2001, Biochemical pharmacology.

[29]  C. Szabó,et al.  The adenosine A3 receptor agonist, N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide, is protective in two murine models of colitis. , 2003, European journal of pharmacology.

[30]  U. Ungerstedt,et al.  Interstitial lactate, inosine and hypoxanthine in rat kidney during normothermic ischaemia and recirculation. , 1991, Acta physiologica Scandinavica.

[31]  A. Deussen.  Metabolic flux rates of adenosine in the heart , 2000, Naunyn-Schmiedeberg's Archives of Pharmacology.

[32]  D. Aviado,et al.  Inosine as a cardiotonic agent that reverses adrenergic beta blockade. , 1977, The Journal of pharmacology and experimental therapeutics.

[33]  E. Vizi,et al.  Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. , 1996, Journal of immunology.

[34]  R. K. Shepherd,et al.  Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. , 1997, The Journal of clinical investigation.

[35]  J. Madsen,et al.  Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[36]  W. Remme,et al.  Myocardial nucleoside and carbohydrate metabolism and hemodynamics during partial occlusion and reperfusion of pig coronary artery. , 1977, Journal of molecular and cellular cardiology.

[37]  Å. Lernmark,et al.  Animal models of endocrine/organ-specific autoimmune diseases: do they really help us to understand human autoimmunity? , 2002, Springer Seminars in Immunopathology.

[38]  O. Bagasra,et al.  Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[39]  E. Vizi,et al.  Adenosine: a potential mediator of immunosuppression in multiple organ failure. , 2002, Current opinion in pharmacology.

[40]  G Burnstock,et al.  Receptors for purines and pyrimidines. , 1998, Pharmacological reviews.

[41]  R. K. Shepherd,et al.  Adenosine-induced vasoconstriction in vivo. Role of the mast cell and A3 adenosine receptor. , 1996, Circulation research.

[42]  C. Szabó,et al.  Inosine improves gut permeability and vascular reactivity in endotoxic shock , 2001, Critical care medicine.

[43]  L. Horrocks,et al.  Inosine Mediates the Protective Effect of Adenosine in Rat Astrocyte Cultures Subjected to Combined Glucose‐Oxygen Deprivation , 1996, Journal of neurochemistry.

[44]  M. H. Williams,et al.  Effect of inosine supplementation on 3-mile treadmill run performance and VO2 peak. , 1990, Medicine and science in sports and exercise.

[45]  P. Routledge,et al.  Intravenous infusion of adenosine but not inosine stimulates respiration in man. , 1987, British journal of clinical pharmacology.

[46]  M. Jacobson,et al.  Adenosine and inosine increase cutaneous vasopermeability by activating A(3) receptors on mast cells. , 2000, The Journal of clinical investigation.

[47]  J. H. Lucas,et al.  Inosine and guanosine preserve neuronal and glial cell viability in mouse spinal cord cultures during chemical hypoxia , 1999, Brain Research.

[48]  J. Linden,et al.  A3 adenosine receptor activation triggers phosphorylation of protein kinase B and protects rat basophilic leukemia 2H3 mast cells from apoptosis. , 2001, Molecular pharmacology.

[49]  B. Kolb,et al.  Inosine induces axonal rewiring and improves behavioral outcome after stroke , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[50]  G E Reed,et al.  Release of nucleosides from canine and human hearts as an index of prior ischemia. , 1979, The American journal of cardiology.

[51]  L. Benowitz,et al.  Axon Outgrowth Is Regulated by an Intracellular Purine-sensitive Mechanism in Retinal Ganglion Cells* , 1998, The Journal of Biological Chemistry.

[52]  C. Szabó,et al.  Inosine Exerts a Broad Range of Antiinflammatory Effects in a Murine Model of Acute Lung Injury , 2002, Annals of surgery.

[53]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[54]  L. Benowitz,et al.  A Purine-Sensitive Pathway Regulates Multiple Genes Involved in Axon Regeneration in Goldfish Retinal Ganglion Cells , 2000, The Journal of Neuroscience.

[55]  C. Szabó,et al.  Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture. , 2001, American journal of respiratory and critical care medicine.

[56]  C. Szabó,et al.  Inosine Inhibits Inflammatory Cytokine Production by a Posttranscriptional Mechanism and Protects Against Endotoxin-Induced Shock1 , 2000, The Journal of Immunology.

[57]  E. Deitch,et al.  Adenosine inhibits IL-12 and TNF-a production via adenosine A 2 a receptor-dependent and independent mechanisms , 2000 .

[58]  J. Garcia-Manteiga,et al.  Complex regulation of nucleoside transporter expression in epithelial and immune system cells , 2001, Molecular membrane biology.

[59]  C. Szabó,et al.  Inosine Protects Against the Development of Diabetes in Multiple-Low-Dose Streptozotocin and Nonobese Diabetic Mouse Models of Type 1 Diabetes , 2003, Molecular medicine.

[60]  H. Koprowski,et al.  Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[61]  L. Mcnaughton,et al.  Inosine supplementation has no effect on aerobic or anaerobic cycling performance. , 1999, International journal of sport nutrition.

[62]  C. Szabó,et al.  Purines inhibit poly(ADP‐ribose) polymerase activation and modulate oxidant‐induced cell death , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[63]  J G Mabley,et al.  Inosine reduces inflammation and improves survival in a murine model of colitis. , 2003, American journal of physiology. Gastrointestinal and liver physiology.

[64]  R. K. Shepherd,et al.  Activation of Adenosine A2a Receptors Inhibits Mast Cell Degranulation and Mast Cell‐Dependent Vasoconstriction , 2000, Microcirculation.

[65]  C. Hohl,et al.  Adenosine, Inosine, and Guanosine Protect Glial Cells During Glucose Deprivation and Mitochondrial Inhibition: Correlation Between Protection and ATP Preservation , 1998, Journal of neurochemistry.