Anxiolytic effects of a novel herbal treatment in mice models of anxiety
Introduction
Anxiety and stress disorders are currently among the ten most important public health concerns, according to the World Health Organization (Thase, 2006) and in recent years, have reached epidemic proportions (Thase, 2006). These disorders are recognized as main risk factors for many diseases, including cardiovascular, metabolic and neuropsychiatric diseases (Cryan and Holmes, 2005, Thase, 2006). There is a growing corpus of data demonstrating that exposure to traumatic events during childhood can increase the risk for developing mood and anxiety disorders later in life (Dube et al., 2001, Heim and Nemeroff, 2001), and that repeated exposure to stressors (such as sexual, emotional, or physical abuse) early in life can have long-term effects on the function of stress-responsive neurobiological systems (Gutman and Nemeroff, 2003).
Finding effective treatments for anxiety and mood disorders is of utmost importance. Selective serotonin reuptake inhibitors (SSRIs) were shown to be effective in treating a wide spectrum of anxiety disorders (Borsini et al., 2002, Hidalgo and Davidson, 2000). Despite their therapeutic actions, SSRIs are also associated with a wide variety of side effects such as weight changes, insomnia, drowsiness or sedation, agitation, fatigue, dry mouth, gastrointestinal disturbances, headache and sexual dysfunction (Dording et al., 2002). Furthermore, recent studies show that their success rates for treating anxiety disorders are not high, reaching 50% at most (for review see Katzman, 2009).
The disadvantages of conventional pharmacological treatment for anxiety disorders have prompted the search for alternative treatments. One such possible treatment is herbal medicines. Phytochemical and behavioral studies have shown that chronic treatment with several herbal medicines, such as St. John's Wort and Kava (Sarris and Kavanagh, 2009, Witte et al., 2005), has a therapeutic potential for psychiatric disorders such as major depression and anxiety disorders. Chronic treatment with several herbal medicines was shown to normalize stress hormone levels (Panossian et al., 1999), and to increase BDNF levels (Hou et al., 2010, Li et al., 2009), similar to the effects seen following SSRIs treatment. Therefore, such compounds can provide a very useful pharmacological tool for the treatment of anxiety disorders.
The aim of the present study was to investigate whether a novel herbal treatment developed in our laboratory has behavioral and physiological anxiolytic effects, in comparison to conventional treatment with the SSRI escitalopram. The treatment was prepared from the following four components: Crataegus pinnatifida, Triticum aestivum, Lilium brownii and Fructus zizyphi jujubae. These components were chosen based on studies demonstrating their anxiolytic effects (Chouinard, 2004, Peng et al., 2000), their ability to regulate the HPA-axis function (Butterweck and Hegger, 2004), and that they can elevate monoamines levels in the brain (Lin et al., 2003, Yamada and Yasuhara, 2004). Therefore, anxiety-like behavior was evaluated in adult mice exposed to stress during childhood following a 1, 2 or 3-week treatment with the novel herbal treatment or escitalopram, using the novel open field and the elevated plus maze procedures. The behavioral evaluation in these mice was followed by a biochemical assessment of their brain hippocampal BDNF levels and blood corticosterone levels.
Section snippets
Drugs
C. pinnatifida, T. aestivum, L. brownii and F. zizyphi jujubae were purchased as freeze-dried granules from KPC Products, Inc. (Irvine, CA, USA). Escitalopram was kindly donated by TEVA Ltd (Israel). The herbal solution was prepared by dissolving the 4 compounds (together) in saline containing 1% DMSO to give a final concentration of 0.47 mg/ml (each). The herbal mixture as well as escitalopram was administered daily at a dose of 15 mg/kg (i.p injection).
Animals
For all experiments, BALB inbred male mice
Results
Table 1 presents a schematic outline of the experimental design.
Discussion
The present study explored the anxiolytic properties of a novel herbal treatment produced in our laboratory, in comparison with the conventional SSRIs treatment. Our study led to three main findings: (1) the novel herbal treatment reduced anxiety-like behavior following unpredictable stress during childhood in two behavioral tests, namely, the novel open field and the EPM. Interestingly, this reduction was observed only following a 3-week treatment (2) the novel treatment reduced the hormonal
Conclusions
This study has demonstrated the potential anxiolytic effects of a novel herbal treatment we have produced in our laboratory. The precise mechanism(s) underlying the effects of our novel treatment remain to be determined but are likely to involve, in part, increased BDNF levels in the brain and a reduction in corticosterone levels in the blood. Additional studies must be performed in order to evaluate the potential side effects of this novel treatment compared to the conventional treatment with
Conflict of interest statement
Dr. Ravid Doron has an approved patent relating the herbal treatment for anxiety disorders (PCT 61‐311,537, USA). All authors assert that none has any commercial or financial involvements that might present an appearance of a conflict of interest in connection with the submitted manuscript.
Acknowledgments
This work was funded by the Israel Science Foundation (ISF 738/11), by the National Institute for Psychobiology in Israel (NIPI-7-2011-12), and by the Open University of Israel. We would like to thank Prof. Shamgar Ben-Eliyahu and his laboratory students for their expert technical assistance in the corticosterone plasma level assessment and analyses. We would also like to thank Mr. Nadav Kataeli for preparing the herbal treatment. We are especially grateful to Mrs. Noa Albelda, for her comments
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