Collectively, these results show, for the first time, that extracts obtained from Magnolia ovata possess antipyretic and anti-inflammatory properties, and costunolide appears to be the compound responsible for these effects.

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.

Inosine, a naturally occurring purine formed from the breakdown of adenosine, is associated with immunoregulatory effects. Evidence shows that inosine modulates lung inflammation and regulates cytokine generation. However, its role in controlling allergen-induced lung inflammation has yet to be identified. In this study, we aimed to investigate the role of inosine and adenosine receptors in a murine model of lung allergy induced by ovalbumin (OVA). Intraperitoneal administration of inosine (0.001-10 mg/kg, 30 min before OVA challenge) significantly reduced the number of leukocytes, macrophages, lymphocytes and eosinophils recovered in the bronchoalveolar lavage fluid of sensitized mice compared with controls. Interestingly, our results showed that pre-treatment with the selective A 2A receptor antagonist (ZM241385), but not with the selective A 2B receptor antagonist (alloxazine), reduced the inhibitory effects of inosine against macrophage count, suggesting that A 2A receptors mediate monocyte recruitment into the lungs. In addition, the pre-treatment of mice with selective A 3 antagonist (MRS3777) also prevented inosine effects against macrophages, lymphocytes and eosinophils. Histological analysis confirmed the effects of inosine and A 2A adenosine receptors on cell recruitment and demonstrated that the treatment with ZM241385 and alloxazine reverted inosine effects against mast cell migration into the lungs. Florianópolis 88040-900, Santa Catarina, Brazil Purinergic Signalling (2013) 9:325-336 DOI 10.1007 Accordingly, the treatment with inosine reduced lung elastance, an effect related to A 2 receptors. Moreover, inosine reduced the levels of Th 2 -cytokines, interleukin-4 and interleukin-5, an effect that was not reversed by A 2A or A 2B selective antagonists. Our data show that inosine acting on A 2A or A 3 adenosine receptors can regulate OVA-induced allergic lung inflammation and also implicate inosine as an endogenous modulator of inflammatory processes observed in the lungs of asthmatic patients.

The present study examined the antinociceptive effects of a hydroalcoholic extract of Polygala paniculata in chemical and thermal behavioural models of pain in mice. The antinociceptive effects of hydroalcoholic extract was evaluated in chemical (acetic-acid, formalin, capsaicin, cinnamaldehyde and glutamate tests) and thermal (tail-flick and hot-plate test) models of pain or by biting behaviour following intratecal administration of both ionotropic and metabotropic agonists of excitatory amino acids receptors glutamate and cytokines such as interleukin-1 β (IL-1 β) and tumour necrosis factor-α (TNF-α) in mice. When given orally, hydroalcoholic extract (0.001-10 mg/kg), produced potent and dose-dependent inhibition of acetic acid-induced visceral pain. In the formalin test, the hydroalcoholic extract (0.0001-0.1 mg/kg orally) also caused significant inhibition of both the early (neurogenic pain) and the late (inflammatory pain) phases of formalin-induced licking. However, it was more potent and efficacious in relation to the late phase of the formalin test. The capsaicin-induced nociception was also reduced at a dose of only 1.0 mg/kg orally. The hydroalcoholic extract significantly reduced the cinnamaldehyde-induced nociception at doses of 0.01, 0.1 and 1.0 mg/kg orally. Moreover, the hydroalcoholic extract (0.001-1.0 mg/kg orally) caused significant and dose-dependent inhibition of glutamate-induced pain. However, only rutin, but not phebalosin or aurapten, isolated from P. paniculata , administered intraperitoneally to mice, produced dose-related inhibition of glutamate-induced pain. Furthermore, the hydroalcoholic extract (0.1-100 mg/kg orally) had no effect in the tail-flick test. On the other hand, the hydroalcoholic extract caused a significant increase in the latency to response at a dose of 10 mg/kg orally, in the hot-plate test. The hydroalcoholic extract (0.1 mg/kg orally) antinociception, in the glutamate test, was neither affected by intraperitoenal treatment of animals with l-arginine (precursor of nitric oxide, 600 mg/kg) and naloxone (opioid receptor antagonist, 1 mg/kg.) nor associated with non-specific effects such as muscle relaxation or sedation. In addition, oral administration of hydroalcoholic extract produced a great inhibition of the pain-related behaviours induced by intrathecal injection of glutamate, N-methyl-d-aspartate (NMDA), IL-1 β and TNF-α , but not by α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), kainate or trans-1-amino-1.3-cyclopentanediocarboxylic acid (trans-ACPD). Together, our results suggest that inhibition of glutamatergic ionotropic receptors, may account for the antinociceptive action reported for the hydroalcoholic extract from P. paniculata in models of chemical pain used in this study.