A novel herbal treatment reduces depressive-like behaviors and increases BDNF levels in the brain of stressed mice

Abstract

Aims

Depression is a chronic, recurring and potentially life-threatening illness. Current treatments for depression are characterized by a low success rate and associated with a wide variety of side effects. The aim of the present study was to evaluate the behavioral and biological anti-depressant effects of a novel herbal treatment (NHT), as well as to assess its potential side effects, in comparison to treatment with the selective serotonin reuptake inhibitor escitalopram.

Main methods

Depressive-like behavior was evaluated using the forced swim test (FST) and the tail suspension test (TST). Sexual behavior was evaluated following treatment by measuring latency before first mount and number of total mounts. Brain derived neurotrophic factor (BDNF) levels were evaluated using enzyme-linked immunosorbent assay. Serotonin transporter (SERT) levels in the pre-frontal cortex (PFC) and hypothalamus were evaluated using high affinity binding assay.

Key findings

(1) The NHT reduced depressive-like behavior in the FST and TST; (2) BDNF levels in the PFC of mice treated both with the NHT and escitalopram were increased; (3) SERT levels in the hypothalamus were significantly higher in the NHT group, in comparison to escitalopram and the control groups, and significantly lower in the PFC of the NHT group in comparison to the escitalopram group; and (4) the NHT led to less sexual dysfunction, compared to treatment with escitalopram.

Significance

Our NHT has the potential of being highly efficacious in treating depression in humans, while causing minimal to no influence on sexual function.

Introduction

Depression is a chronic and potentially life-threatening illness, with a life prevalence of 20–25% of women and 10–17% of men (Levinson, 2006). Recent work has indicated that stress exposure may interact with genetic risk factors to increase susceptibility to depression (Caspi et al., 2003, Kaufman et al., 2006). The relation between stress and risk for depression has been documented for both acute (Kendler et al., 1998) and chronic stress (Hammen et al., 2009).

Finding adequate treatments for depression is of the utmost importance. There are several pharmaco-therapeutic approaches in the treatment of depression, including tricyclic drugs, monoamine oxidase inhibitors, serotonin–norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors (SSRIs). Nevertheless, these are characterized by a low success rate and associated with a wide variety of side effects (Lam and Kennedy, 2004).

The disadvantages of conventional pharmacological treatment have prompted the search for alternative treatments for depression. One such treatment is the use of herbal medicines. Studies have shown therapeutic potential of chronic treatment with several herbal medicines, such as St. John's Wort (Linde et al., 2008) and Kava (Witte et al., 2005), in various psychiatric disorders. Chronic treatment with such herbal medicines was shown to have antidepressant-like effect, to normalize brain transmitter levels (Simmen et al., 1999) and to increase brain derived neurotrophic factor (BDNF) levels (Hou et al., 2010, Li et al., 2009), similar to the effects seen following SSRI treatment. The exact mechanisms of action of the herbal compounds are still unclear, but the available research clearly shows that various bioactive constituents contribute to the clinical effects reported, often in a synergistic manner and with minimal or nonexisting side effects.

The present study has focused on two main goals: (a) evaluating the behavioral and biological anti-depressant effects of a novel herbal treatment (NHT) (U.S. PCT No. 61/311,537), in comparison to the conventional SSRI treatment, namely, escitalopram, and (b) assessing one of the main side effects of the conventional treatment, namely, sexual dysfunction, as a result of treatment with NHT in comparison to treatment with escitalopram. The NHT was prepared from the following four components: Crataegus pinnatifida, Triticum aestivu, Lilium brownie and Fructus zizyphi jujubae, as a modification of a classical Chinese formula used in the treatment of mental disorders since the 2nd century A.D. (Scheid et al., 2009). Previous studies have pointed at the behavioral and biological anti-depressant effects of the NHT components (Butterweck et al., 2001, Chen et al., 2012, Lin et al., 2003, Seely and Singh, 2007, Zhu et al., 2006). We (Doron et al., 2012) have previously found that this treatment displayed behavioral and biological anxiolytic effects in treated mice, compared to control mice and similar to the ones found following escitalopram treatment. In the present study we evaluated depressive-like behavior in adult mice exposed to stress during adolescence following three weeks of treatment with the NHT or escitalopram. The behavioral evaluation in these mice was followed by analysis of BDNF and serotonin transporter (SERT) levels in the brain. In addition, following three weeks of treatment with either the NHT or escitalopram, naïve and stressed mice were tested for one of the main side effects of SSRI treatment: sexual dysfunction.