Chlorogenic acid, a polyphenol from Prunus domestica (Mirabelle), with coupled anxiolytic and antioxidant effects

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Abstract

Background

Oxidative stress is linked to neurodegenerative diseases, cancer, cardiovascular diseases and to some behaviors, such as anxiety and depression. In particular, recent research observed a close relationship between oxidative stress and anxiety.

Methods

We investigated the anxiolytic effect of chlorogenic acid, a dietary antioxidant present in fruits, in mouse models of anxiety including the light/dark test, the elevated plus maze and the free exploratory test. Moreover, the antioxidative effect of chlorogenic acid on peripheral blood granulocytes was investigated.

Results

Chlorogenic acid (20 mg/kg) induced a decrease in anxiety-related behaviors suggesting an anxiolytic-like effect of this polyphenol. The anti-anxiety effect was blocked by flumazenil suggesting that anxiety is reduced by activation of the benzodiazepine receptor. In vitro, chlorogenic acid protected granulocytes from oxidative stress.

Conclusions

Chlorogenic acid is one of the most abundant polyphenols in fruits. We demonstrated in vivo and in vitro for the first time, that chlorogenic acid has anxiolytic effects coupled with antioxidant activity. Thus, fruits such as plums (Mirabelle), apples and cherries may provide health-promoting advantages to consumers.

Introduction

A link between oxidative stress and levels of anxiety has been recently postulated. Hovatta et al. [1] reported the close relationship existing between the expression of two cerebral genes which protect the cells against oxidative damage and anxiety-related behavioral phenotypes in six inbred mouse strains. These authors [1] hypothesized that glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Local overexpression in the murine brain of these two genes resulted in increase of anxiety-like behavior anxiety, while inhibition of glutathione reductase 1 expression produced low-anxiety mice. However, the relation between trait anxiety and central oxidative status is more complex given that glyoxalase 1 is expressed at higher levels in low anxiety mice compared with anxious mice. The same phenotype-dependent difference was found in red blood cells [2], [3]. The implication of oxidative stress in the pathogenesis of anxiety disorders (obsessive–compulsive disorder and panic disorder) was also suggested by Kuloglu et al. [4], [5] who observed that erythrocytes of patients with anxiety disorders may have higher levels of the antioxidant enzymes glutathione peroxidase and superoxide dismutases. We have reported statistically significant linear relationships between oxidative status of blood granulocytes and level of anxiety in mice [6]. In the present study, we investigated the effect of a polyphenol called chlorogenic acid (Fig. 1) naturally presents in fruits (plums, apples, cherries, etc) and reputed by its antioxidant activity [7], [8] on two types of anxieties in mice (state anxiety and trait anxiety). In our laboratory, chlorogenic acid was initially identified and quantified in Mirabelle (Prunus x domestica L) using reversed-phase high-performance liquid chromatography. To estimate state anxiety, the light/dark test and elevated plus maze were used. To evaluate trait anxiety, the free exploratory test was employed. Moreover, we studied in vitro the antioxidative effect of chlorogenic acid on peripheral blood granulocytes.

Section snippets

Animals

Swiss albino male mice (OF1) aged 9 weeks at the receipt from the breeder company (Charles River, France) and weighing 40–45 g were used. The animals were housed under a 12-h light:12-h dark schedule (lights on starting at 8:00 p.m.) with water and food ad libitum (SD Dietex-France). Animal rooms were at a constant temperature of 21 ± 2 °C and relative humidity of 55 ± 10%. All animal procedures were carried out in accordance with the European Communities Council Directive of 24 November 1986

Light/dark choice test

ANOVA revealed significant differences between groups of mice with respect to latency time (F(5,50) = 2.59; p = 0.03), number of transitions (F(5,50) = 3.11; p = 0.01), time in the lit box (F(5,50) = 2.59; p = 0.03) ), locomotion in the lit box (F(5,50) = 7.39; p < 0.0001) and total locomotion (F(5,50) = 2.94; p = 0.02). There were no significant differences between groups with respect to locomotion in the dark box (F(5,50) = 0.69; p > 0.05) (Fig. 2).

Mice administered chlorogenic acid (Chl) at 20 mg/kg and diazepam

Discussion

Chlorogenic acid was tested at several doses in the light/dark test, and its dose–response curve appeared to have an inverted U-shape: 20 mg/kg was active, but 2, 10 and 40 mg/kg were not (Fig. 2). The well-known anxiolytic diazepam at 1 mg/kg and chlorogenic acid at 20 mg/kg caused a similar spectrum of behavioral change compared to the vehicle (NaCl 0.9%). Both molecules increased the number of transitions from the dark to the lit box, the cumulative time spent in the lit box and locomotor

Acknowledgements

We are grateful to Pr. Didier Desor (Neurosciences, URAFPA, Université Henri Poincaré, Nancy) for helpful discussions and to Frédéric Desor for his technical assistance.

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