Anti-depressant effects of Gastrodia elata Blume and its compounds gastrodin and 4-hydroxybenzyl alcohol, via the monoaminergic system and neuronal cytoskeletal remodeling

Abstract

Ethnopharmacology relevance

Gastrodia elata Blume is a highly valuable traditional Chinese medicine used in the treatment of depression. However, compounds with antidepressant effects in water extracts of G. elata Bl. (WGE) have not been identified. The aims of this study were to determine the major antidepressant compound in WGE and to evaluate the antidepressant effects of WGE and its active compounds which involved the monoaminergic system and neuronal cytoskeletal remodeling.

Materials and methods

Gastrodin (GAS) and 4-hydroxybenzyl alcohol (HBA) in WGE, were analyzed with high-performance liquid chromatography (HPLC)-ultraviolet detection.

The forced swimming test (FST) was used to induce depression-like symptoms in 9 weeks old male Sprague-Dawley rats. The open field test (OFT) was used to measure anxiety after WGE, GAS, and HBA treatments. The levels of monoamine such as serotonin (5-HT), dopamine (DA), and their metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured using HPLC-electrochemical detection. Western blotting was used to examine the 5-HT1A receptor and the neuronal cytoskeleton remodeling-related proteins, Slit, dihydropyrimidinase-related protein 2 (DPYSL2, also called CRMP2), Ras homologous member A (RhoA), and profilin 1 (PFN1) in vivo. Slit1 expression was evaluated in Hs683 cell line after treated with WGE (0.5 mg/mL), GAS (50, 100 and 100 μM), and HBA (50, 100 and 100 μM).

Results

Oral administration of WGE (500 mg/kg bw), GAS (100 mg/kg bw), and HBA (100 mg/kg bw) exhibited the anti-depressant effect by significantly reducing the immobility time in FST, monoamine metabolism including the 5-HT to 5-HIAA in the hippocampus and DA to DOPAC and HVA ratios in the frontal cortex, amygdala, and hippocampus. In the hippocampus, the expression of the neuronal cytoskeleton remodeling-related negative regulators Slit1 and RhoA were significantly down-regulated. In addition, the positive regulators CRMP2 and PFN1 were significantly up-regulated following GAS, HBA, and WGE treatments. Moreover, WGE, GAS, and HBA were directly down-regulated Slit1 expression in Hs683 cells.

Conclusion

WGE, GAS, and HBA exhibited potential anti-depressant effects in rats by decreasing monoamine metabolism and modulated cytoskeleton remodeling-related protein expression in the Slit-Robo pathway. These results suggest that WGE can be used as agent for depressive prevention.

Introduction

Major depression disorder (MDD) is a human psychiatric disease (Goldberg and Huxley, 1992) that affects more than 350 million people worldwide and results in a significant burden and disruption in the daily lives of patients (World Health Organization, 2012). MDD strongly correlates with suicide attempts (Chen and Dilsaver, 1996, Placidi et al., 2001), and the World Health Organization predicts that MDD will result in the highest global disease burden by 2030 (Mathers et al., 2008). Some studies have attempted to increase neuroplasticity or ameliorate neurotransmitter dysfunction to improve the depression symptoms of patients with MDD (Pittenger and Duman, 2008, Delgado, 2004, Castrén, 2005).

In earlier study, neurocytoskeletal remodeling (also called neurocytoskeletal rearrangement) and neuroplasticity showed a strong association with depression (Piubelli et al., 2011). Neuroplasticity, a fundamental mechanism of neuronal adaptation, strengthens synaptic signals through the regulation of neurotransmission, including receptor subunit phosphorylation and surface expression, intracellular signaling cascades of pre- and post-synaptic proteins, and regulation of the expression of genes implicated in growth, survival, and synaptic transmission. The function of neuroplasticity is disrupted in mood disorders and in animal models of stress (Pittenger and Duman, 2008). It is believed to be important for cellular resilience and mood stabilization in clinical trials (Pittenger and Duman, 2008, Soeiro-de-Souza et al., 2012).

The monoamine hypothesis of depression suggests that mood disorders are caused by neurotransmitter imbalances in the brains of patients as shown in those attempting suicide (Asberg et al., 1987). Some antidepressants have been developed to maintain the monoamine concentration in the brain (Delgado, 2004, Castrén, 2005). However, several undesired side effects, such as sleep disorder, gastrointestinal effects, nausea, vomiting, and weight change, are induced by antidepressant drugs (Khawam et al., 2006). Thus, most patients with depression tend to avoid medical therapies (Gonzalez et al., 2005).

Many traditional herbal medicines contain a wide variety of phytochemicals that prevent or ameliorate many diseases, including cancer, cardiovascular diseases, diabetes, and neurodegeneration. Fewer side effects are known to result from phytochemicals of traditional herbal medicines that have been used for hundreds or thousands of years. Therefore, elucidating the active compounds in phytomedicines will be helpful for developing an alternative therapy to treat depression.

Gastrodia elata Blume (Tian-ma) is a common Chinese medicinal herb that has been recorded to have various pharmacological effects including promoting blood circulation, improving psychosomatic illness, and ameliorating neural disorders (Chen and Sheen, 2011). In addition, G. elata Bl. is considered a food ingredient in Taiwan, and is commonly consumed with food to ameliorate headaches, dizziness, and convulsions. G. elata Bl. has also been reported to act as an anti-inflammatory (Hwang et al., 2009), anti-convulsant (Hsieh et al., 2001), antioxidant (Liu and Mori, 1992), antiepileptic (Ojemann et al., 2006, Hsieh et al., 2007), memory enhancer (Chen et al., 2011), and a neuroprotective agent against Parkinson's disease (An et al., 2010), ischemic damage (Kim et al., 2003), and amyloid β-induced cell death (Mishra et al., 2011). In summary, these studies suggest that G. elata Bl. is a potential candidate for ameliorating neurodegeneration.

In our previous studies, the water extract of G. elata Bl. (WGE) improved depressive symptoms in rats by decreasing monoamine metabolism and down-regulating the Slit-Robo pathway processes (Chen et al., 2009, Lin et al., 2014). Because gastrodin (GAS; p-hydroxymethylphenyl-β-D-glucopyranoside) and 4-hydroxybenzyl alcohol (HBA) are active components of WGE, both compounds have been used for neuroprotection (Zeng et al., 2006, Peng et al., 2015, Yu et al., 2005, Kim et al., 2012), memory improvement (Hsieh et al., 1997, Wang et al., 2014), epilepsy prevention (An et al., 2003), and oxidant protection (Jiankang and Akitane, 1993, Park et al., 2010). Although the functions of GAS and HBA have been described, the antidepressant effects of GAS and HBA from WGE remain unknown. Our previous studies showed that WGE could ameliorate depression symptoms in rats in the forced swimming test (FST) through monoaminergic neurotransmitters and neuroplasticity (Chen et al., 2009, Lin et al., 2014). In this regard, we further evaluated the anti-depressant effects of GAS and HBA in the brain of rats by investigating the effects of those compounds on monoamine metabolism and neuronal cytoskeleton remodeling.