Research Progresson The Mechanism Of Cistanche in The Treatment Of Alzheimer's Disease

WU Xiao-rong1,2；YANG Zhan-jun1,2；YAN Xu-sheng1,2；JIA Jian-xin1,2* 

( 1.Baotou Medical College of Inner Mongolia University of Science and Technology，Baotou 014000，China; 2.Department of Human Anatomy, Baotou Medical College of Inner Mongolia University of Science and Technology）

Abstract: 

Herba cistanches deserticola, also known as golden bamboo shoots, goblins, commonly known as cistanches, is a dry, fleshy stem with scaly leaves of Cistanche, a plant of the genus Cistanche in the orobanceae. It has the effects of Tonifying Kidney Yang, benefiting essence and blood, moistening intestines and defecating, and is a famous tonic traditional Chinese medicine. Modern pharmacological studies have confirmed that Cistanche deserticola and its extract have significant neuroprotective effects and can be used to prevent and treat neurodegenerative diseases such as alzheimer's disease (AD), parkinson's disease (PD), huntington's disease (hd), amyotrophic lateral sclerosis (ALS). 

Cistanche extract powder-Anti Alzheimer's disease

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Ad is a common chronic disease, which mainly occurs in the middle-aged and elderly population. With the aging of the population, the burden of the disease is becoming more and more serious. At present, there is little systematic evaluation on the prevention and treatment of AD by Cistanche deserticola and its extract. Existing experimental studies have found that Cistanche deserticola and its extracts not only have anti-inflammatory, anti-oxidation, anti neuronal damage, immune regulation and mitochondrial protection functions, but also have good hypoglycemic activity, which can participate in the physiological regulation of intestinal flora, autophagy, sex hormones and so on. The study on the mechanism of action and therapeutic targets of Cistanche deserticola and its extract in ad will provide new therapeutic ideas for clinic, which is of great significance. This paper reviews the extensive biological activities of Cistanche deserticola and its extracts, comprehensively reviews the possible mechanism of action of Cistanche deserticola and its extracts in the prevention and treatment of AD, and puts forward some prospects.

Key Words: Cistanche deserticola; Alzheimer's disease; Mechanism

Alzheimer's disease (AD), also known as Alzheimer's disease, is a common degenerative disease of the central nervous system. Its main clinical manifestations include memory, speech, and intellectual impairment, as well as various noncognitive neuropsychiatric symptoms. In severe cases, patients may lose their ability to live. The main pathological features of AD patients are amyloid plaque deposition, neuronal fiber tangles, and changes in tau protein phosphorylation [2].

The current hypotheses about the pathogenesis of AD include the hypothesis of amyloid-like proteins and microtubule-related proteins, the hypothesis of cholinergic damage, the hypothesis of gene mutation, the hypothesis of free radical damage, and the hypothesis of inflammation [3]. However, the pathogenesis of most AD patients is not yet clear. AD mainly occurs in middle-aged and elderly people. According to the 2019 World Alzheimer's Disease Report, the global number of AD patients has reached 50 million [4], and AD has become one of the most common neurodegenerative diseases in middle-aged and elderly people. With the increasingly prominent problem of population aging, the incidence rate of AD will gradually increase, and it will become one of the major diseases threatening human health in the future society. Currently, the drugs used to treat Alzheimer's disease are mostly Western medicine, which can only improve the patient's learning and cognitive function appropriately and cannot prevent the progression of the disease. Therefore, it is still necessary to search for AD treatment drugs with low side effects and strong persistence. Unlike Western medicine, traditional Chinese medicine has accumulated over thousands of years of sedimentation and has advantages such as wide sources, good safety, fewer side effects, and suitability for long-term administration. Especially in the treatment of chronic and refractory diseases, it is superior to other drugs [5,6].

Cistanche deserticola is a parasitic plant that mainly adheres to the roots of some sand-fixing plants. Traditional Chinese medicine believes that Cistanche deserticola has the effects of tonifying the kidney, nourishing qi, moistening the intestines, and relieving constipation. After drying or drying, it is cut into thin slices and can be used to treat symptoms such as impotence, ejaculation, infertility, waist and knee fatigue, and chronic constipation. In vitro and in vivo experiments have shown that the stems, roots, and extracts of Cistanche deserticola have a wide range of biological activities, including regulating immune function, antioxidant, anti-apoptotic, anti-inflammatory, anti-fatigue, and neuroprotective effects [8-11]. In recent years, the neuroprotective effect of this drug has become a focus of researchers' attention. Existing studies have confirmed its effectiveness in alleviating AD symptoms [12,13], and its low side effects indicate that Cistanche deserticola is a very promising anti-dementia drug.

Effects Of Cistanche-Anti Alzheimer's disease

At present, there is little in-depth research on Cistanche deserticola. In order to gain a more comprehensive understanding of the therapeutic effect of Cistanche deserticola on Alzheimer's disease, this article reviews the mechanism of Cistanche deserticola and its extracts in the prevention and treatment of Alzheimer's disease, as well as the application prospects of this treatment method.

1. Antioxidant and anti-inflammatory

The interaction between oxidative stress and neuroinflammatory response is a key factor in the occurrence of neurodegenerative diseases. Recent studies have shown that there are significant changes in oxidative markers in the brain of AD patients, and inflammatory factors are closely related to their progression [14,15]. In a study of spinal cord injury rats, it was found that supplementing with Cistanche deserticola extract oligosaccharides resulted in tumor necrosis factor- α （Tumor necrosis factor， TNF- α）、 The levels of inflammatory markers such as interleukin-6 (IL-6) were significantly reduced [16]. Wang et al. found that oligosaccharide monomers may downregulate MAPK and NF in macrophages stimulated by the lipopolysaccharide (LPS)- κ B signaling pathway to the attenuate inflammatory response. Most extracts of Cistanche deserticola have scavenging effects on oxygen free radicals, and phenylethanolamine glycosides (PhGs) isolated and purified from Cistanche deserticola are considered the main bioactive components. Many studies have shown that PhGs have a wide range of biological effects, including antibacterial, anti-inflammatory, and neuroprotective effects [18,19]. PhGs or anthocyanins (VB) can protect A by antioxidants and reducing the ratio of Bax/Bcl2 β Memory deficits or neuronal damage caused by [20-22]. In addition, echinacea (ECH), an extract of Cistanche deserticola, can inhibit the production of reactive oxygen species in diabetes rats, and reduce cholesterol, triglycerides, and TNF- α And IL-6 levels, while improving lipid peroxidation and insulin resistance levels in rats [23].

Desert ginseng-Anti-Inflammatory

Oxidative stress is considered to be an imbalance between the body's oxidative process and antioxidant defense. The brain is highly susceptible to oxidative stress, which can occur early in AD patients, and excessive production of free radicals can lead to A β The accumulation of tau protein, which is a hallmark of AD, utilizing the scavenging effect of Cistanche deserticola and its extract on oxygen free radicals to regulate oxidative stress will be a new target for treating AD.

2 .Neuroprotection

Neuron damage can lead to learning and cognitive impairment, decreased memory, and emotional changes. Neurons have the ability to self-repair, and as they age, their ability to repair decreases, causing progressive damage to neurons, and leading to AD. Yin et al. [24] found that the effective component of Cistanche deserticola polysaccharides (CDPS) in the study of the neuroprotective effect of Cistanche deserticola on Parkinson's model rats can enhance rats' autonomous activity, improve clinical symptoms, and significantly upregulate Wnt1 and Wnt1 in the substantia nigra β- The expression of catenin, while GSK-3 β The expression of is inhibited. The author speculates that CDPS may activate Wnt/ β- Catenin signaling pathway, inhibiting GSK-3 β Activate and exerting dopamine neuroprotective effects. In another study, a team found that Cistanche glycoside (GC) can promote learning and memory function in vascular dementia rats by inhibiting the neurotoxic effect of amyloid protein [25, 26]. In addition, this study also found that compared with the vascular dementia group, the expression of cytokeratin (KRT6A) in the GC treatment group was significantly reduced, and mitochondrial precursor protein inhibited the production of oxygen free radicals, which suggested that GC may play a key role in the formation of synaptic cytoskeleton morphology and mitochondrial energy metabolism.

Desert living cistanche-Anti Alzheimer's disease

Recent studies have shown that PhGs can improve the learning and cognitive function of AD rats by blocking amyloid protein deposition, increasing acetylcholine and choline acetyltransferase expression, and restoring hippocampal dopaminergic neuron function [27-30]. As an effective component of Cistanche deserticola, PhGs can also enhance the body's antioxidant capacity and scavenge oxygen free radicals, reduce the expression of Keap1 protein, avoid the accumulation of nuclear factor - red blood cell 2 related factor 2 (Nrf2) in the hippocampus, and ultimately regulate oxidative stress and mitochondrial function through the Keap1-Nrf2-ARE pathway [31, 32]. VB, another extract of Cistanche deserticola, can also significantly improve the memory ability of AD mice induced by D-neneneba galactose and AlCl3, and its mechanism is to reduce the expression of caspase3 and inhibit A β Aggregation of [33]. In vitro experiments, CDPS significantly increased the activity of mouse brain neurons induced by D-neneneba galactose and reduced the number of neuronal apoptosis cells induced by glutamate excitotoxicity, indicating that CDPS can effectively protect neurons [34]. Exposure to A β After injecting U251 cells with 1-42 into Cistanche deserticola extract, the cell viability significantly increased, while the concentrations of Ca2+ and reactive oxygen species decreased [35]. In another study, VB has a significant protective effect on the damage of PC12 nerve cells induced by D-neneneba galactose, and its mechanism may be related to the upregulation of the cAMP/PKA/CREB signaling pathway [36], which indicates that the Cistanche deserticola also has a neuroprotective effect in vitro.

Neuron damage is one of the important causes of learning and cognitive impairment in AD patients. Cistanche deserticola has a certain neuroprotective effect, which provides help in alleviating clinical symptoms. Therefore, it is important to focus on exploring the neuroprotective mechanism of Cistanche deserticola neurons in order to play more roles in preventing and treating AD.

3. Improve immunity

Cistanche supplement near me-Improve immunity

Decreased immunity is one of the common and complex factors in elderly diseases. Research has shown that compared to healthy elderly people, elderly people with age-related diseases seem to have weaker immune function [37], and aging can also cause immune dysfunction and trigger neurodegenerative mechanisms [38]. Studies have found that Cistanche deserticola has varying degrees of anti-aging and immune regulatory effects [39]. The aqueous extract of Cistanche deserticola (AECCD) can induce a strong cellular immune response characterized by spleen cell proliferation and activated T cell response, and upregulate the expression of Th-related cytokines. It is worth noting that in vitro experiments, AECCD can induce dendritic cell (DC) activation by promoting phenotype maturation, cytokine interception, and allogeneic stimulation activity [40]. In addition, Toll-like receptor 4 (TLR4) is a necessary receptor for the direct binding of DC to AECCD, NF- κ B inhibitors can reduce the expression of CD40, CD80, and CD86 on the surface of DC, leading to the production of TNF- α The ability to interact with IL-6 decreases [41]. It is speculated that AECCD can be detected through TLR4-related NF- κ The B pathway is involved in the expression of cytokines to activate DC, thereby inducing a strong and persistent antigen-specific immune response.

Recently, it has been found that adaptive immunity plays an important role in the pathogenesis and progression of AD. Cistanche deserticola extract, as a potential immune modulator, can participate in the immune response, maintain body homeostasis, and may delay the progression of AD.

4. Reduce blood sugar

Diabetes has recently been proven to be closely related to AD [42], which led to new research on anti-diabetes drugs in AD and showed good results [43]. Some studies have found that ECH can play a certain hypoglycemic role. After ECH is injected into diabetes mice, serum insulin and glucagon are reduced, and blood sugar and glucose tolerance levels are increased. In addition, ECH can also activate the AMPK/SIRT1 pathway in the liver to alleviate liver injury in diabetes [44]. These results indicate that ECH can effectively prevent and treat diabetes and its complications. In another study, Zhu et al. [45] demonstrated that the hypoglycemic effect of total glycosides of Cistanche deserticola (TGCT) was time-dependent and dose-dependent. The experimental results showed that there was no statistically significant difference between the high-dose group and the metformin group in TGCT, indicating that high-dose TGCT can only exert its hypoglycemic effect.

Both diabetes and AD are complex chronic diseases. There are many pathophysiological homologies between the two diseases. The hypoglycemic effect of Cistanche deserticola has recently come into people's sight. However, there are still many problems to be solved urgently regarding how diabetes affects AD and how to promote the derivative strategy of more effective treatment using the hypoglycemic effect of Cistanche deserticola.

5. Regulating gut microbiota

More and more studies have shown that gut microbiota disorders can alter brain function through the brain-gut axis, and bidirectional communication between the central nervous system and the gastrointestinal tract plays a crucial role in the pathogenesis of AD. A clinical trial calculated the bifidobacteria/Enterobacteriaceae (B/E) value of 100 elderly AD patients, and the results showed that the P-tau protein, IL-6, IL-1 β, And TNF- α The levels were higher than those of the control group [47]. This result suggests that intestinal microbiota imbalance may exacerbate the clinical symptoms of AD patients. In the experiment studying the effect of Cistanche deserticola extract (CTE) on the behavior of depression model rats, changes in fecal microbiota were also detected. The results showed an increase in the richness and diversity of fecal microbiota in the CTE group, such as a decrease in the phylum level of Firmicutes and Bacteroides, and an increase in the genus level of Bacteroides [48]. Fu et al. [49] found that CDPS can promote the growth of numerous beneficial bacteria, including Pseudomonas aeruginosa. In addition, it can also improve the production of short-chain fatty acids (SCFAs) and enhance the absorption of ECH, thereby having a positive effect. It is speculated that CDPS enhances the absorption of ECH through the joint action of gut microbiota and SCFAs. In addition, CDPS can significantly increase the level of intestinal Bacteroidetes and improve cognitive function in aging mice by restoring the homeostasis of the gut microbiota brain axis [50, 51]. In summary, Cistanche deserticola and its extracts have certain therapeutic potential for patients with learning and memory disorders, especially those with intestinal microbiota imbalance.

Effects Of Cistanche-Relaxing bowel

In 2019, the team led by Geng Meiyu from the Shanghai Institute of Pharmacy proposed that neuroinflammation induced by intestinal microbiota disturbance is one of the important pathogenesis of AD. In recent years, researchers have found that regulating gut microbiota can improve neuroinflammation and thus control the progression of AD. Meanwhile, AD can also affect the composition of the gut microbiota. It has been confirmed that Cistanche deserticola extract can restore brain-gut axis homeostasis to improve cognitive function, but its specific mechanism still needs further exploration.

6. Regulating autophagy

An increase in abnormal protein production or dysfunction of the autophagy-lysosome system in AD patients may lead to an increase in autophagic vesicles. Research has found that VB can reduce the formation of autophagosomes in hypoxic-ischemic rats and increase the expression of autophagy markers such as Beclin-1, LC3-II/I, and p62 [52]. This indicates that VB can not only inhibit the excessive activation of autophagy but also maintain a certain degree of autophagy activity, exerting potential neuroprotective effects. Another extract of Cistanche deserticola, ECH, can maintain cell viability and regulate autophagy. It can upregulate the expression of foxo1 by activating Sirt1, thereby alleviating damage to dopaminergic neurons in the substantia nigra striatum [53]. In addition, Cistanche deserticola can also regulate autophagy pathways in liver cells and osteoblasts to exert related therapeutic effects [54, 55].

There is widespread autophagy damage in AD, and these pathological mechanisms are not yet clear, such as whether the decrease in autophagy flux is related to neuroinflammation in the brain, and whether it plays a role in regulating autophagy pathways. Numerous studies have shown that Cistanche deserticola and its extracts can activate autophagy, but further research is needed on how autophagy is regulated to exert its effects in AD patients, which may be a new option for future treatment of AD.

Chinese herb cistanche-Antioxidant

7.  Estrogenic effects

The decrease in estrogen levels is a risk factor for cognitive dysfunction in perimenopausal women, greatly increasing their risk of developing AD. Research has reported that Cistanche deserticola extract has estrogenic effects, which can correct the imbalance of ER/AR levels in perimenopausal model rats and improve neuroendocrine-immune function [56]. Noha et al. [57] found that telmisartan and/or estrogen treatment can improve the cognitive dysfunction of rats, which may be related to the observed reduction of tissue damage in the hippocampus. Other studies have found that gender also has an impact on AD at the genetic level. Changes in apolipoprotein (APOE) seem to make women more susceptible to the disease than men, and changes in APOE4 may lead to a higher mortality rate in elderly female patients [58]. It can be seen that estrogen plays a subtle and important role in the pathological process of AD.

Research has found that resveratrol [59] and wood brass [60] can exert estrogenic effects to prevent and treat Alzheimer's disease. However, there is currently little research on the role of Cistanche deserticola in the prevention and treatment of Alzheimer's disease, which can serve as a new entry point for further exploration.

Summary and Outlook

AD is the most common neurodegenerative disease related to aging, and its exact etiology and pathogenesis are still controversial. At present, the treatment of AD mainly focuses on improving its clinical symptoms. In terms of efficacy and symptom control, Western medicine is superior to traditional Chinese medicine in the short term. In contrast, traditional Chinese medicine has become a research hotspot in recent years due to its advantages of multi-component and overall regulation. Cistanche deserticola, a traditional Chinese medicine with extensive therapeutic properties, can enhance antioxidant capacity, enhance immunity, regulate autophagy, etc. It plays an important role in protecting the central nervous system and has great potential in treating AD. The therapeutic mechanism of Cistanche deserticola covers most of the pathogenesis of AD, and the two are closely related. Future research should focus on the regulation of identified signaling pathways and cascade reactions between signaling pathways in Cistanche deserticola. Cistanche deserticola is expected to become a candidate drug for the prevention and treatment of AD.

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