Antidepressant-like effect of rutin isolated from the ethanolic extract from Schinus molle L. in mice: Evidence for the involvement of the serotonergic and noradrenergic systems

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Abstract

We have recently shown that the hexanic extract from leaves of Schinus molle produces antidepressant-like effects in the tail suspension test in mice. This study investigated the antidepressant-like effect of the ethanolic extract from aerial part of S. molle in the forced swimming test and tail suspension test in mice, two predictive models of depression. Moreover, we investigated the antidepressant potential of rutin, a flavonoid isolated from the ethanolic extract of this plant and the influence of the pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester (PCPA) and α-methyl-p-tyrosine (AMPT), respectively in the antidepressant-like effect of this flavonoid. The administration of the ethanolic extract produced a reduction in the immobility time in the tail suspension test (dose range 600–1000 mg/kg, p.o.), but not in the forced swimming test. It also produced a reduction in the ambulation in the open-field test in mice not previously habituated to the arena, but no effect in the locomotor activity in mice previously habituated to the open-field. The administration of rutin reduced the immobility time in the tail suspension test (0.3–3 mg/kg, p.o.), but not in the forced swimming test, without producing alteration in the locomotor activity. In addition, pretreatment of mice with PCPA (100 mg/kg, i.p., for 4 consecutive days) or AMPT (100 mg/kg, i.p.) prevented the anti-immobility effect of rutin (0.3 mg/kg, p.o.) in the tail suspension test. The results firstly indicated the antidepressant-like effect of the ethanolic extract of S. molle in the tail suspension test may be dependent on the presence of rutin that likely exerts its antidepressant-like effect by increasing the availability of serotonin and noradrenaline in the synaptic cleft.

Introduction

Pharmacological studies carried out with extracts from Schinus molle L. (Anacardiaceae) show that this plant exerts several biological effects, such as: antitumoral (Ruffa et al., 2002), antispasmodic (Bello et al., 1998), anti-inflammatory (Yueqin et al., 2003), and analgesic (Barrachina et al., 1997). This plant is also traditionally used for the treatment of depression (Taylor, 2005). It was recently demonstrated by our group that the administration of the hexanic extract from leaves of S. molle produces an the antidepressant-like effect in tail suspension test (Machado et al., 2007), a behavioral model frequently used to evaluate the efficacy of antidepressant drugs (Steru et al., 1985). Our results show that this antidepressant-like action of the hexanic extract from S. molle is mediated by its interaction with the serotonergic, noradrenergic and dopaminergic systems (Machado et al., 2007).

Flavonoids produce a variety of biological effects in numerous mammalian cell systems, in vitro and in vivo (Zhao et al., 2007). Rutin is a glycoside flavonol which belongs to an important class of flavonoids, being extensively found in many plants, including S. molle. This flavonoid has been shown to exert several biological activities, such as: antimicrobial (Arima et al., 2002), anti-inflammatory (Guardia et al., 2001, Afanas'ev et al., 2001), antioxidant (Ostrakhovitcha and Afanas'ev, 2001), neuroprotective (Gupta et al., 2003), antiviral (Middleton et al., 2000), and antiulcerogenic (La Casa et al., 2000). A study from Noldner and Schotz (2002) has indicated that rutin is essential for the antidepressant activity of Hypericum perforatum extract, a plant used in many countries for the treatment of mild to moderate forms of depression (Linde and Knüppel, 2005), since it caused a synergistic effect with H. perforatum extract in the forced swimming test. This observation raises the hypothesis that rutin may be important for the antidepressant-like action of S. molle.

According to the World Health Organization (2001) report, mood disorders are the second leading cause worldwide of disability adjusted life years and the leading cause of years lived with disability in all ages. Each drug used to treat this disorder has a success rate of about 60%. In addition, most therapies require several weeks of treatment before improvement of signs and symptoms is observed and there are numerous side effects caused by antidepressants (Wong and Licinio, 2001). Thus, the high prevalence of depression and the fact that a significant proportion of individuals do not respond well to any currently marketed antidepressants or treatments support the need for new therapeutics to treat depression.

Numerous antidepressant compounds are now available, presumably acting via different mechanisms including serotonergic, noradrenergic and/or dopaminergic systems (Elhwuegi, 2004). However, heterogeneity of clinical response to antidepressant and susceptibility to adverse effects are major clinical problems. Despite the advances in drug discovery and therapeutic options there are still multiple shortcomings that need to be improved. Medical plant therapies may be effective alternatives in the treatment of depression, and has progressed significantly in the past decade (Zhang, 2004).

Therefore, the present work aimed to evaluate firstly the antidepressant-like effect of the ethanolic extract from aerial part of S. molle in the models predictive of antidepressant action, and, secondly, to investigate the antidepressant potential of rutin, compound isolated from the ethanolic extract of this plant. In addiction, this study sought to examine the influence of the pretreatment with the inhibitors of serotonin or noradrenaline and dopamine synthesis, p-chlorophenylalanine methyl ester (PCPA) and α-methyl-p-tyrosine (AMPT), respectively in the antidepressant-like effect of this flavonoid in the tail suspension test.

Section snippets

Plant material and preparation of the ethanolic extract

Stems and leaves (aerial part) of Schinus molle L. (Anacardiaceae) were collected in Florianópolis, Santa Catarina, and identified by Dr. Daniel de Barcellos Falkenberg, Department of Botany, Federal University of Santa Catarina. A voucher specimen (FLOR 34411) was deposited in the Herbarium of the Department of Botany, Federal University of Santa Catarina, Florianópolis — SC, Brazil. Botanical material were dried under air circulation and minced. Firstly, dried sample was extracted with hexane

Effect of the ethanolic extract from S. molle in the immobility time in the forced swimming test, tail suspension test and on the locomotor activity in the open-field test

The effects of the oral administration of the ethanolic extract from S. molle in the immobility time in the forced swimming test and tail suspension test were shown in Fig. 1A and B, respectively. As depicted in Fig. 1A, the extract given by oral route at doses of 30, 100, 300, 600 and 1000 mg/kg did not significantly decrease the immobility time in the forced swimming test as compared to the control group, but significantly decreased the immobility time in the tail suspension test at the doses

Discussion

The forced swimming test and tail suspension test are the most common animal models of depression used for antidepressant screening. In both tests, animals are placed in an inescapable situation and the antidepressant-like activity is expressed by the decrease of immobility duration (Porsolt et al., 1977, Steru et al., 1985). In the present study we provide convincing evidence that the ethanolic extract from S. molle administered by oral route produces a specific antidepressant-like effect in

Acknowledgements

This study was supported by a grant from FAPESC-SC, CNPq and CAPES (Brazil). We thank Dr. Daniel B. Falkenberg for identifying the specie of S. molle.

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