Inosine Inhibits Inflammatory Cytokine Production By A PostTranscriptional Mechanism And Protects Against Endotoxin-Induced Shock
Hasko G, Kuhel DG, Nemeth ZH, Mabley JG, Stachlewitz RF, Virag L, Lohinai Z, Southan GJ, Salzman AL, Szabo C
J Immunol 2000 Jan 15;164(2):1013-9
Inotek Corp., Beverly, MA 01915, USA
PMID# 10623851; UI# 20090895
ExtraCellular Purines, including Adenosine and ATP, are potent endogenous ImmunoModulatory Molecules. Inosine, a degradation product of these Purines, can reach high concentrations in the ExtraCellular space under conditions associated with cellular metabolic stress such as Inflammation or Ischemia.
In the present study, we investigated whether ExtraCellular Inosine can affect Inflammatory/Immune processes.
In ImmunoStimulated Macrophages and Spleen Cells, Inosine potently inhibited the production of the ProInflammatory Cytokines TNF-, IL-1, IL-12, Macrophage-Inflammatory Protein-1, and IFN-γ, but failed to alter the production of the AntiInflammatory Cytokine IL-10.
The effect of Inosine did not require cellular uptake by Nucleoside Transporters and was partially reversed by blockade of Adenosine A1 and A2 receptors. Inosine inhibited Cytokine production by a PostTranscriptional mechanism.
The activity of Inosine was independent of activation of the p38 and p42/p44 Mitogen-activated protein kinases, the Phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of IntraCellular cAMP.
Inosine suppressed ProInflammatory Cytokine production and mortality in a mouse EndoToxemic model. Taken together, Inosine has multiple AntiInflammatory Effects.
These findings, coupled with the fact that Inosine has very low toxicity, suggest that this agent may be useful in the treatment of Inflammatory/Ischemic Diseases.
Therapeutic Intervention In EAE By Administration Of Uric Acid Precursors
Scott GS, Spitsin SV, Kean RB, Mikheeva T, Koprowski H, Hooper DC
Proc Natl Acad Sci USA 2002 Nov 25
Thomas Jefferson University, Department of Microbiology and Immunology, Philadelphia, PA 19107
Uric Acid (UA) is a purine metabolite that selectively inhibits PerOxynitrite-mediated reactions implicated in the pathogenesis of Multiple Sclerosis (MS) and other NeuroDegenerative Diseases.
Serum UA levels are inversely associated with the incidence of MS in humans because MS patients have low Serum UA levels and individuals with HyperUricemia (Gout) rarely develop the disease.
Moreover, the administration of UA is therapeutic in Experimental Allergic Encephalomyelitis (EAE), an animal model of MS. Thus, raising Serum UA levels in MS patients, by oral administration of a UA precursor such as Inosine, may have therapeutic value.
We have assessed the effects of Inosine, as well as Inosinic Acid, on parameters relevant to the chemical reactivity of PerOxynitrite and the pathogenesis of EAE.
Both had no effect on chemical reactions associated with PerOxynitrite, such as Tyrosine nitration, or on the activation of inflammatory cells in vitro.
Moreover, when mice treated with the Urate Oxidase Inhibitor Potassium Oxonate were fed Inosine or Inosinic Acid, Serum UA levels were elevated markedly for a period of hours, whereas only a minor, transient increase in Serum Inosine was detected.
Administration of Inosinic Acid suppressed the appearance of clinical signs of EAE and promoted recovery from ongoing disease.
The therapeutic effect on animals with active EAE was associated with increased UA, but not Inosine, levels in CNS tissue. We, therefore, conclude that the mode of action of Inosine and Inosinic Acid in EAE is via their metabolism to UA.
Serum Uric Acid levels In Multiple Sclerosis Correlate With Activity Of Disease And Blood-Brain Barrier Dysfunction
Toncev G, Milicic B, Toncev S, Samardzic G
Eur J Neurol 2002 May;9(3):221-6
Clinical Hospital Center Kragujevac, Center of Neurology, Svetozara Markovica, Yugoslavia
Several findings suggest lower levels of Serum Uric Acid in Multiple Sclerosis (MS) patients. The aim of this study is to investigate relationships of Uric Acid Serum levels in Relapse/Remitting (RR) MS patients with clinical activity of disease and Blood-Brain Barrier (BBB) condition.
Sixty-three definite RRMS patients and 40 controls divided into two groups: 20 healthy donors and 20 patients with Other Inflammatory Neurological Diseases (OINDs) were analyzed.
By using a quantitative enzymatic assay according to the manufacture's protocol and a commercial Uric Acid standard solution.
Serum Uric Acid levels were measured and the results were standardized. To investigate BBB function, Magnetic Resonance Imaging after administration of Gadolinium was used.
MS patients were found to have significantly lower Serum Uric Acid levels (193.89 +/- 49.05 micromol/l; mean value +/-SD) in comparison with healthy donors (292.7 +/- 58.65 micromol/l; P=0.000) and OIND patients (242.7 +/- 46.66 micromol/l; P=0.001).
We found that MS patients with relapse had significantly lower Serum Uric Acid levels (161.49 +/- 23.61 micromol/l) than MS patients with remission (234.39 +/- 41.96 micromol/l; P=0.000).
And more over, MS patients with BBB disruption had significantly lower Serum Uric Acid levels (163.95 +/- 26.07 micromol/l) than those with normal BBB (252.48 +/- 25.94 micromol/l; P=0.000).
Further, we also found that Serum Uric Acid level independently correlated with disease activity, BBB disruption, and gender.
These results indicate that lower Uric Acid Levels in MS patients are associated with relapse and suggest that uric acid might be beneficial in the treatment of MS.
Serum Uric Acid And Multiple Sclerosis
Sotgiu S, Pugliatti M, Sanna A, Sotgiu A, Fois ML, Arru G, Rosati G
Neurol Sci 2002 Oct;23(4):183-8
University of Sassari, Institute of Clinical Neurology, Faculty of Medicine, Viale San Pietro 10, I-07100 Sassari, Italy
Several studies indicate that patients with Multiple Sclerosis (MS) have low Serum levels of the endogenous AntiOxidant Uric Acid (UA), although it has not been established whether UA is primarily deficient or secondarily reduced due to its Peroxynitrite scavenging activity.
We measured Serum Urate levels in 124 MS patients and 124 age- and sex-matched controls with Other Neurological Diseases.
In addition, we compared UA levels when MS patients were stratified according to disease activity (by means of clinical examination and MRI), duration, disability and course.
MS patients had significantly lower Serum Uric levels than controls ( p= 0.001). However, UA levels did not significantly correlate with disease activity, duration, disability or course.
Our study favors the view that reduced UA in MS is a primary, constitutive loss of protection against Oxidative agents, which deserves further pathogenetic elucidation aimed at future therapeutic strategies.
Changes In Serum And Urinary Uric Acid Levels In Normal Human Subjects Fed Purine-Rich Foods Containing Different Amounts Of Adenine And Hypoxanthine
Brule D, Sarwar G, Savoie L
J Am Coll Nutr 1992;11(3):353-8
Bureau of Nutritional Sciences, Food Directorate, Health Protection Branch, Banting Research Centre, Ottawa, Ontario, Canada
The effect of ingesting some Purine-rich foods (Beef Liver, Haddock Fillets and Soybeans) on Uric Acid metabolism was investigated in 18 male subjects with no history of Gout or Kidney Disorder.
In a crossover design, three IsoEnergetic and IsoNitrogenous meals were fed to volunteers during a 3-week period. Only the content of Uricogenic bases (Adenine and HypoXanthine) varied among the test meals.
Ingestion of all experimental meals caused an increase in Serum Uric Acid levels at 120 minutes and this increase was more marked (about twofold) with Haddock and Soybean ingestion.
In all groups, the postprandial Serum Uric Acid levels at 240 minutes were lower than those obtained at 120 minutes, but still remained elevated in comparison to the fasting level.
The test foods had little or no effect on Serum and Urinary Creatinine values. As expected, 24-hour Urinary Uric Acid excretion was similar for the three test meals due to the IsoNitrogenous load of Proteins and Purines.
Assessment of each Purine base content rather than the total Purine content of foods should be considered in future recommendations for HyperUricemic individuals.
Copyright © 1992 by American College of Nutrition. Reprinted by permission.
Knapp CM, Constantinescu CS, Tan JH, McLean R, Cherryman GR, Gottlob I
Mult Scler 2004 Jun;10(3):278-80
University of Leicester, Faculty of Medicine and Biological Sciences, Robert Kilpatrick Clinical Sciences Building, Department of Ophthalmology, The Leicester Royal Infirmary, Leicester LE2 7LX, UK
Uric Acid, an AntiOxidant, is reduced in Multiple Sclerosis (MS). Patients with Gout have a reduced incidence of MS. Optic Neuritis (ON), often the first manifestation of MS, is not known to be associated with reduced Uric Acid.
Patients with recent onset of ON were investigated to determine whether Uric Acid levels were reduced at presentation. Twenty-one patients with ON were included, 17 females and 4 males.
The mean (SD) Serum Uric Acid in the ON female group was 184.4 ( +/-55.1) micromol/L (range, 116-309 micromol/L), whilst in the control group it was 235.2 (+/- 50.2) micromol/L (range, 172-381 micromol/L).
The difference was statistically significant (chi2 = 8.93, P = 0.003). In the small male cohort, mean (SD) Serum Uric Acid was 305 (+/- 52.1) micromol/L, whilst in the control group it was 328 (+/- 80.4) micromol/L.
These differences were not statistically significant. Reduced AntiOxidant reserve is possibly an early pathogenic mechanism in Inflammatory DeMyelination, and raises the possibility that low Uric Acid levels could be an indicator of disease activity.
Since Optic Neuropathies of other causes were not investigated, future research needs to determine whether low Uric Acid represents a unique feature of Optic Neuritis or is seen in other Optic Neuropathies.
Serum Uric Acid Levels And Leukocyte Nitric Oxide Production In Multiple Sclerosis Patients Outside Relapses
Mostert JP, Ramsaransing GS, Heersema DJ, Heerings M, Wilczak N, De Keyser J
J Neurol Sci 2005 Apr 15;231(1-2):41-4
Academisch Ziekenhuis Groningen, Department of Neurology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
A number of studies found that patients with Multiple Sclerosis (MS) have low Serum levels of Uric Acid. It is unclear whether this represents a primary deficit or secondary effect.
Uric Acid is a scavenger of Peroxynitrite, which is the product of Nitric Oxide (NO) and superoxide.
Because peripheral blood Leukocyte NO production and NO metabolites in serum are raised in MS patients, associations might be expected between Serum Uric Acid levels and peripheral NO production.
Serum levels of Uric Acid and NO production by peripheral blood Leukocytes were measured in 60 patients with MS without a relapse in the past 3 months, and 30 age- and sex-matched healthy controls.
Uric Acid was determined with the uricase PAP method, and NO production was assayed by measuring Nitrite concentration in supernatants of lysed Leukocytes.
Serum Uric Acid levels were not different between MS patients and controls. Compared to controls, patients with MS had significantly higher peripheral blood Leukocytes nitrite concentrations (p < 0.001).
There was no correlation between Leukocyte Nitrite concentration and Serum Uric Acid levels.
Our findings suggest that in MS patients there is no primary deficit in Serum Uric Acid. NO production by peripheral blood Leukocytes is increased, but there is no association with Serum Uric Acid levels.
The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion Into The Central Nervous System In Experimental Allergic Encephalomyelitis Through Maintenance Of Blood-Central Nervous System Barrier Integrity
J Immunol 2000 Dec 1;165(11):6511-8
The Peroxynitrite scavenger Uric Acid prevents inflammatory cell invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through maintenance of Blood-Central Nervous System Barrier integrity
Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC
Thomas Jefferson University, Department of MicroBiology and Immunology, Philadelphia, PA 19107, USA
Uric Acid (UA), a product of Purine metabolism, is a known scavenger of Peroxynitrite (ONOO(-)), which has been implicated in the pathogenesis of Multiple Sclerosis and Experimental Allergic Encephalomyelitis (EAE).
To determine whether the known therapeutic action of UA in EAE is mediated through its capacity to inactivate ONOO(-) or some other Immunoregulatory phenomenon, the effects of UA on Ag presentation, T-Cell reactivity, Ab production, and evidence of CNS inflammation were assessed.
The inclusion of physiological levels of UA in culture effectively inhibited ONOO(-)-mediated oxidation as well as Tyrosine nitration, which has been associated with damage in EAE and Multiple Sclerosis, but had no inhibitory effect on the T-Cell-proliferative response to Myelin Basic Protein (MBP) or on APC function.
In addition, UA treatment was found to have no notable effect on the development of the Immune response to MBP in vivo, as measured by the production of MBP-specific Ab and the induction of MBP-specific T-Cells
The appearance of cells expressing mRNA for inducible NO synthase in the circulation of MBP-Immunized mice was also unaffected by UA treatment.
However, in UA-treated animals, the Blood-CNS Barrier breakdown normally associated with EAE did not occur, and inducible NO synthase-positive cells most often failed to reach CNS tissue.
These findings are consistent with the notion that UA is therapeutic in EAE by inactivating ONOO(-), or a related molecule, which is produced by activated Monocytes and contributes to both enhanced Blood-CNS Barrier permeability as well as CNS tissue pathology.