PHARMACOLOGICAL INTEREST OF ADENOSINE IN RELATION TO ITS ANTI-TNF PROPERTIES

At physiological and pharmacological doses, adenosine protects tissues against a varieties of injuries : ischemia-reperfusion, convulsions, inflammation... We tested the hypothesis that the antiinflammatory pro perties of adenosine occur via a down-regulation of TNF. Agonists of a denosine receptors (ARA) and agents potentiating endogenous adenosine (APA) were evaluated for their effects on TNF production by endotoxin- stimulated human monocytes. Additionnally, one of the most potent agon ists, R-phenylisopropyladenosine (R-PIA), was tested on two experiment al models of acute phase response, endotoxin shock and carrageenan-ind uced plantar oedema. Several ARA and APA inhibited monocyte TNF produc tion in a concentration-dependent manner. R-PIA and other ARA were act ive at micromolar concentrations. The property is pharmacologically re levant since rats receiving a lethal dose of endotoxin were protected by R-PIA and endotoxin-induced serum TNF levels were abolished by a pr etreatment with R-PIA. Inhibitory effects on serum TNF production were obtained with similar doses of dexamethasone sodium phosphate and one hundred-fold higher doses of pentoxifylline. R-PIA was also found act ive on carrageenan-induced oedema. The anti-oedematous properties of R -PIA were associated with a marked reduction of locally-produced TNF a nd were also observed after the administration of dexamethasone, pento xifylline and a neutralizing anti-TNF antibody. Our results indicate t hat adenosine is a potent inhibitor of TNF production induced by diffe rent stimuli. This property could lead to therapeutic applications in inflammatory diseases and other in which TNF is known to play a pathog enic or aggravating role. Comparison between ARA and APA in terms of t olerance and efficacy merits further attention.