Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

Abstract

Adenosine and its metabolite, inosine, have been described as molecules that participate in regulation of inflammatory response. The aim of this study was to investigate the effect of adenosine and inosine in a mouse model of carrageenan-induced pleurisy as well as the participation of adenosine receptors in this response. Injection of carrageenan into the pleural cavity induced an acute inflammatory response characterized by leukocyte migration, pleural exudation, and increased release of interleukin-1β and tumor necrosis factor-α in pleural exudates. The treatment with adenosine (0.3-100 mg/kg, i.p.) and inosine (0.1-300 mg/ kg, i.p.) 30 min before carrageenan injection reduced significantly all these parameters analyzed. Our results also demonstrated that A 2A and A 2B receptors seem to mediate the adenosine and inosine effects observed, since pretreatment with selective antagonists of adenosine A 2A (ZM241385) and A 2B (alloxazine) receptors, reverted the inhibitory effects of adenosine and inosine in pleural inflammation. The involvement of A 2 receptors was reinforced with adenosine receptor agonist CGS21680 treatment, since its anti-inflammatory effects were reversed completely and partially with ZM241385 and alloxazine injection, respectively. Moreover, the combined treatment with subeffective dose of adenosine (0.3 mg/kg) and inosine (1.0 mg/kg) induced a synergistic anti-inflammatory effect. Thus, based on these findings, we propose that inosine contributes with adenosine to exert anti-inflammatory effects in pleural inflammation, reinforcing the notion that endogenous nucleosides play an important role in controlling inflammatory diseases. This effect is likely mediated by the activation of adenosine A 2 subtype receptors and inhibition of production or release of pro-inflammatory cytokines.

Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A2A and A3 receptors

“…In addition, an inosine analogue (INO-2002) demonstrated similar anti-inflammatory properties in an acute respiratory distress syndrome model [22]. In agreement, a recent study from our group have revealed that inosine significantly reduces pleural acute inflammation, reducing pleural leakage, neutrophil count, TNF-α and IL-1β levels in pleural exudates, an effect dependent on A 2A adenosine receptor activation [23]. Because inosine exerts regulatory effects on immune response [5] and increased tissue inosine levels are quantified in the inflamed sites [4,32], our data suggest that purines constitute a target pathway for the control of allergic asthma.…”

“…Despite all that is known about the effects of inosine, the mechanisms underlying its role in controlling the lung repercussions of allergic inflammation are still unknown. Recent data obtained from our group showed that inosine reduced carrageenan-induced acute pleural inflammation, an effect that involves A 2A and A 2B adenosine receptors [23]. Accordingly, literature data indicates that the activation of A 2 adenosine receptors subtypes is related with downregulation of inflammation and immune responses [4,24,25].…”

“…The same selective antagonists were given in absence of inosine to evaluate the per se effects. The doses of antagonists used here were based on previous in vivo studies [23,26].…”

The Antiepileptic Potential of Nucleosides

“…However, more detailed studies are necessary to reveal this novel possibility. In addition, the anti-inflammatory effects of not only Ado [197,198,201,424] but also of Urd and Ino have been demonstrated [403,[424][425][426]; thus, investigation of the effect of Urd and Ino on inflammationinduced exacerbation of epileptic activity [192,193] may also be an interesting and promising novel drug discovery target in epilepsy research.…”

Is cIMP a second messenger with functions opposite to those of cGMP?

“…By analogy to the cAMP-adenosine-adenine system (Jackson and Raghvendra 2004), extracellular cIMP may then be hydrolyzed to inosine and hypoxanthine. Inosine and hypoxanthine, in turn, could exert biological effects via adenosine or adenine receptors, respectively (Schiedel et al 2007;da Rocha Lapa et al 2012). These two mechanisms of action of cIMP were not addressed in the study by Chen et al (2014).…”