Uliginosin B, a Possible New Analgesic Drug, Acts by Modulating the Adenosinergic System.

Eveline Dischkaln Stolz,Carla Bonan,Ana Maria Oliveira Battastini,Gilsane Lino Von Poser,Liciane Fernandes Medeiros,Stela Maris Kuze Rates,Andressa Souza,Paola Fontoura Da Costa,Iraci L S Torres

doi:10.1155/2016/5890590

Abstract

Uliginosin B (ULI) is a natural acylphloroglucinol that has been proposed as a new molecular scaffold for developing analgesic and antidepressant drugs. Its effects seem to be due to its ability to increase monoamines in the synaptic cleft by inhibiting their neuronal uptake without binding to their respective transporters, but its exact mode of action is still unknown. Considering the importance of the purinergic system to pain transmission and its modulation by monoamines availability, the aim of this study was to investigate the involvement of adenosinergic signaling in antinociceptive effect of uliginosin B. The selective adenosine A1 receptor antagonist DPCPX and the selective A2A antagonist ZM 241385 prevented the effect of ULI in the hot-plate test in mice. Pretreatment with inhibitors of adenosine reuptake (dipyridamole) or adenosine deaminase (EHNA) did not affect the ULI effect. On the other hand, its effect was completely prevented by an inhibitor of ecto-5′-nucleotidase (AMPCP). This finding was confirmed ex vivo, whereby ULI treatment increased AMP and ATP hydrolysis in spinal cord and cerebral cortex synaptosomes, respectively. Altogether, these data indicate that activation of A1 and A2A receptors and the modulation of ecto-5′-nucleotidase activity contribute to the antinociceptive effect of ULI.

Highlights

Uliginosin B (ULI) is a dimeric acylphloroglucinol consisting of filicinic acid and phloroglucinol moieties, which occurs in Hypericum species native to South America [1]
One-way analysis of variance (ANOVA) revealed a significant antinociceptive effect of ULI (Figure 2(a): F(3,35) = 25.611, p < 0.001; Figure 2(b): F(3,35) = 19.555, p < 0.001), which was prevented by pretreatment with the adenosine A1 receptor antagonist DPCPX (p < 0.001) and the adenosine A2A receptor antagonist ZM 241385 (p < 0.001)
One-way ANOVA revealed a significant effect only in the group treated with ULI (Figure 3(c): F(3,35) = 12.981, p < 0.001), which was prevented by the AMPCP pretreatment (p < 0.001)

Summary

Introduction

Uliginosin B (ULI) is a dimeric acylphloroglucinol consisting of filicinic acid and phloroglucinol moieties, which occurs in Hypericum species native to South America [1]. This molecular pattern has been proposed as a prototype to develop analgesic and antidepressant drugs [2,3,4,5]. Preclinical studies suggested that ULI has antidepressant properties, which seems to be due to its ability to increase monoamines availability in the synaptic cleft by inhibiting their neuronal uptake [2]. ULI does not bind to the monoamine sites on neuronal transporters, which indicates that it acts differently from the classical antidepressants [2].

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Conclusion