atl-313 and Inflammation

A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFα in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.

Topics: Adenosine A2 Receptor Agonists; Animals; Cells, Cultured; Chronic Disease; Constriction, Pathologic; Cyclic AMP-Dependent Protein Kinases; Hyperalgesia; Inflammation; Injections, Spinal; Ligation; Male; Piperidines; Protein Kinase C; Random Allocation; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Signal Transduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats.. Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration.. The ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected.. We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.

Topics: Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CXCL1; Dinoprostone; Gastric Mucosa; Indomethacin; Inflammation; Interleukin-1beta; Male; Peroxidase; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Stomach Ulcer; Triazines; Triazoles; Tumor Necrosis Factor-alpha

The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A 2A adenosine receptor (AR) agonist treated and untreated animals during experimental sepsis.. Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (Escherichia coli or Staphylococcus aureus) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A 2A AR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days.. There was a significant survival benefit in mice infected with live E. coli (100% vs. 20%, p = 0.013) or S. aureus (60% vs. 20%, p = 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, p = 0.005). The serum concentrations of TNF-alpha, MIP-1 alpha, MCP-1, IFN-gamma, and IL-17 were decreased by ATL313 after LPS injection (p < 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (p < 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (p < 0.01).. Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.

Topics: Animals; Anti-Inflammatory Agents; Ceftriaxone; Cytokines; Disease Models, Animal; Escherichia coli Infections; Female; Inflammation; Leukocytes; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Piperidines; Receptor, Adenosine A2A; Sepsis; Staphylococcal Infections; Survival Analysis