Reducing joint destruction due to septic arthrosis using an adenosine_2A receptor agonist

Abstract

We assessed the efficacy of a new adenosine AZA agonist ATL146e, a potent inhibitor of white blood cell chemotaxis, to reduce cartilage damage in the treatment of septic arthrosis. A live septic arthrosis model was created using Staphylococcus aureus in rabbit knees. Animals were divided into five treatment groups: (1) untreated infected control, (2) antibiotics control, and antibiotics plus ATL146e for (3) 24, (4) 48, or (5) 72 h and assessed at I , 4, and 7 days.Knees in all ATL 146e treated animals exhibited no detectable effusion, and histologic examination revealed near normal cartilage and diminished synovial inflammatory response. Synovial WBC counts decreased with the addition of ATL146e when compared to infected and antibiotic controls. Histologic grading of osteochondral specimens demonstrated improved scores for animals treated with ATLl46e compared to infected (p < 0.00004) and antibiotics controls (p < 0.05). Analysis of glycosaminoglycan content revealed significantly decreased loss of articular cartilage following infection in the ATL 146e groups when compared to infected (p < 0.03) and antibiotics controls (p < 0.05).Addition of an adenosine AZA agonist to antibiotic therapy decreases joint inflammation and articular cartilage destruction without compromising bacterial clearance in rabbit knees following intraarticular bacterial infection. The use of adenosine agonists selective to the AZA receptor to augment conventional treatment of joint sepsis may be chondroprotective and ultimately help prevent arthrosis.

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…In fact, adenosine is a potent anti-inflammatory agent with A 2A Rs triggering BOFF^signals in activated immune cells, which constitutes one of the most fundamental and immediate tissue-protecting mechanisms (reviewed in [295,296]). A 2A R agonists were even named Bthe most potent anti-inflammatory drug known to mankind.^Ac-cordingly, activation of A 2A Rs has been shown to confer a robust protection against tissue damage from ischemiaYreperfusion injury in different organ such as heart [297Y299], blood vessels [300], kidney [301,302], liver [303,304], lung [305,306], joints [307], skin [308,309], and even in the spinal cord [310,311] and in the brain following hemorrhage [312] or acute infection [313]. Thus, it is the activation (rather the blockade) of A 2A Rs that confers protection against damage triggered by inflammation in peripheral tissues, precisely the opposite of what is observed in the damaged adult brain.…”

Pulsed electromagnetic fields reduce knee osteoarthritic lesion progression in the aged Dunkin Hartley guinea pig

“…Recent therapy in clinical use today bases its effectiveness on the selective inhibition of cyclooxygenase-2, an enzyme that is expressed under the stimulus of varying inflammatory factors [33]. Adenosine has been recognized as a potent endogenous anti-inflammatory agent that mediates its effect by interacting with specific membrane receptors (most interestingly A2a receptors) which are considered to be specifically involved in the natural inhibitory mechanism and/or termination of inflammation [4,12,37,45,48]. The expression of adenosine receptor gene transcripts by ~5 1 .…”

Purinergic signalling in the musculoskeletal system

“…A 2A receptor agonists have been used to reduce joint destruction due to septic arthritis [446] and they may reduce the destructive effects of polyethylene wear debris and prevent joint prosthesis loosening [447].…”