Cistanches Herba: A Neuropharmacology Review

Cistanches Herba: A Neuropharmacology Review

Cistanche extract products (family

Orobanchaceae), commonly known as “desert ginseng” or Rou Cong Rong, is a global genus and commonly used for its

neuroprotective, immunomodulatory, anti-oxidative, kidney impotence, laxative, anti-inflammatory,

hepatoprotective, anti-bacterial, anti-viral, and anti-tumor effects in traditional herbal formulations in North

Africa, Arabic, and Asian countries. The major bioactive compound present in this plant is phenylethanoid

glycosides. In recent years, there has been great important in scientific investigation of the

neuropharmacological effects of the bioactive compounds. The in vitro and in vivo studies suggests these compounds

demonstrate neuropharmacological activities against a wide range of complex nervous system diseases which occurs

through different mechanisms include improving immunity function and kidney aging, anti-lipid peroxidation,

scavenging free radical, inducing the activation of caspase-3 and caspase-8. This review aims to summaries the

various neuropharmacological effects and mechanisms of Cistanches Herba extracts and related compounds, including

its efficacy as a cure for Alzheimer’s disease and Parkinson’s disease with reference to the published

literature. Which provides guidance for further research on the clinical application of Cistanches Herba.

    Introduction

    Cistanches Herba, the dried stem of Cistanches species Cistanche deserticola Y.C.Ma (Figure 1) and

Cistanche raw materials, is recorded in the Chinese Pharmacopeia

(Committee, 2015). Other non-official species, such as C. sinensis Beck and C. salsa (C. A. Mey) Beck, are also

used as Cistanches Herba in certain regions of China due to resource shortage. Cistanches Herba is one of the most

valuable herbal drugs in traditional Chinese medicine, which supplements kidney functions, boosts the essence of

blood, and moistens the large intestines to free stool (Medicine, 2005). Therefore, it is called “desert ginseng

” in China because of the excellent medicinal functions and nourishing effects (Wang et al., 2012). Cistanches

Herba, a global genus of holoparasitic desert plant, which is primarily endemic in North Africa, Arabic, and Asian

countries (Nan et al., 2013). The primary producing areas of Cistanches Herba in China are Inner Mongolia and the

provinces of Xinjiang, Gansu and Qinghai.

    Several chemical groups were isolated from Cistanches Herba, including PhGs (Figure 1), lignans, iridoids, and

polysaccharides (Chen et al., 2013). Pharmacological studies demonstrated that Cistanches Herba exhibits

neuroprotective, kidney impotence, laxative, anti-inflammatory, hepatoprotective, immunomodulatory, anti-

oxidative, anti-bacterial, anti-viral, and anti-tumor effects (Hu and Feng, 2012). And our previous studies have

distinguished Cistanches Herba from different geographic origins using a combination of DNA barcoding and UPLC-Q-

TOF/MS technology.

    The Consumer Price Indexdatabase of China reports that 58 drugs from 12 different groups, including glycosides

of Cistanche capsules and compound Cistanche Yizhicapsules, are authorized for the treatment of AD. Cistanches

Herba wine and tea are produced in Alashan, Inner Mongolia, China, which might assist in Runchang catharsis and

enhance the immune, endocrine regulation, and anti-aging systems of the body. Boschnalosides used as a therapeutic

agent in Japan to treat sexual dysfunction and amnesia, and echinacoside is used in healthcare products in the

United States to improve immunity (Cheng et al., 2005).

    Some researchers recently focused on the neuroprotective effects of

Cistanche health products, but these effects have

not been studied thoroughly (Table 1). This review presents and analyzes recent developments in the

neuropharmacology of Cistanches Herba and provides a reference for the further study and clinical application of

this medicinal plant.

    Cistanches Herba medicines have a long history of practical use, but scientists worldwide only began to

disclose their chemical composition in the1980s. Figure 2 shows an analysis of the related literature. The

cumulative histogram shows the number of studies increased over time, and the Chinese literature occupies the

greatest proportion, which reveals the potential research value of Cistanches Herba. Figure 2A shows that the

neuropharmacology related literature occupies the largest proportion of the nine areas of pharmacology, and this

topic has become the most important area for research. Figure 2B exhibits the chemical research diversity of

Cistanches Herba, with a substantial proportion of research on content determination. Further research may focus

on neuropharmacology and component content.

    Cistanches Herba has a long history as a medicinal plant in China and Japan because of its wide spectrum of

pharmacological activities. It is commonly called Rou Cong Rong in Chinese, and it was first listed medicinal use

as a tonic agent in the Chinese Materia Medica Shen Nong’s Herbal Classic (Estern Han Dynasty) 2000 years ago,

and later recorded in Yao Xing Lun in 1590. The Compendium of Materia Medica (Ben Cao Gang Mu, 1619) documented

that Cistanches Herba invigorated the kidney to treat kidney deficiencies and geriatric constipation strengthened

and nourished marrow and essence, protected semen, and moistened dryness to relax the bowels. 

    These properties were also written in Ben Cao Hui Yan in 1619. A total of 200 medicinal books recorded the

pharmacodynamics and use of Cistanches Herba in Chinese history. Cistanches Herba ranks first in Chinese

traditional medicine to strengthen prescriptions, which ranks second in anti-aging prescriptions at the same time,

behind Panax ginseng in past dynasties. Modern pharmacological investigations demonstrated that Cistanches Herba

was used as a kidney-yang reinforcing Chinese medicinal tonic, but it is also exhibits anti-aging, improves

memory, and enhances immunity effects (Table 1), which indicate that extracts or constituents from Cistanches

Herba have a promising future for the treatment of diseases, particularly nervous system disorders. However,

systematic data on the pharmacological activities of this agent is lacking. It is urgent and important to study

the pharmacological effects and mechanisms of Cistanches Herba deeply in the future.

    Aging is an inevitable process of life. This process involves a series of degenerative changes in tissues and

organ functions with advancing age. Studies on aging and anti-aging medicines have made significant progress in

recent years. Therefore, anti-aging drugs are a current and prominent issue in gerontology. The aging process

reflects a confluence of in vivo and in vitro factors. Aging is closely related to type 2 diabetes,

atherosclerosis, and AD. Aging is also related to the decreased regeneration of cells, viscera deficiency,

increased free radicals, body poisoning, and lack of rhythm when eating (Lopez-Otin et al., 2013). Aging is an

inevitable process, but delaying this process is now possible.

    Several historical Chinese herbal pharmacopeias describe that Cistanche tubulosa supplements possesses anti-aging

properties. PhGs and oligosaccharides are two types compounds isolated from Cistanches Herba that are the main

active ingredients of this plant. In vivo studies established an aging mouse model caused by D-galactose. The mice

were divided into normal control, model, Vitamin E and total glycoside groups, and all groups received different

doses of various materials. The results suggested that the glycosides exhibited protective effects on the

hippocampal ultrastructure, and glycosides may play a role in the delay of aging and the prevention and treatment

of senile dementia via anti-oxidation (Wang X. et al., 2015). Xu et al. investigated the protective effect of

Cistanches Herba alcohol extract on hepatic mitochondria and established an aging rat model caused by D-galactose.

Rats were administered Cistanches Herba alcohol extract for 6 weeks. The results indicated that Ca2+-ATP enzyme

activity was enhanced, and the MDA content in the hepatic mitochondria was reduced. These results further

suggested that the Cistanches Herba alcohol extract effectively protected hepatic mitochondria in the D-galactose

aging rat model (Xu et al., 2007). Xu and Liu (2008) examined the anti-aging effect of PhGs isolated from

Cistanches Herba. The results confirmed that the PhGs improved learning and memory, exhibited antioxidant

activity, and boosted the immune system. The results also demonstrated that the PhGs exhibited anti-aging effects

via enhancement of anti-oxidation. The mechanism may be related to the free radical scavenging ability of PhGs.

Polysaccharides of Cistanches Herba exhibit the same function as PhGs on anti-aging (Xu et al., 2008; Zhang et

al., 2011). Zhang et al. (2014) also investigated a Cistanches Herba extraction 2014 and found that this extract

extended life span. The results of studies on echinacoside and acteoside suggest that these components exhibit

positive anti-aging effects (Zhang et al., 2008; Xie et al., 2009). Many studies of anti-aging involve Cistanches

Herba, but these works are limited because the anti-aging mechanism is not known. There are three possible

pathways to anti-aging, including improving immunity function and kidney aging, anti-lipid peroxidation. Immune

theory of aging said that the decline of immune function is closely related to the aging organism. Thus, the

immune function of the body can indirectly reflect the aging organism in a certain extent. The raised index of

thymus and spleen, increased content of IFN-γin serum and decreased content of IL-6, increased capacity of

peritoneal macrophage phagocytic and lymphocyte proliferation response always can improve the immunity aging, and

then delay the organism aging. The expression of p53 from human fibroblastic cell down-regulated significantly in

a dose dependent manner after treatment with echinacoside, and which may be correlated with the up-regulation of

SIRT1. The PhGs can scavenge different ROS, including. O–2, H2O2 and ?OH, effectively and protect DNA damage

through scavenging ?OH. In addition, the PhGs also can increase the content of RNS- NO, and then reduce the lipid

peroxidation. Therefore, the real effective components of Cistanches Herba and what a role in anti-aging are

important and appealing future research directions.

    Anti-oxidative and Anti-apoptotic Activity

    Cistanches Herba exhibits anti-oxidative, free radical-scavenging and anti-apoptotic activity via different

mechanisms. Recent studies demonstrated the anti-oxidant activity of Cistanches Herba, particularly in the

clearing of all types of free radicals in vivo and in vitro, improvement in the activity of anti-oxidant enzymes

in the body, and inhibition of the formation of lipid peroxide, MDA, and brown fat (Wang et al., 2001; Wu and Fu,

2004; Luo et al., 2012; Song, 2013). Current studies demonstrated that cell apoptosis or programmed cell death is

determined by heredity and is related to oxidation (Martin, 2011). Deng used the MTT assay to examine cell

survival rate, agarose gel electrophoresis of DNA, and flow cytometry to detect cell apoptosis. The results

suggested that the echinacoside extracted from Cistanches Herba exhibited protective effects on TNFα-induced SH-

SY5Y cell apoptosis (Deng et al., 2005). Nerve cell protection exhibits a close connection with the reduction of

active oxygen levels in cells, inhibition of caspasc-3 activity and maintenance of a high-energy state of

mitochondrial membrane potential. Bao et al. (2010) investigated an extract of Cistanche tubulosa and discussed

its anti-oxidant ability. These researchers conducted an in vitro study to compare the anti-oxidative properties

of methanol and ethanol extracts. The results suggested that the two extracts exhibited high anti-oxidant ability,

and 70% ethanol was the best extraction agent of C. tubulosa to ensure improved anti-oxidant activity (Bao et al.,

2010). The PhGs from Cistanches Herba are considered the effective ingredients for anti-oxidative and anti-

apoptotic activity in recent studies. The anti-oxidant mechanism is mainly related to the radical-scavenging

activity. PhGs compounds, which are mostly provided with different amounts of phenolic hydroxyl, can be used as

hydrogen donor to reductive radicals, and then reach to the purpose of radical scavenging. The

herbal cistanches

extract powder scavenge the free radicals mainly in two ways, including directly involving in the removal of

free radicals or blocking their production and regulating the anti-oxidant enzymes related to the free radical

metabolism in vivo, such as SOD, CAT and GPX (Ko and Leung, 2007). For another, the Glycosides of Cistanches Herba

can prevent the apoptosis of cerebellar granule neurons by inhibiting the activities of caspase-3 and caspase-8.

Therefore, the good oxidation resistance and anti-aging ability of Cistanches Herba may be applied to cosmetics.

This application may be a new research direction in the future.

    Learning and Memory Enhancement

    Learning and memory are advanced functions of the brain, and these functions are important factors in

determining intelligence. Learning and memory impairment is a common symptom in different types of encephalopathy,

such as attention deficit and hyperactivity disorder in childhood, adolescent chorea, lobar atrophy disease,

neurosis, senile cerebral arteriosclerosis, and dementia. Medicinal research demonstrated that the impairment of

learning and memory is closely related to the impairment of synaptic transmission in the brain and the metabolism

of neurotransmitters, other substances, and energy in the brain (Chen, 1993). Modern pharmacological studies

determined that Cistanches Herba significantly improves learning and memory, and PhGs are the active chemical

ingredients of this effect.

    Traditional Chinese medicine shows that learning and memory dysfunction exists in the Yang deficiency model of

the spleen and kidney. Therefore, these two models are more suitable for the study of tonics in traditional

Chinese medicine. Gao et al. (2005) examined the effects of Cistanches Herba glycosides on the learning and memory

of kidney Yang deficiency mice. The results of this study demonstrated that the Yang deficiency symptoms of each

dose group improved, and the number of animal deaths decreased significantly. However, the jumping latency of each

dose group after hydrocortisone administration was significantly prolonged, and the number of errors during a 5-

min period was reduced. Therefore, glycosides improved the learning and memory of kidney Yang deficiency mice

induced by hydrocortisone and reduced the death rate of these animals (Gao et al., 2005). The current researchers

established a scopolamine-induced learning and memory impairment mouse model to investigate the effects of the

PhGs of Cistanches Herba. The results demonstrated that the PhGs of Cistanches Herba enhanced learning and memory

(Li, 2011; Liu et al., 2011). Choi et al. (2011) also demonstrated that Cistanches Herba enhanced learning and

memory via the induction of nerve growth factor. Vary factors related to cerebrovascular disease induce vascular

dementia. This condition is an acquired intelligence-damaging syndrome of cognitive impairment, which is a primary

type of senile dementia. Ischemic cerebrovascular disease occurs frequently in many cerebrovascular diseases

induced by vascular dementia. Traditional medicine and modern pharmacology demonstrated that PhGs play an active

role in neuroprotection (Feng et al., 2013; Liu et al., 2013; Zhu et al., 2013; Zhang, 2014). The reason why

Cistanches Herba extract can improve learning and memory is partly due to neuronal cell differentiation, neurite

outgrowth and presynaptic formation promoted. Cistanches Herba also improved cognitive behavior related to memory

ability. Therefore, Cistanches Herba is a potential candidate for cognitive enhancement owing to its action as a

nerve growth factor modulator. However, extensive research is necessary to discover the neuroprotective mechanism

deeply. Further studies to determine the specific type of PhGs are expected to play a leading role in improving

learning and addressing memory impairment.