Part Ⅱ：Herba Cistanche (Rou Cong Rong): A Review Of Its Phytochemistry And Pharmacology

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Antioxidation

Antioxidation activity is against free radicals. Antioxidant drugs can reduce the damage of oxygen free radicals to the blood vessel wall, thus playing an antibacterial sclerosis role. Shi et al.⁹⁸⁾ first found that extracts from Cistanche species had a lipid peroxidation suppression- effect and an immunological enhancement effect. The PhGs from Cistanches Herba could lower the levels of lipid hydroperoxide in humans, which was regarded as effective for antioxidative activity.^99,100) The phenolic hydroxyl group in PhGs is necessary for antioxidant activity. A study found that because of the phenolic hydroxy structure, PhGs can combine with free radicals and activate antioxidant defense systems, and by increasing the number of phenolic hydroxyl groups, the antioxidant activity is increased.³⁴⁾ In another study, Cistanche glycosides showed inhibitory effects on lipid hydroperoxide and thromboxane production in rabbit blood, revealing that these glycosides had protective effects against hemorrhagic shock and reperfusion injury.¹⁰¹⁾ Wu et al.¹⁰²⁾ found that PhGs from C. salsa possessed very high antioxidant activities. Other studies found that PhGs fromC. deserticola dramatically increased superoxide dismutase activities, which decreased malondialdehyde levels in mouse hearts, livers, and brains; thus, the authors believed that PhGs could protect skeletal muscles from oxidative injury by eliminating the over-accumulation of free radicals.¹⁰³⁾ Researchers focused attention on natural antioxidants to combat diabetic- nephropathy disease and study results have indicated that PhGs from C. deserticola could inhibit reactive oxygen free radicals in vitro and repair free radical damage related to diabetic nephropathy.¹⁰⁴⁾ Liang et al.¹⁰⁵⁾ pointed out that PhGs extracted from Herba Cistanche had protective effects on human sperm DNA with oxidative damage in 2015. Compound 18 obtained from Cistanche plants could increase pheochromocytoma cell (PC12 cell) viability against H2O2-induced cytotoxicity and decrease the apoptotic rate at the same time.¹⁰⁶⁾ Wang and Zhao¹⁰⁷⁾ established the antioxidant activity of C. deserticola polysaccharides in vitro and found that polysaccharides could scavenge free radicals including the hydroxyl radical, superoxide anion radical, singlet oxygen, and diphenyl acyl. In 2016, an efficient ultrasonic-cellulase-assist- ed extraction of C. tubulosa polysaccharides was established, and its polysaccharides showed appreciable antioxidant activity.¹⁰⁸⁾ Another study pointed out that polysaccharides from C. tubulosa also had great antioxidant activities when evaluated for diphenyl acyl and hydroxyl radicals as well as the scavenging ability of copper ions in vitro.¹⁰⁹⁾ In summary, PhGs and polysaccharides in Cistanche plants are the main antioxidants.

Cistanche glycosides benefit

Anti-Alzheimer’s Disease

AD is one of the most harmful neurological diseases facing elderly individuals and is the focus of much research. As a TCM, studies have proven that water and alcohol extracts of Cistanches Herba have good anti-Alzheimer’s effects. The Consumer Price Index database of China announced that glycosides in Cistanche and Cistanche Yizhi capsules are authorized for the treatment of AD.¹¹⁰⁾ Nerve growth factor (NGF) can enhance memory function, and Korea scholars¹¹¹⁾ found that Cistanches Herba could stimulate NGF secretion, improving cognitive behaviors related to memory abilities. An intracisternal infusion of amyloid β peptide 1–42 (Aβ1–42) into rats was primarily deposited in the frontal cortex and hippocampus, causing memory deficits in behavioral tasks and inducing an AD-like pathology. The extracts from C. tubulosa have been proven to reduce cognitive impairment caused by Aβ1–42 by reversing cholinergic neuronal function and blocking amyloid deposition.¹¹²⁾ Amyloid β peptide 25–35 (Aβ25–35) neurotoxicity can lead to cholinergic system damage, which is an important determinant of cognitive dysfunction. AD. Luo¹¹³⁾ explained the effects and mechanism of Cistanche glycosides in a rat model of AD induced by Aβ25–35, proposing that PhGs could decrease acetylcholinesterase activities and Ca²⁺ contents in the hippocampus in AD model rats, which would promote normal acetylcholine levels and improve the learning and memory capabilities of AD rats.¹¹⁴⁾ Additionally, C. tubulosa extract, which contains PhGs, similar to compounds 2 and 11, could ameliorate the cognitive dysfunction caused by Aβ1–42 via blocking amyloid deposition and reversing cholinergic and hippocampal dopaminergic neuronal function.¹¹⁵⁾ Li et al.¹¹⁶⁾ evaluated the neuroprotective effects of Cistanches Herba on AD patients and found that the levels of total tau protein, tumor necrosis factor-α, and interleukin-1β were decreased in the Cistanches Herba capsule group, which proved that this plant has potential neuroprotective effects for AD. PhGs have protective effects on cognitive dysfunction by improving synaptic plasticity in an AD rat model. Jia et al.¹¹⁷⁾ revealed that this AD protective mechanism may inhibit cytotoxicity mediated by Aβ1–42 administration and reduce oxidant stress. Another experiment also found that PhGs protect neurons by lowering the expression of Aβ1–42 and Aβ1–40 protein in the mouse hippocampus. All of these results provide theoretical support for the further development of new drugs against AD.118)

Anti-Parkinson’s Disease

PD is a chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, and its main clinical manifestations include dyskinesia, muscle stiffness, postural instability, and resting tremors.¹¹⁹⁾ To date, the etiology of PD has not been fully revealed. However, previous studies consider oxidative stress due to the cellular dysfunction between the production and scavenging of free radicals as the primary mechanism associated with neuronal death.¹¹⁰⁾ Echinacoside (11), a PhG compound, has been proven by many studies to have anti-PD effects. This compound showed neuroprotection in PD mice induced with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP).¹²⁰⁾ Geng et al.¹²¹⁾ found that compound 11 could improve the behavioral and neuro-chemical outcomes in an MPTP mouse model of PD, which suggested that it can be used as a therapeutic compound for PD. Moreover, Chen et al.¹²²⁾ also concluded that compound 11 could protect striatal dopaminergic neurons by increasing the levels of monoamine neurotransmitters including dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in 6hydroxydopamine (6-OHDA) lesion rats and may be useful in the prevention and treatment of PD. Compound 11 also protected PC12 cells against 6-OHDA by increasing the mitochondrial membrane potential while decreasing the mitochondria-mediated apoptosis rate, which reduced cytotoxicity and produced a significant neuroprotective effect.¹²³⁾ Furthermore, acteoside (2), an isomer of compound 11, is another important active PhG compound from Cistanche species that showed anti-PD potential by inhibiting 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced SH-SY5Y cell apoptosis; the mechanism of action was also elucidated.¹²⁴⁾ Additionally, compound 2 also had a significant protective effect on MPP⁺-induced cerebellar granule neurons, which may be due to the inhibition of active caspase-3 and proteolytic poly polymerase fragment expression.¹²⁵⁾ Compounds 18 and 37, which are bioactive compounds from Cistanche plants, have also been indicated to possess effective neuroprotective effects against PD.^126,127)

Endocrine Regulation Activities

Androgen plays a key role in the development of male reproductive tissues, and its imbalance can cause kinds of symptoms, including kidney- yang deficiency. As we all know, Cistanches Herba is one of the most frequently used tonic drugs in the prescription for in- invigorating the kidney-yang. Research has confirmed that there are two main ways to replenish the kidney-yang. One is by enhancing the function of the hypothalamus-pituitary-adrenal axis and promoting the release of related neurotransmitters and hormones in the body, the other is by fighting fatigue and improving physical function.¹²⁸⁾ Cistanche can increase the number of pituitary cells, promote the secretion of ovarian progesterone, enhance the expression of estrogen receptor and progesterone receptor of the gonadal axis, and inhibit the expression of interleukin-2 receptor in ovaries and interstitial. At the same time, it also can stimulate the production of androgen due to the result of one test that the index of prostate and testis increased significantly in the castrated mice group compared with the healthy group.^129–132) PhGs in Cistanche have some intervention on lipid peroxidation damage of sperm membrane in test rats, and they also play a protective role in the structure and function of the sperm membrane.¹³³⁾ Studies have shown that PhGs have obvious therapeutic effect on spermato- genic disorders induced by cyclophosphamide in mice, and its mechanism may be related to the improvement of testosterone level in testis.¹³⁴⁾ PhGs have the function of inhibiting the disorder of sexual hormones in perimenopausal model rats and mice, adjusting the imbalance of androgen receptor and estrogen receptor and improving the pathological changes of uterus, thymus, spleen, and pituitary.¹³⁵⁾ In addition, a decoction of Cistanche can improve the anti-fatigue effect of yang deficiency mice.¹³⁶⁾ In 2004, Pan and Min¹³⁷⁾ found that the alcohol extracts from Cistanche could prevent atrophy of the adrenal cortex in mice with kidney-yang deficiency, and also had certain protective effects on renal function. Wu et al.¹³⁸⁾ thought that C. deserticola and C. tubulosa both had certain tonic effect on kidney-yang, and their decoction could significantly increase the weight and obviously prolong the cold tolerance time of kidney yang deficiency model mice. C. deserticola decoction was reported to be able to increase the content of serum testosterone and the weight of seminal vesicles and the prostate gland in male rats.¹³⁹⁾ In another research,C. deserticola decoction eased the reproductive toxicity in male rats caused by Leigongteng glycoside.¹⁴⁰⁾ Jiang et al.¹⁴¹⁾ pointed out that a 70% ethanol extract of C. tubulosa could reverse testicular and sperm damage in Sprague-Dawley (SD) rats by upregulating steroidogenesis enzymes in the gonad axis, and compound 11 was one of the active constituents. Moreover, Wang et al.¹⁴²⁾ found that C. tubulosa extracts could improve SD rat progesterone and testosterone levels. In 1996, Zong et al.¹⁴³⁾