Suppression of experimental zymosan‐induced arthritis by intraperitoneal administration of adenosine

Abstract

The anti-inflammatory effect of methotrexate (MTX) is mediated by the increasing extracellular concentration of adenosine. The response of the immune system to activation of cell membrane subclass receptors for adenosine initiates intracellular signaling pathways, which causes immunomodulatory responses. To test the direct immunomodulatory effects of systemic administration of adenosine on animal model of inflammation, zymosan induced arthritis (ZIA) in mice was employed. Sterile zymosan (30 mg) was injected directly into the knee cleft of 60 mice, divided into 3 equal groups. The experimental groups received, every second day, 0, 0.25, and 0.5 mg/kg adenosine intraperitoneally. Inflammatory intensity was evaluated clinically by knee swelling measurement, histology, the total white blood cell (WBC) count, and serum tumor necrosis factor-alpha (TNF-a) levels served as markers of systemic inflammatory reaction. As observed, only the mice that received the higher dose of 0.5 mg/kg adenosine developed a significantly milder arthritis. A 23.9% reduction (P o 0.004) of the mean knee diameter swelling was noted. The histological inflammatory parameters and WBC count in the 0.5 mg/kg adenosine-treated mice were also decreased (6,555 7 510/mm 3 vs. 9,250 7 530 WBC/mm 3 in the untreated mice, P 4 0.006; 9,188 7 588 WBC/mm 3 in the 0.25 mg/kg adenosine-treated group). Serum TNF-a levels were significantly reduced (78.1 pg/ml in the 0.5 mg/kg adenosine-treated group vs. 124.3 pg/ml, in the control group, P o 0.004). The data indicate a remarkable clinical beneficial effect, as well as a local and systemic anti-inflammatory response that was noted on administration of 0.5 mg/kg adenosine every alternate day to mice with inflammatory arthritis. Drug Dev.

Pathophysiology and Therapeutic Potential of Purinergic Signaling

“…Spinal P1 receptor activation has been claimed to inhibit inflammation and joint destruction in rat adjuvant-induced arthritis, supporting the view that therapeutic strategies, which target the CNS, might be useful in arthritis (Boyle et al, 2002;Sorkin et al, 2003). Suppression of experimental zymosan-induced arthritis by intraperitoneal administration of adenosine has also been described (Baharav et al, 2002).…”

<p>Targeting the A₃ adenosine receptor to treat cytokine release syndrome in cancer immunotherapy</p>

“…Cytokine inhibition was counteracted by antagonizing the A 3 AR or A 2a AR (but not A 1 AR and A 2b AR), demonstrating that at least part of the adenosine effect was A 3 AR mediated 43. In the zymosan-induced arthritis model, adenosine reduced TNF-α secretion 44…”

“…Adjuvant-induced arthritis, collagen-induced arthritis, and tropomyosin-induced arthritis – IB-MECA reduced TNF-α level in the spleen, lymph node, and the synovial tissue manifested also by significant reduction in joint inflammation 44,57…”

“…CF102 treatment also decreased the expression level of phosphorylated GSK-3β, NF-κB, and TNF-α and prevented apoptosis in the liver of Con.A mice 48Adjuvant-induced arthritis, collagen-induced arthritis, and tropomyosin-induced arthritis – IB-MECA reduced TNF-α level in the spleen, lymph node, and the synovial tissue manifested also by significant reduction in joint inflammation 44,57Experimental autoimmune uveitis (EAU) – CF101 treatment reduced the secretion of IL-2, TNF-α, and IFN-γ measured in the condition medium of lymph node cells derived from EAU mice 58…”

Purinergic signalling in the musculoskeletal system

“…An early study reported the suppression of zymosaninduced inflammatory arthritis by intraperitoneal administration of adenosine [421]. Later evidence from a phase II clinical trial has suggested that A 3 receptor agonists could be used to treat RA [422][423][424].…”