Research Progress Of Cistanche Glycoside in Improving Central Nervous System Disease

Abstract: Cistanche glycoside is the main active component of Cistanche deserticola, with a variety of pharmacological activities such as anti-tumor, anti-inflammatory, immune enhancement, anti-hepatotoxicity, antioxidant, etc. Cistanche glycoside can protect against central nervous system disease through multiple targets and pathways, for example, Cistanche glycoside has an antidepressant effect and has a protective effect on Alzheimer's disease, Parkinson's disease, ischemic stroke, and multiple sclerosis. In order to further expand the application of cistanche glycoside in clinical treatment, this article reviews the improvement of central nervous system diseases by cistanche glycoside and its mechanism of action.  

Phenylethanol glycoside is the main active component of Cistanche deserticola

Keywords: Cistanche glycoside; Antidepressant effect; Alzheimer's disease; Parkinson's disease; Ischemic stroke; Multiple sclerosis

Cistanche deserticola is a perennial herbaceous plant of the genus Cistanche in the Berberidaceae family, originally recorded in the "Shennong Herbal Classic". Its medicinal sources are mainly from the Berberidaceae plants Cistanche deserticola, Cistanche arrowleaf, Cistanche pubescent, or the dried leaves of Cistanche koreana. It has the functions of tonifying the liver and kidney, strengthening muscles and bones, dispelling wind and dampness, and benefiting essence and qi [1]. The extract of Cistanche deserticola contains over 260 compounds, among which Cistanche glycoside is the main active ingredient in Cistanche deserticola. Research shows that cistanche glycoside has a variety of pharmacological activities such as anti-tumor, anti-inflammatory, immune enhancement, anti-hepatotoxicity, antioxidant, etc. [3-5]. In recent years, a large number of studies have shown that Cistanche glycosides can have protective effects on central nervous system diseases through multiple targets and pathways. For example, Cistanche glycosides have antidepressant effects and protective effects on Alzheimer's disease, Parkinson's disease, ischemic stroke, and multiple sclerosis. In order to further expand the application of cistanche glycoside in clinical treatment, this article reviews the improvement of central nervous system diseases by cistanche glycoside and its mechanism of action.

Chinese herb cistanche—Treating depression by tonifying the kidney

1. Antidepressant effect

Depression is a complex and common mental health disorder, with main symptoms including emotions, pessimistic attitudes, lack of passion and vitality, poor sleep and quality of life, and a high risk of suicide. Cistanche glycosides have shown antidepressant effects in various classic depression models, mainly manifested in shortening immobility time and increasing sugar preference [7]. Pan et al. [8] found that male Wistar rats receiving a continuous 4-week ig of 60 mg/kg of Cistanche glycoside could significantly alleviate the loss of pleasure induced by chronic unpredictable mild stress, and inhibit serum levels of corticosterone and corticotropin-releasing factor (CRF). Liu Yunqin et al. [9] found that in cistanche glycoside 30, 60 mg/kg can significantly reduce the expression of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and adrenocortical actin (CORT) in the brain tissue of depressed mice, and its binding force can alleviate the depressive behavior of mice. Consistent with this, Wu et al. [10] also found that continuous ig of Cistanche glycoside (5,10,20 mg/kg) for 28 days can alleviate the formation of aversion induced by social frustration stress in mice, which may be achieved by regulating the function of the hypothalamic-pituitary adrenal cortex (HPA) axis and the expression of brain-derived neurotrophic factor (BDNF). In addition, continuous 35-day ig of Cistanche glycoside at 20 and 40 mg/kg in rats can significantly reverse the increased expression of GR, glucocorticoid-induced kinase 1 (SGK 1), and FK506 binding protein 5 (FKBP5) in the hippocampus and prefrontal cortex of depressed rats, thereby exerting an antidepressant effect [11].

The above studies indicate that the antidepressant activity of Cistanche glycosides may be achieved by regulating the neuroendocrine system or restoring negative feedback regulation of the HPA axis. In recent years, research has reported that Cistanche glycosides can exert their antidepressant effects by regulating central nervous system inflammation [9,12]. Liu et al. [12] found that Cistanche glycosides at 20 and 40 mg/kg can improve depression-like behavior induced by chronic unpredictable mild stress in rats, possibly by inhibiting hippocampal nuclear factors- κ B（NF- κ B) Activation of signaling pathways and Nod-like receptor protein 3 (NLRP3) inflammasomes/caspase-1/interleukin-1 (IL-1) β Axis increases the anti-inflammatory and antioxidant abilities of brain tissue. Serum tumor necrosis factor (TNF) after ig of Cistanche glycoside in mice (30,60 mg/kg)- α The levels of IL-6 were significantly lower than those in the depression group and decreased with increasing dose [9]. Ig Cistanche glycoside 20 mg/kg can improve hippocampal neuroinflammatory response in mice by inhibiting high mobility group protein B1 (HMGB1)/advanced glycation end products (RAGE) signaling, while activating Toll-like receptor 4 (TLR4) - shear type X-box binding protein 1 (XBP1) related NF- κ B signal to exert neuroprotective effects [13]. Zhang Yanxiu [14] treated astrocyte with glucocorticoid in vitro to simulate the state of astrocyte at the early stage of depression, analyzed the antidepressant action pathway of active ingredients of different Chinese medicines and found that after treatment with cistanche glycoside (5, 10, 20 mmol/L), the expression of thioredoxin binding protein (TXNIP) in model cells decreased, the level of thioredoxin 1 (TRX-1) increased, and the level of total reactive oxygen species (ROS) in cells decreased, And inhibit the activation of NLRP3 inflammasome and IL-1 β The cleavage maturation of proteins produces a protective effect on astrocytes. Xue Yalan et al. [15] found that in cistanche glycoside 20 mg/kg can reduce superoxide dismutase (SOD), glutathione peroxidase (GSH Px), nitric oxide (NO), and inflammatory factor TNF in the hippocampus of rats- α、 IL-6、IL-1 β Level to improve depression-like behavior in rats. The above research results emphasize the crucial role of central nervous system immune inflammation in the antidepressant pathway of Cistanche glycosides.

Effects of Cistanche—Treating depression by tonifying the kidney

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In addition, the antidepressant effect of Cistanche glycosides may also be related to other mechanisms. After treatment with 40 and 80 mg/kg of Cistanche glycoside for 35 days, the expression levels of mGluR1, mGluR5 protein, and mRNA in the hippocampus and prefrontal cortex of SD mice were significantly reduced, while the levels of EAAT2 protein and mRNA increased. The depressive behavior of SD mice was significantly alleviated [16]. Zhang Cong et al. [17] found that icariin 10, 20, and 40 mg/kg significantly increased the levels of norepinephrine (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) in the hippocampus, cortex, and striatum of rats, alleviating the depression-like behavior induced by chronic unpredictable mild stress. Cao et al. [18] found that different doses (12.5, 25, 50 mg/kg) of Cistanche deserticola glycoside in treatment can improve the depressive symptoms of menopausal female rats by regulating the PI3K/Akt pathway, promoting the regulation of PI3K to methylenep85 and catalytic expression of methylenep110, increasing the relative expression of p-Akt, promoting the expression of anti-apoptotic factor Bcl-2, and thereby increasing the level of Bcl-2/Bax.

2. Protective effects on Alzheimer's disease

Effects of Cistanche—Anti Alzheimer's disease

Alzheimer's disease is a neurocognitive dysfunction syndrome, accounting for approximately 70% of the total number of elderly dementia patients. The main clinical manifestation is a significant decrease in learning and memory abilities [19]. The onset of Alzheimer's disease involves different pathological and physiological processes, such as abnormal protein aggregation, neuroinflammation, mitochondrial damage, and oxidative stress [20]. Among them β Amyloid protein (A β） The extracellular accumulation and intracellular aggregation of Tau protein (also known as neurofibrillary tangles) are the main neuropathological features of Alzheimer's disease, therefore A β Tau protein has become an important target for the treatment of Alzheimer's disease. Zhang et al. [21] constructed transgenic Alzheimer's disease mice with amyloid precursor protein (APP) and found that icariin reduced APP and β Reducing the expression of APP cleaving enzyme 1 (BACE-1) in mouse hippocampus A β Load and amyloid plaques improve learning and memory impairment. Consistent with this, Li et al. [22] also found that icariin can reduce hippocampal APP and A levels after continuous treatment with ig Cistanche glycoside 60 mg/kg for 3 months β The expression level enhanced the hippocampal neurogenesis of mice and played an anti-Alzheimer disease role. In addition, the phosphorylation level and phosphorylation process of Tau protein are closely related to the development of Alzheimer's disease. Zeng et al. [23] reported that Cistanche glycoside (20 mmol/L) can significantly reduce A by inhibiting hyperphosphorylation at the Ser396, Ser404, and Thr205 sites of Tau proteins in PC12 cells β 25-35 induced cytotoxicity and apoptosis.

Li Ying et al. [24] used an Alzheimer's disease-like cell model induced by Okada acid in SH-SY5Y cells after intervention with Cistanche deserticola glycoside (2.5 mmol/L) and found that Cistanche deserticola glycoside can promote SH-SY5Y cell proliferation, significantly reducing p-Tau expression levels, and accompanied by glycogen synthase kinase 3 β （GSK-3 β） Decreased expression. After treatment with ig Cistanche glycoside (30, 60 mg/kg) in the three transgenic mice with Alzheimer's disease, it was found that the phosphorylation level of Tau protein in the icariin group significantly decreased at Ser396/404, Ser199/202, Thr231, Thr217, and Ser422 sites, thereby improving neuronal damage and exerting the anti-Alzheimer's disease effect of Cistanche glycoside [25].

The cholinergic hypothesis has also been widely studied in the anti-Alzheimer's disease process of Cistanche glycosides. He et al. [26] showed that different doses of Cistanche glycosides (75, 150 mg/kg) in ig can rapidly improve cognitive impairment in mice by inhibiting acetylcholinesterase (AChE) activity. In addition, literature reports suggest that Cistanche glycoside (30, 60, 120 mg/kg) can significantly improve A β The learning and memory abilities of Alzheimer's disease rats induced by 25-35 may be related to their protective effects on cholinergic neurotransmitter metabolism and their effects on the hippocampus β- The inhibitory effect of secretase expression is related [27]. Ma et al. [28] found that different concentrations of Cistanche glycosides (0.1, 1, 10, 20 mmol/L) can promote the survival, proliferation, and migration of neural stem cells in vitro. Similarly, it was found in animal experiments that ig icariin 20 mg/kg can promote the proliferation and differentiation of rat neural stem cells into neurons, increasing the number of cholinergic neurons in the basal forebrain. Gao Linna et al. [29] also reported that cistanche glycoside (50, 100, 200 mg/kg) can increase the content of acetylcholine in the cerebral cortex of mice with Alzheimer's disease, improve the binding capacity of M-cholinergic receptor (MCBC) and the activity of acetylcholine transferase (ChAT) in the cortex of mice, thereby improving the learning and memory of mice. The above research results indicate that Cistanche glycosides can improve nervous system function through the cholinergic hypothesis, thereby enhancing learning and memory abilities.

The BDNF signaling cascade plays an important role in the pathogenesis of Alzheimer's disease. Sheng et al. [30] showed that different doses of Cistanche glycosides (30, 60, 120 mg/kg) in it had an impact on A β 1-42 induced Alzheimer's disease rats have neuroprotective effects, which can reverse the decreased expression of PSD-95, BDNF, pTrkB, pAkt, and pCREB, and prevent the deterioration of the synaptic structure. Lu et al. [31] treated A with 20 mmol/L Cistanche glycoside β After cell modeling, it was found that the activity and differentiation ability of neural stem cells in the Cistanche glycoside group increased, accompanied by a decrease in BDNF and TrkB levels and an increase in ERK/Akt phosphorylation levels. Meanwhile, Tang et al. [32] found that treatment with 20 mmol/L Cistanche glycoside could reverse A through the GR/BDNF signaling pathway β The damage of hippocampal neurons induced by 25-35 is mainly manifested in the enhancement of cell viability, inhibition of cell apoptosis and lactate dehydrogenase release, promotion of SOD activity and the expression of GR, BDNF, Bcl-2, and inhibition of Caspase-3 and Bax expression.

3. Protective effects on Parkinson's disease

Effects of Cistanche—Anti-Parkinson's disease

Parkinson's disease is one of the most common neurodegenerative diseases, mainly characterized by progressive degeneration and loss of dopaminergic neurons in the substantia nigra compacta [33]. The classic clinical features of Parkinson's disease mainly include bradykinesia, muscle rigidity, and static tremor. Research has shown that oxidative stress and neuroinflammation play an important role in the progression of Parkinson's disease. Inflammatory mediator TNF- α、 IL-1 β、 Elevated levels of IL-6, iNOS, and others in the striatum and substantia nigra lead to dysfunction of dopamine neurons [34]. Overexpression of trigger receptor 2 (TREM2) expressed on myeloid cells protects dopaminergic neurons by reducing neuroinflammatory response [35]. In the MPTP-induced Parkinson's disease model, the lack of TLR4 leads to IL-1 β、 The expression of iNOS and COX-2 is reduced, and the expression of NLRP3 inflammasome is reduced [36]. Therefore, inhibiting neuroinflammation may be a potential strategy for the treatment of Parkinson's disease. Jiang Mingchun [37] established a microglial inflammation model using lipopolysaccharide and found TNF in the lipopolysaccharide group- α、 IL-1 β、 The expression levels of COX-2 and iNOS mRNA increased, while the expression of inflammatory factors decreased after treatment with different concentrations of icariin (1, 10, 20, 50 mmol/L). Zhang et al. [38] established a Parkinson's disease model by stereotactic injection of 6-hydroxydopamine (6-OHDA) and found that Cistanche glycoside 60 mg/kg inhibited the neuroinflammatory response in mice, and produced neuroprotective effects on dopaminergic neurons by activating nuclear factor E2 related factor 2 (Nrf2) signals. At the same time, 0.1 mmol/L Cistanche glycoside combined with L-3,4-dihydroxyphenylalanine (L-DOPA, an effective drug for treating Parkinson's disease) can significantly reduce 6-OHDA-induced PC12 cell damage and apoptosis, thereby improving the loss of dopaminergic neurons; In addition, the combination therapy of the two can inhibit the inflammatory factor TNF- α、 IL-1 β、 Protein expression of COX-2 [39]. The above research results indicate that Cistanche glycosides can improve the damage of dopaminergic neurons through the neuroinflammatory system.

In addition, mitochondrial dysfunction is a recognized initiating factor for dopaminergic neuronal degeneration [40]. Research has shown that α- Synuclein, LRRK2, CHCHD2, and VPS35 play important roles in the development of Parkinson's disease and are closely related to mitochondrial-related functions [41]. α- Synuclein is reported to not only affect the morphology of mitochondria but also activate receptors by regulating peroxisome proliferators γ Co activation factor 1- α （PGC1 α） It affects the biogenesis of mitochondria [42]. LRRK2 and VPS35 mediate the pathological effects of mitochondria through their interaction with mitochondrial fission/fusion [43-44]. The reduced expression of CHCHD2 will reduce the activity of mitochondrial complex IV, leading to increased ROS production and mitochondrial fragmentation [45]. Studies have shown that in Parkinson's disease rats with mitochondrial damage induced by rotenone, continuous 5-week ig of Cistanche glycoside (15,30 mg/kg) significantly increased the number of dopaminergic neurons and mitochondrial respiratory function in rats, α- The expression of synuclein protein decreases, resulting in a protective effect on mitochondria [46]. Another study pointed out that administration of 15 and 30 mg/kg Cistanche glycoside ig can alleviate the damage of dopaminergic neurons in a rat model of Parkinson's disease induced by rotenone, mainly related to the activation of SIRT3, upregulation of mitochondrial complex II activity, and reduction of ROS accumulation [47]. In addition, Zeng et al. [48] found that Cistanche glycosides can improve mitochondrial function and reduce neuronal damage by regulating cell autophagy (mainly manifested by increasing LC3- Ⅱ, Beclin-1 proteins, and reducing P62 protein expression) after administering 15 and 30 mg/kg of ig to Parkinson's disease rats.

4. Protective effects on ischemic stroke

Effects of Cistanche—Anti-Parkinson's disease

Stroke, also known as stroke, is an acute brain injury caused by rupture or accidental obstruction of cerebral blood vessels, leading to corresponding physical dysfunction. Stroke includes ischemic stroke and hemorrhagic stroke, with ischemic stroke accounting for 80% of stroke. At present, the pathogenesis of ischemic stroke mainly involves energy metabolism disorders, excitatory glutamate toxicity, cell apoptosis, and inflammation [50]. Zheng et al. [51] established an ischemic stroke model using the transient middle cerebral artery occlusion (MCAO) method and found that different doses of Cistanche glycosides (10, 20, 40 mg/kg) in ig could improve neurological deficits, brain edema, and pathological damage in rats; In addition, cistanche glycoside promotes neuronal survival, inhibits the activation of microglia and IL-1 β The expression of GRP78, NLRP3, Caspase-1 and other proteins are reduced, thereby alleviating inflammatory damage. Wu et al. [52] found that ip Cistanche glycoside 60 mg/kg can improve body mass reduction, nerve damage, infarct volume, and pathological changes in acute ischemic stroke mice; In addition, it can also inhibit neuronal cell apoptosis, oxidative stress response, and extracellular matrix accumulation, thereby achieving effective treatment of ischemic stroke. Dai et al. [53] found that Cistanche glycoside 60 mg/kg caused TNF in the brain tissue of MCAO rats- α、 Down-regulation of IL-6, C-Caspase-3 and Bax expression activates peroxisome proliferator-activated receptors (PPARs)/Nrf2/NF- κ The B and JAK2/STAT3 pathways increase the expression of Bcl-2, indicating that Cistanche glycosides can be expressed through PPARs/Nrf2/NF- κ B and JAK2/STAT3/NF- κ B pathway suppresses NF- κ Activation of B in experimental stroke promotes neuroprotection induced by mild hypothermia. Consistent with this, Xiong et al. [54] also found that Cistanche glycosides can inhibit NF after 3 consecutive days of ig treatment with Cistanche glycosides (10, 30 mg/kg)- κ B、PPAR α、 PPAR γ Mediated inflammatory response has a neuroprotective effect on ischemic stroke in rats. In addition, the combination therapy of ig icariin 60 mg/kg and mesenchymal stem cells showed that the combination therapy can significantly improve the neurological deficits and behavior of motor and somatosensory functions in rats, and respond to ischemic stroke by activating the PI3K and ERK1/2 pathways in the hippocampus and cortex to increase the expression of vascular endothelial growth factor (VEGF) and BDNF [55].

Other studies have shown that administration of 100 mg/kg Cistanche glycoside ig can increase cortical SIRT1 and PGC-1 in experimental stroke rats α The expression of the gene to protect against ischemic brain injury may become a neuroprotective agent for ischemic brain injury [56]. The above studies indicate that Cistanche glycosides have neuroprotective effects on ischemic stroke through anti-apoptotic, anti-inflammatory, and different signaling pathways, thus becoming a potential drug component for the treatment of ischemic stroke.

5. Protective effect on multiple sclerosis

Cistanche deserticola experiment

Multiple sclerosis is an inflammatory disease of the central nervous system, characterized by chronic demyelination, damage to axons and myelin sheaths. Approximately 85% of patients with multiple sclerosis have a course of relapse remission, manifested as motor, sensory, mental, and cognitive impairments, with progressive exacerbation [57]. The remission phase is generally considered the myelin regeneration phase, which is a critical time for repairing damaged myelin sheaths and axons [58]. Therefore, drug therapy during the remission period may have a significant effect on myelin regeneration. In an animal model of multiple sclerosis induced by cyclohexanone oxalyldihydrazone (CPZ), it was found that different doses of icariin (6.25, 12.5, 25 mg/kg) at ig can promote mouse myelin regeneration, enhance axonal repair, increase the number of mature oligodendrocytes, and promote the expression of nerve growth factor (NGF), These results suggest that Cistanche glycosides may alleviate the symptoms of multiple sclerosis by promoting oligodendrocyte regeneration and NGF expression [59].

Numerous literature reports suggest that neuroinflammation plays an important role in its pathogenesis and treatment. If an increase in IL-17 levels and a decrease in IL-4 levels are found in peripheral blood mononuclear cells of patients with multiple sclerosis; After treatment with Cistanche glycoside, the levels of IL-17 and IL-4 were inhibited, reducing the inflammatory response [60]. Han Qingxian [61] found that lipopolysaccharide induces microglia to secrete a large amount of TNF in vitro- α、 IL-1 β Inflammatory factors, while treatment with 15 mg/mL of Cistanche glycoside resulted in TNF- α、 IL-1 β The level of decline; In vivo experiments, using CPZ to construct a demyelination model, it was found that ip Cistanche glycoside 50 mg/kg can improve the demyelination of CPZ mice and inhibit the inflammatory factor TNF- α、 IL-1 β Promote the expression of anti-inflammatory factors IL-10 and TNF- β Expression of. 25 mg/kg of Cistanche glycoside was administered to experimental autoimmune encephalomyelitis (EAE) mice, and it was found that Cistanche glycoside can inhibit the frequency of Th17 cell appearance in monocytes of the central nervous system in mice, and affect Th1 and Th17 cell differentiation by regulating dendritic cells. This suggests that Cistanche glycoside improves EAE and inhibits Th1 and Th17 cell differentiation [62]. Cong et al. [63] also found in EAE mice that continuous treatment with ig Cistanche glycoside (12.5, 25 mg/kg) for 42 days can significantly improve spinal cord inflammation and demyelination in EAE mice; In addition, Cistanche glycosides significantly reduced the iNOS and TNF increased by EAE- α、 CD206 and Transforming Growth Factor β 1（TGF- β 1) However, it further reduced the transcription of IL-10 mRNA in mice; More importantly, Cistanche glycosides can significantly reduce inflammation related NF in the brain of EAE mice- κ B. The phosphorylation of AKT, ERK1/2, p38, c-Jun, and MEK indicates that Cistanche glycosides mainly improve the progression of EAE by downregulating the main inflammatory-related signaling pathways in mice. Therefore, the above research results indicate that Cistanche glycosides can improve multiple sclerosis through the neuroinflammatory system.

6. Conclusion

Cistanche glycosides, as the main active ingredient in traditional Chinese medicine Cistanche deserticola, have a protective effect on depression, which mainly involves regulating the HPA axis, inhibiting inflammatory reactions, and regulating the expression of neurotransmitters and their receptors; The protective effect on Alzheimer's disease is mainly related to the inhibition of A β The expression is related to Tau protein phosphorylation levels, affects the expression of cholinergic neurotransmitters, and BDNF signaling cascade reactions; The improvement effect on Parkinson's disease is related to inflammatory response and mitochondrial dysfunction; The protective effects on ischemic stroke mainly involve anti-apoptotic and anti-inflammatory responses; At the same time, the protective effect on multiple sclerosis is also achieved by regulating inflammation-related signaling pathways. These results indicate that the protective effect of cistanche glycoside on central nervous system disease is achieved through multiple targets and pathways.

Cistanche powder

Due to the complexity of the mechanism of action of cistanche glycoside, and the difference in pharmacological effects in vivo and in vitro, new technologies such as transcriptome, proteomics, metabolomics, and so on should be used in future research to deeply explore the expression of cistanche glycoside at different levels. For the exploration of molecular pathways, agonists, antagonists, gene knockout/overexpression, and other methods can be used to clarify the expression of signaling pathways and upstream and downstream molecules regulated by Cistanche glycosides, to find more new pathways and targets for Cistanche glycosides.

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