Research report
Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: A promising new molecular pattern for the development of antidepressant drugs

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Abstract

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 μg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC50 = 90 ± 38 nM), serotonin (IC50 = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.

Highlights

H. polyanthemum and uliginosin B cause antidepressant effect in forced swimming test. ► H. polyanthemum and uliginosin B potentiate antidepressants antiimobility activity in forced swimming test. ► Uliginosin B antidepressant-like effect depends on monoaminergic neurotransmission. ► Uliginosin B inhibits monoamines uptake without binding to their transporters. ► Uliginosin B provides a new molecular pattern to develop innovative antidepressants.

Introduction

New compounds that could improve conventional antidepressant therapies are still needed, since depressive disorders have high incidence in the world population [1], [2] and the treatment of depression with conventional antidepressants provides a complete remission just by 50% of the individuals [3] and presents pronounced side effects [4], which reduce the patients treatment compliance [5].

Natural products scaffolds have been well recognized as being privileged structures in terms of their ability to be the basis for successful drugs [6]. Extracts of Hypericum perforatum (St. John's wort) have been accepted as a treatment for depression and the components associated with this activity include phloroglucinol derivatives (hyperforin), naphthodianthrones (hypericin) and flavonoids (e.g. quercitrin) [2], [7].

Our group has been studying chemical and pharmacological features of South Brazilian Hypericum species [8], [9], [10], [11], [12], [13], [14]. The species of Hypericum native to southern Brazil, studied so far, do not produce hypericin or pseudohypericin [15], which is consistent with the absence of dark glands in species belonging to the sections Brathys and Trigynobrathys [16]. Differently from the well-known hyperforin and adhyperforin isolated from H. perforatum that are polyisoprenylated phloroglucinols, Brazilian species are a source of dimeric structures, consisting of filicinic acid and a phloroglucinol moieties [17]. Hypericum polyanthemum (POL) major chemical constituents are three benzopyrans (HP1, HP2, HP3), and a phloroglucinol derivative, named uliginosin B (ULI) [18]. The structure of ULI presents a prenyl substituent cyclized with an adjacent hydroxyl group originating a pyran nucleus (Fig. 1).

With regard to the central nervous system activity, H. piriai petroleum ether extract, H. caprifoliatum and H. polyanthemum chloroform extract and the benzopyrans showed in vitro MAOI (monoamino oxidase inhibitory) activity [19]. However, this activity does not appear to be relevant for the antidepressant-like effect, since the extracts which displayed this activity were not active in the forced swimming test (FST) [19]. H. caprifoliatum cyclohexane extract has antidepressant-like activity on the FST through activation of three monoaminergic systems by its phloroglucinol derivative HC1 [13]. The antinociceptive effect of the cyclohexane extract of H. polyanthemum (POL) and its benzopyrans, HP1, HP2 and HP3, were studied in mice [12], [20]. The extract and HP1 showed a dose-dependent effect on the hot-plate test which was impaired by naloxone indicating an involvement of the opioid system in this effect [20].

The aim of this study was to investigate the potential antidepressant effect of H. polyanthemum cyclohexane extract (POL) and uliginosin B (ULI) and search for its action on monoaminergic neurotransmission. We have investigated the antidepressant-like effect of single doses of ULI and POL as well as the combined administration of sub-effective doses of POL and ULI with sub-effective doses of antidepressants from different classes (imipramine, a serotonin/noradrenalin reuptake inhibitor; bupropion, a noradrenalin/dopamine reuptake inhibitor; fluoxetine, a serotonin reuptake inhibitor) in the FST. In addition, the involvement of the monoaminergic neurotransmission in the antidepressant-like effect of ULI was investigated through the use of pharmacological manipulations in the FST as well as by monoamine synaptosomal uptake and monoamine transporters binding assays.

Section snippets

Plant material

H. polyanthemum aerial parts were collected in the region of Caçapava do Sul, state of Rio Grande do Sul – Brazil (October, 2008). The voucher specimens were deposited at the herbarium of Universidade Federal do Rio Grande do Sul (ICN Bordignon, 3118 Herbário do Departamento de Botânica – Instituto de Biociências – UFRGS). The plant collection was authorized by IBAMA (Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renováveis) (n° 003/2008; Protocol 02000.001717/2008 – 60).

Preparation of extract and uliginosin B isolation

To

Forced swimming test

In rats, POL 270 mg/kg/day, p.o. significantly reduced immobility time [one-way ANOVA: F (2,30) = 4.55; P < 0.05] (Fig. 2A). The effect of POL in the mice FST is presented in the Fig. 2B. One way ANOVA revealed a significant effect of POL [F (4,51) = 12.22, P < 0.001]; post hoc analysis indicated a significant decrease in the immobility time elicited by the administration of POL at the doses of 90, 180 (P < 0.001) and 270 mg/kg (P < 0.01) when compared with saline group. The administration of POL (90 and 270 

Discussion

In this study we have continued our ongoing project to detect bioactive molecules in southern Brazilian species of the genus Hypericum. Herein, we have shown that the cyclohexane extract from H. polyanthemum (POL) administered orally produced a significant antidepressant-like effect in the FST of both rats and mice. This effect was also observed with its main phloroglucinol derivative uliginosin B (ULI), which is likely to be the main active substance of H. polyanthemum.

The anti-immobility

Acknowledgments

This work was supported by CAPES-COFECUB (418/03 and 656/09), CNPq and Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF-UFRGS). The authors are thankful to A. Braga, F.B. Centurião and D. Hasse for technical assistance during the experiments.

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