title: A(2A) adenosine receptors are differentially modulated by pharmacological treatments in rheumatoid arthritis patients and their stimulation ameliorates adjuvant-induced arthritis in rats.
abstract: A(2A) adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A(2A)ARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A(2A)AR stimulation in a rat model of arthritis. We investigated A(2A)AR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A(2A)ARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A(2A)AR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A(2A)AR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A(2A)AR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A(2A)AR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A(2A)AR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A(2A)ARs in lymphocytes from RA patients. The effectiveness of A(2A)AR stimulation in a rat model of arthritis supported the role of A(2A)AR agonists as potential pharmacological treatment for RA.
authors: Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy.
authors: Fabrizio
authors: F
authors: Vincenzi
authors: Melissa
authors: M
authors: Padovan
authors: Martina
authors: M
authors: Targa
authors: Carmen
authors: C
authors: Corciulo
authors: Sarah
authors: S
authors: Giacuzzo
authors: Stefania
authors: S
authors: Merighi
authors: Stefania
authors: S
authors: Gessi
authors: Marcello
authors: M
authors: Govoni
authors: Pier Andrea
authors: PA
authors: Borea
authors: Katia
authors: K
authors: Varani
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D018501:Antirheumatic Agents / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008137:Longitudinal Studies; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D010627:Phenethylamines / Q000008:administration & dosage*; D058906:Purinergic P1 Receptor Agonists / Q000008:administration & dosage*; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D000069283:Rituximab; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000069283:Rituximab; D000241:Adenosine; D008727:Methotrexate