​Antidepressant Activity And Metabolism Of Cistanche in Vivo And in Vitro

Abstract: Cistanche  is the dry fleshy stem with scaly leaves of Cisanche desericola Y.C.Ma or Cistanche tubulosa (Schenk) R.Wight. It is a famous tonic Chinese medicine. Modern pharmacological research has confirmed that Cistanche has significant neuroprotective effects, and its antidepressant effect has also been confirmed in recent years. However, the basis and mechanism of its antidepressant active substances have not yet been fully elucidated. Based on the traditional efficacy of Cistanche , we conducted anti-depressant activity and in vitro and in vivo metabolism studies. Here we summarize the research ideas to provide data and reference for the later development of drugs related to the antidepressant efficacy of Cistanche . 

Keywords: Cistanche , depression metabolic activity

HOW LONG DOES IT TAKE FOR CISTANCHE TO WORK?

Depression is a disease characterized by mood disorders. Its main symptoms include sadness, loss of interest, anhedonia, loss of appetite, guilt, low self-worth, sleep disorders, fatigue, poor concentration, etc. n1, and in severe cases, suicide Concepts and behaviors have become the disease with the highest suicide rate in psychiatry. According to statistics from the World Health Organization in 2017, there are an estimated 350 million patients with depression worldwide. By 2020, it will become the second largest disease in the world, with an incidence rate as high as 20%. Depression is a complex psychological disease caused by multiple factors including genetics, development, and living environment¨51. Among them, stress is considered to be the main cause of depressionI61.

At present, the main clinical drugs for the treatment of depression include tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors. These drugs generally have shortcomings such as narrow antidepressant spectrum, drug resistance, and high toxic and side effects. 1. Since the pathogenesis of depression is relatively complex and there are many inducing factors, it is often difficult for drugs that target a single link to achieve satisfactory efficacy. Therefore, , Domestic and foreign researchers are paying more and more attention to the development and application of natural drugs that are safer, more efficient, and have fewer side effects in the development of antidepressants" 2.1".

Cistanche deserticola Y. C． Ma Received date: 2018-06-10 Revision date: 2018-07-15 or Cistanche C. Dry scales of tubulosa (Schenk) Wight

The fleshy stem of the leaves [15.6] is a famous tonic traditional Chinese medicine. It was first recorded in "Shen Nong's Materia Medica" and is listed as top grade. It has the functions of nourishing kidney yang, replenishing essence and blood, moistening the intestines and laxative, etc., and is often used for kidney yang deficiency. , deficiency of essence and blood, impotence and infertility, soreness and weakness of waist and knees, weakness of muscles and bones, intestinal dryness and constipation. It is the most frequently used kidney-yang medicine in the past dynasties. Starting from its traditional efficacy, we explored the antidepressant activity of Cistanche and its in vitro and in vivo metabolism based on its chemical composition and related reports. This article summarizes and reviews this research idea to provide data and reference for the later development of drugs related to the antidepressant efficacy of Cistanche .

1 Antidepressant activity of Cistanche

At present, drugs for the clinical treatment of depression generally have shortcomings such as narrow antidepressant spectrum, drug resistance, and high toxic and side effects (gastrointestinal reactions, sexual dysfunction, headache, insomnia, and rash). Clinically used first-line antidepressants, such as venlafaxine and fluoxetine, have serious side effects such as cardiotoxicity, hypertension, sexual dysfunction, and sleep disorders. It is particularly worth noting that a study showed that 59.1% (604/1022) of patients who used antidepressants experienced toxic side effects of sexual dysfunction, and about 40% of patients with depression reported that antidepressants caused Sexual dysfunction is considered an unacceptable side effect, seriously affecting drug compliance. Among them, norepinephrine reuptake inhibitors and serotonin reuptake inhibitors have the highest incidence of sexual dysfunction1'221.

Therefore, in view of the current clinical treatment methods for depression and the shortcomings of existing drugs, Cistanche , as the most frequently used kidney-yang-tonifying drug in the past, will have great research significance and application value.

1.1 Traditional efficacy and antidepressant activity of Cistanche

Cistanche has a long history of use and has been recorded in herbal medicine throughout the ages. Records about the medicinal properties and efficacy of Cistanche first appeared in the "Shen Nong's Materia Medica", which is listed as top grade. It states: "Cistanche has a sweet taste and is slightly warm. It can treat five kinds of labor and seven injuries. It can nourish the middle, remove cold and heat pain in the stem, nourish the five internal organs, and strengthen yin. It replenishes essence and Qi, leads to more children, and makes women addicted to it. If it is taken for a long time, it will lighten the body." Xin 31. "Treatise on Medicinal Properties" contains: "Cistanche can benefit the marrow, please the color, prolong life, treat women's hemorrhage, aphrodisiac, and can benefit twice as much as the sun. It is mainly used for redness and whiteness, tonify essence failure, dark complexion, and labor injuries." "Illustrations and Materia Medica" records: "Cistanche is often used as food by Westerners. Scrape off the scales, wash with wine, remove the black juice, cut into thin slices, and mix with potato and mutton to make soup. It is very delicious and beneficial to people. It is a good food. Take tonic"∞,. "Compendium of Materia Medica" records that Cistanche "replenishes the fire of the gate of life, nourishes the five internal organs, replenishes the marrow and strengthens the muscles" [261]. The 2015 edition of "Chinese Pharmacopoeia" records: "Sweet, salty, warm. Returns to the kidney and large intestine meridian. Replenishes kidney yang, replenishes essence and blood, moistens the intestines and relieves constipation. It is used for insufficient kidney yang, deficiency of essence and blood, impotence and infertility. Soreness and weakness in the waist and knees, weakness of the muscles and bones, dryness of the intestines and constipation."

"Shen Nong's Materia Medica" first records that Cistanche can "treat the five labors and seven injuries", and the five labors and seven injuries include "anger injuring the liver, overworking the mind injuring the mind, and fear injuring the will", etc. "Compendium of Materia Medica" There are also descriptions of Cistanche in treating neurasthenia and impotence [281], indicating that the traditional effects of Cistanche include antidepressant effects. Therefore, Cistanche has been recorded in ancient times for treating depression and other neurological diseases.

1.2 Chemical composition and antidepressant activity of Cistanche

Research on the chemical composition of Cistanche began in the early 1980s. Studies have confirmed that Cistanche mainly contains phenylethanol glycosides, iridoids and their glycosides, lignans and their glycosides, phenyl alcohol glycosides, sugars Alcohols, oligosaccharides and polysaccharides, volatile oils and other ingredients. To date, more than 100 compounds have been discovered in Cistanche , including 120 species of desert Cistanche and 75 species of tubular Cistanche . With the development of science and technology and the in-depth exploration of the efficacy of Cistanche , research on the efficacy and pharmacological activity of Cistanche has made a series of progress in recent years. Modern pharmacological activity studies have confirmed that Cistanche has neuroprotective effects. 0.34,. In particular, "Cistanche total glycosides" capsules, which are mainly composed of phenylethanol glycosides in Cistanche , are used in the clinical treatment of Alzheimer's disease. 51. Phenylethanoid glycosides can exert anti-Parkinsonian effects by increasing the expression of tyrosine hydroxylase in the substantia nigra and the content of dopamine (DA) in the striatum. The "monoamine transmitter imbalance hypothesis" of the pathogenesis of depression believes that reduced synthesis and release of neurotransmitters such as DA in the brain is one of the pathogenesis of depression -36,371.

Therefore, the phenylethanol glycosides in Cistanche may have antidepressant activity. In addition, iridoid glycosides are one of the main chemical components of Cistanche . Among the iridoid glycosides, catalpol and genipin have been confirmed to have an effect on improving depression [38.91. Therefore, we speculate that Cistanche may have some antidepressant activity.

1.3 Animal Experimental Study on the Antidepressant Activity of Cistanche

According to reports (4), phenylethanoid glycosides from Cistanche can regulate depressive-like behaviors in perimenopausal syndrome in mice. The mechanism may be by regulating estrogen disorders in the model mice, thereby improving monoamine neurotransmitters in the brain. level. Wang et al. III] found that Cistanche water decoction can improve the cumulative immobility time of mice in the tail suspension test and has good antidepressant activity. Our research shows that ∞1, Cistanches tubulosa can significantly improve the depressive-like behavioral characteristics of mice in a desperate environment model; continuous administration of Cistanches tubulosa extract can significantly improve the effects of chronic unpredictable stimulation.

Depression model rats show depressive-like behavioral characteristics in behavioral tests such as forced swimming, sucrose preference, open field test, and eating inhibition in new environments. Further separation and screening of Cistanche extract found that 1"l, Fr. 2 parts can significantly reduce the cumulative immobility time in the tail suspension test of mice, and are more active than other polar parts. The main components of Fr. 2 parts include There are 3 iridoid glycosides, 2 phenylethanoid glycosides and 2 phenolic glycosides, among which the iridoid glycoside components 6-deoxycatalpol and 8-epiloganic acid have the highest content [3813 91, ring]. The ether terpenes catalpol and geniposide both have antidepressant activity, and 6-deoxycatalpol (6-deoxycatalp01) present in the Fr. 2 part is a structural analog of catalpol, 8-epiloganic acid and gluroside It is a structural analog of geniposide, suggesting that iridoid glycosides may be one of the antidepressant substances of Cistanche tubulosa. In addition, Fr. 2 also contains some phenylethanoid glycosides. The antidepressant activity of Cistanche extract is higher than the antidepressant activity of its polar parts, suggesting that Cistanche tubulosa may also produce antidepressant activity through the synergistic effect of each polar part. This result needs to be further confirmed. Follow-up research needs to further isolate the chemical components of Cistanche and evaluate its antidepressant efficacy.

1.4 Research on the antidepressant activity mechanism of Cistanche

Although the antidepressant activity of Cistanche has been confirmed, the basis and mechanism of its active substances have not been fully elucidated. Our research shows that Cistanches tubulosa extract can significantly increase the expression of 5-HT and BDNF in the hippocampus of depression model rats, increase the expression of 5-HT in the colon, and significantly improve hippocampal neuronal cells in rat brain tissue. atrophy and has a protective effect on nerve cells. It is reported that catalpol, an iridoid glycoside component, can also improve depression by restoring HPA axis dysfunction and up-regulating the expression of brain derived neurotrophic factor (BDNF). Geniposide can improve depression through Modulating the HPA axis to achieve antidepressant effects -8'39,. These results suggest that iridoids may be one of the bases for the antidepressant activity of Cistanche . Cistanche extract may increase the content of 5-HT in the body by stimulating the synthesis of 5-HT in the colon, thus

Increase the expression of 5-HT in the brain and improve the protective effect of BDNF on brain nerve cells to achieve anti-depressant purposes. However, the relevant molecular mechanism of the antidepressant pharmacological activity target of Cistanche is still unclear, such as which neurotransmitters regulate receptors and neurotrophic factors regulate the receptors.

The relevant role played by the body remains to be further studied.

In recent years, a large number of studies have confirmed that intestinal flora can affect the physiological functions, emotions and behavioral characteristics of the central nervous system by affecting the "gut-brain axis". It has been reported that H2.31 has a close relationship between depression and the "gut-brain axis". Changes in intestinal flora are most likely to affect the immune system and the hypothalamic-pituitary-adrenal (HPA) axis. ), neurotransmitter signaling and other mechanisms to affect depression. Our study also proved that Cistanche tubulosa can regulate the disordered intestinal flora and intestinal flora metabolite short-chain fatty acids in rats with depression caused by chronic unpredictable stimulation.

The production of intestinal flora restores the structural stability of the intestinal flora. Correlation analysis found that Cistanche tubulosa improves the intestinal flora of rats with depression and is related to its improvement of depression-related indicators, indicating that Cistanche tubulosa extract may disturb the brain's single cells by changing the structure and composition of the intestinal flora. Amine neurotransmitters, neurotrophic factors in the brain, colonic serotonin, and changes in the production of short-chain fatty acids to achieve antidepressant purposes.