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The effects of glycosides of cistanche on learning and memory in β-amyloid peptide induced Alzheimers disease in mice and its possible mechanism
Abstract
Aim: To study the protective effects of glycosides cistanche (GCs) on model of Alzheimers disease(AD) in mice induced by β-amyloid peptide (β-AP) and its mechanism. Methods: AD animal model was established by a single intracerebroventricular injection of micromolar doses of β-AP 25-35 in mice. After 10 days, a step-through type passive avoidance training was performed on the mice for one time, followed by a ability assessment of learning and memory; superoxidase dismutase (SOD) activities, gultathionine peroxides (GSH-Px) activities and malondialdehyde (MDA) contents in mice brain were also assessed; the pathological changes in the AD mice brain were observed by electronic microscopy; TUNEL method was used to observe the apoptosis of cells; the immunohistochemical SABC method was used to determine expression of Bcl-2 and Bax. Results: GCs markedly enhanced the ability of learning and memory which induce by β-AP in AD mice and increased the activity of SOD and GSH-Px, and reduced MDA contents in mice brain; GCs also ameliorated some pathological features of AD mice brain and significantly decreased cell apoptosis in mice brain. A decrease in the Bax expression and a increase in the Bcl-2 expression were also observed. Conclusions: GCs significantly improves the ability of learning and memory induced by β-AP in AD mice and its possible mechanism of action may involve: Enhancement of free radical scavengers; inhibition of lipid peroxidation; inhibition of β-AP precipitation and apoptosis in mice brain cells induced by β-AP.
... GCs were used in 13 studies, CDPS in 5 studies, AS in 4 studies, ECH in 2 studies and PhGs in 1 study. AD models were established by using Aβ , Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) or Aβ(1-40) cerebral ventricle infusion (n = 7), using D-galactose (D-gal, n = 6), scopolamine (n = 6), sodium nitrite (n = 4), aluminium chloride (AlCl3, n = 2) or quinolinic acid (n = 1) intraperitoneal injection, or using SAMP8 mice (n = 2) and APP/PS1 transgenic mice (n = 1) directly. The non-Aging and Disease • Volume 10, Number 5, October 2019 functional liquid/normal saline/no treatment control was introduced in all 20 studies; however, WCM control was introduced in 6studies, by donepezil [33,47,48] or huperzine A [40,50,51]. ...
... Three studies [33,43,49] showed ECC were marked in decreasing Aβ deposition (n = 32, MD = −2.65, 95%CI [−3.74 to −1.57], P<0.00001; heterogeneity: χ 2 = 1.37, df = 2 (P = 0.51); I 2 = 0%; Fig. 7A), 4 studies [34,35,38,43] in decreasing apoptosis (n = 80, MD = −3.54, 95%CI [−4.33 to −2.76], P<0.00001; heterogeneity: χ 2 = 9.98, df = 3 (P = 0.02); I 2 = 70%; Fig. 7B) and 2 studies [38,42] in decreasing Caspase-3 (n = 40, MD = −2.64, ...
... Two studies [34,37] in decreasing of calcium deposition in the ECC group, with 1 study [37] indicating an increase in synapse number rather than a change in extrinsic features. Two studies [35,38] obviously showed ECC increased the expression of Bcl-2 compared with controls. One study [33] provided data of the ECC and WCM control groups on Aβ deposition, but no intergroup differences were found. ...
Currently, disease-modified strategies to prevent, halt or reverse the progress of Alzheimer's disease (AD) are still lacking. Previous studies indicated extracts or compounds from Cistanches (ECC) exert a potential neuroprotective effect against AD. Thus, we conducted a preclinical systematic review to assess preclinical evidence and possible mechanisms of ECC in experimental AD. A systematical searching strategy was carried out across seven databases from their inceptions to July 2018. Twenty studies with 1696 rats or mice were involved. Neurobehavioral function indices as primary outcome measures were established by the Morris water maze test (n = 11), step-down test (n = 10), electrical Y-maze test (n = 4), step-through test (n = 3), open field test (n = 2) and passage water maze test (n = 1). Compared with controls, the results of the meta-analysis showed ECC exerted a significant effect in decreasing the escape latency, error times and wrong reaction latency in both the training test and the retention test, and in increasing the exact time and the percentage of time in the platform-quadrant and the number of platform crossings (all P<0.01). In conclusion, ECC exert potential neuroprotective effects in experimental AD, mainly through mechanisms involving antioxidant stress and antiapoptosic effects, inhibiting Aβ deposition and tau protein hyperphosphorylation and promoting synapse protection. Thus, ECC could be a candidate for AD treatment and further clinical trials.
... Cistanche tubulosa (Schenk) R. Wight (abbreviated as CT) is commonly used by traditional Chinese physicians to treat forgetfulness, impotence and senile constipation [5]. Recent studies have shown that pretreatment with total phenylethanoid glycosides of CT could improve the impairment of inhibitory avoidance response and neuronal apoptosis caused by quinolinic acid, Aβ 25-35, or common carotid artery ligation in mice [6][7][8] via its antioxidant activity and increasing the activities of intracellular antioxidant enzymes such superoxide dismutase and glutathione peroxidase [9]. Total phenylethanoid glycosides mainly include 2'-acetylacteoside, acteoside, cistanosides, echinacoside and isoacteoside [10]. ...
... The intra-gastric administration of CT extract (100, 200 mg/kg) throughout Aβ 1-42 infusion period ameliorated the observed behavior deficits caused by Aβ 1-42. This memory-improving effect is consistent with other reports showing that total phenylethanoid glycosides of Cistanche species could protect the impairment of inhibitory avoidance response caused by an acute intracisternal injection of Aβ 25-35 in mice [6]. Recent clinical report also indicated that AD patients given with CT glycosides for 48 weeks showed no exacerbation of cognitive function [21]. ...
... From these pathological and biochemical results, we suggested that CT extract at 200 mg/kg reversed cortical and hippocampal cholinergic function by decreasing the deposition of Aβ. Other reports indicated that total phenylethanoid glycosides of Cistanche species or acteoside could protect the memory deficits or neuronal damage caused by Aβ 25-35 through an antioxidant mechanism and decreasing the ratio of Bax/Bcl2 in vivo or in vitro [6,24]. Recent report further indicated that acteoside inhibited Aβ 1-42 aggregation in a dose-dependent manner by using the thioflavin-T assay [25]. ...
Background
Cistanche tubulosa (Schenk) R. Wight (CT) is commonly used to treat forgetfulness by traditional Chinese physicians. This study presents the ameliorating effects of CT extract which was quantified with three phenylpropanoid glycosides in Alzheimer’s disease (AD)-like rat model.
Methods
Amyloid β peptide 1-42 (Aβ 1-42) intracisternally infused to rats by osmotic pump (Alzet 2002) was used as an AD-like rat model. The major pathological makers were measured including Aβ 1-42 immunohistochemical stain, behavioral tests (inhibitory avoidance task and Morris water maze) and central neurotransmitter functions.
Results
Aβ 1-42 caused the cognitive deficits, the increase in the amyloid deposition and acetylcholinesterase activities, and the decrease in the levels of brain’s acetylcholine and dopamine. Daily administration of CT extract throughout Aβ 1-42 infusion periods ameliorated the cognitive deficits, decreased amyloid deposition and reversed cholinergic and hippocampal dopaminergic dysfunction caused by Aβ 1-42. Donepezil also ameliorated the cognitive dysfunction, but only blocked the amyloid deposition and cholinergic dysfunction caused by Aβ 1-42.
Conclusions
We suggest that CT extract, containing enough echinacoside and acteoside, ameliorated the cognitive dysfunction caused by Aβ 1-42 via blocking amyloid deposition, reversing cholinergic and hippocampal dopaminergic neuronal function.
... Broomrape protected the brain cells by scavenging oxygen free radicals and reducing lipid peroxidation damage to brain tissue [61,62]. It improved the learning and memory of AD mice by decreasing the content of MDA, increasing the activity of SOD, GSH-Px, and decreasing the activity of AChE, the apoptosis rate of brain cells, and the accumulation of calcium in brain tissue [63][64][65]. In AD patients, Broomrape improved the cognitive and self-care ability and delayed the progress of dementia [66]. ...
... Similarly, Acrous tatrinouill shots [49,51,103], Polygona sibiricum [52], and Cynomorium songaricum Rupr [54-56, 104, 105] also increased the brain SOD, reduced MDA, and improved the impairment of learning and memory, whereas Alpinia oxyphylla miq. fruit, Broomrape, and Astragalus membranaceus are antioxidative and antiapoptotic [57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]87], and Salvia miltiorrhiza decreased the brain lipid peroxidase in AD rats [76,80,81]. Ligusticum chuanxiong Hort inhibited free radicals in hypoxia and reduced neuronal apoptosis [85]. ...
With rapidly increased construction of nuclear power plants worldwide to reduce energy shortage and subsequent environment contamination, routine use of radiotherapy and radiodiagnosis equipment in the clinical medicine, the research on the health effect of radiation exposure has become a very important area to explore. Traditional Chinese Medicine (TCM) may be an ideal candidate therapy as it usually produces fewer side effects even with long-term administration. In this paper, we reviewed current therapeutic approaches to prevent radiation-induced brain neuropathological and functional changes. Neuroprotective effects of TCM in different brain injury models have been briefly summarized. We then reviewed the neuroprotective and radioprotective effect of TCM in different radiation exposure models and discussed the potential molecular mechanism(s) of the neuroprotective and radioprotective effect of TCM. The conclusions and future research directions were made in the last part of the paper.
... Herba (H.) Cistanche, a Chinese herbal medicine commonly used in mainland China for nourishing the kidneys and replenishing essence and blood, has been used to treat memory loss and senile constipation (17). Phenylethanoid glycoside (PhG), one of the major constituents in H. Cistanche, improves the impairment of neuronal apoptosis caused by Aβ 25-35 via its anti-oxidant effects (18,19). A previous study identified five major components from total PhGs, namely acteoside, 2'-acetylacteoside, echinacoside, cistanosides and isoacteoside (20). ...
The present study aimed to investigate the neuroprotective effects of phenylethanol glycosides (PhGs) on H2O2- and β-amyloid peptide (Aβ)1-42-induced injury of PC12 cells as an in vitro model of Alzheimer's disease (AD). The optimal induction conditions were established through screening of various incubation times and concentrations. PC12 cells were treated with 0.5 µM Aβ1-42 and H2O2 in the presence of PhGs for 24 h and the cell viability was then evaluated by an MTT assay; lactate dehydrogenase (LDH) release and malondialdehyde (MDA) content were also measured. The optimal conditions for establishing the AD model were the treatment of PC12 cells with 0.5 µM Aβ1-42 for 48 h, or with 25 µM H2O2 dissolved in DMEM with PBS. PhGs at concentrations of 5, 25 and 50 µg/ml increased the viability and decreased LDH and MDA release by PC12 cells injured with Aβ1-42 or H2O2. In conclusion, the model of Aβ1-42- and H2O2-induced PC12 cell injury was successfully established. PhGs were shown to have a significant neuroprotective effect against Aβ1-42- or H2O2-induced cell injury.
... Repeated administration of glycosides of Cistanche for 10 days reduced the MDA content and apoptosis rate of brain cells, improved SOD and GSH-Px, weakened Bax expression, and enhanced Bc-l2 expression. Bax weakening and enhanced Bc-l2 may induce the enhanced free removal of enzyme activity, reduced lipid oxidation reaction and inhibition of apoptosis of brain cells (Liu et al., 2006). Luo et al. also used the AD mouse model induced by the subcutaneous injection of aluminum chloride and demonstrated that Cistanches Herba enhanced learning and memory. ...
Cistanches Herba (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.
... b) Mechanism of action -Biactractylolide improves learning and memory in two different AD rat models and decreases AChE activity [20,21]. b) Mechanism of action -Glycosides of cistanche improve learning and memory in a mouse AD model, inhibit apoptosis and are anti-inflammatory [23]. The glycosides decrease cholinesterase activity, maintain ACh levels and improve learning and memory in a rat AD model [24]. ...
Several plant medicines are presented that have not been previously discussed in detail and are used in China and the USA for the management of Alzheimer's disease. These plant medicines may provide new leads for drug therapy of this disease. Prevention of Alzheimer's disease is presented as potentially the best way to manage the disease.
... In China, glycosides isolated from the stems of C. tubulosa have been approved as a treatment for vascular dementia. This is a government-approved drug containing phenylethanoid glycosides which have shown antioxidant properties and a neuroprotective function with ECH as a quality control compound (content more than 25%) [7,8]. It has recently been demonstrated that ECH protects against hepatotoxicity and is a potent promoter of neuronal survival that is induced by TNF-α and MPTP [9,10]. ...
We investigated whether suppression of nitric oxide (NO) implicated in the protective effect of echinacoside (ECH), a phenylethanoid glycoside, on H2O2-induced injury to the rat pheochromocytoma cell line (PC12 cells). Data show that application of ECH to H2O2-injured PC12 cells (HIPCs) increased cell viability and decreased the necrotic ratio. Laser scanning confocal microscopic (LSCM) analysis suggested that ECH exerted an inhibitory effect on the formation of NO. In addition, RT-PCR analysis revealed that ECH down-regulated p65 and iNOS mRNA expressions in HIPCs. In summary, suppression of NO is related to the protective effect of ECH on HIPCs.
... , as a quality control compound (content is more than 25 %) [12,13]. ECH is the first compound that was defined as a phenylethanoid glycoside. ...
We have investigated the protective effects of echinacoside (ECH), one of the phenylethanoid glycosides, on H(2)O(2)-induced cytotoxicity in the rat pheochromocytoma cell line (PC12 cells). Our data show that application of ECH to H(2)O(2)-injured PC12 cells (HIPCs) increased cell viability and decreased the apoptotic ratio. Flow cytometry (FCM) and laser scanning confocal microscopy (LSCM) analysis suggested that ECH exerted its inhibitory effects on the formation of reactive oxygen species (ROS) and the accumulation of intracellular free Ca(2+) ([Ca(2+)]i). In addition, ECH elevated the mitochondrial membrane potential (MMP) in HIPCs. Furthermore, Western blot analysis revealed that ECH prevented an H(2)O(2)-induced increase of the Bax/Bcl-2 ratio by down-regulating Bax protein expression and upregulating Bcl-2 protein expression. In summary, ECH showed significant neuroprotective effects on HIPCs through the mitochondrial apoptotic pathway, and could be a potential candidate for intervention in neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
Background: Some researches demonstrate that tea polyphenols (TP) has protective effects on neurotoxicity of hippocampal nerve cells induced by β-amyloid peptide (Aβ), 6-hydroxydopamine (6-OHDA) and oxidative substances. In addition, clinical preliminary examination indicates that TP plays a certain preventive and therapeutic effects on the reduction of recognition function in high-risk population with Alzheimer disease (AD); however, its target and mechanism are still hot topics. Objective: To observe the interfering effects of TP on cerebral nerve cell apoptosis induced by D-galactose and Aβ25-35 in mice. Design: Randomized controlled animal study. Setting: Department of Pharmacology, Pharmacological College of Jinan University. Materials: The experiment was carried out in the Experimental Center of Jinan University from September 2004 to January 2005. A total of 90 healthy Kumning mice, aged 2 months, each gender in half, weighing 26-28 g, were provided by Guangdong Provincial Medical Laboratory Animal Center. Tea polyphenols was provided by Zhejiang Oriental Tea Science and Technology Corporation (batch number: 20040203); D-galactose by Shanghai Number 2 Reagent Plant (batch number: 20030708); Aβ 25-35 by Sigma (batch number: 13/01/2004); vitamin E (Vit-E) by Shanghai Xinyi Pharmaceutical Factory (batch number: 20030708). Methods: Experimental interference: Mice based on body mass were randomly divided into 6 groups: sham operation group (n=17), model group (n=16), vitamin E group (n=16), low-dose (n=13), moderate-dose (n=14) and high-dose (n=14) tea polyphenols groups. In above-mentioned animals, except those in the sham operation group, all were given 120 mg/(kg · d) D-galactose for 12 consecutive weeks, and Aβ 25-35 (4 nmol) was slowly injected into the lateral cerebral ventricle. In sham operation group, the same volume of artificial cerebral spinal fluid (CSF) was internally injected into lateral ventricle. Drug treatment began at the first week. Mice in the sham operation group and model group were given distilled water, and the animals in other groups were given the above-mentioned drugs (100 mg/kg Vit-E, 100, 250 and 625 mg/kg TP), respectively. The volume of perfusion was 10 mL/kg, and the treatment lasted for 12 consecutive weeks. Experimental evaluation: After administration, LW-II water maze was used to measure learning and memory condition; brain, liver tissues and serum were obtained to measure activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA); Fura-2/AM loading method was used to measure Ca2+ concentration in erythrocytes and neurons; flow cytometer was used to detect cerebral nerve cell apoptosis. Main outcome measures: 1 Learning and memory ability; 2 SOD activity and MDA content in serum, liver and brain tissues; 3 Ca2+ concentration in erythrocytes and neurons; 4 cerebral nerve cell apoptosis. Results: All 90 mice were involved in the final analysis. 1 At 12 weeks after administration, time to swim out of the water maze in the moderate-dose and high-dose TP groups and Vit-E group was shorter than that in the model group, and numbers of errors in passing the blind alleys in the water maze was reduced as compared with those in the model group, and there was significant difference (P < 0.05-0.01). 2 SOD activities in the moderate-dose and high-dose TP groups were increased as compared with that in the model group, but MDA content in the high-dose TP group was decreased as compared with that in the model group. There was significant difference (P < 0.05 -0.01). 3 Ca2+ concentration in erythrocytes and neurons in the moderate-dose and high-dose TP groups and Vit-E group was lower than that in the model group, and there was significant difference (P < 0.05-0.01). 4 The rates of brain neurons apoptosis in treatment groups with different doses of TP were 12.6%, 18.6%, and 24.1% respectively, exhibiting significant difference as compared with the mice in sham operation group (P < 0.05-0.01) Conclusion: TP can inhibit cerebral nerve cell apoptosis induced by D-galactose and Aβ25-35 and improve learning and memory ability in model mice. The effects may be related to its action of raising general anti-oxidative ability and improvement of intracellular Ca overload induced by oxidative stress injury.
Aim: To study the protective effects of timosaponin B II on primary neurons against beta amyloid peptide 25-35 induced toxicity. Methods Immunofluorescence was used to identify primary neurons. MTT(tetrazolium salt) assay was used to measure neurons metabolic state. Spectrophotometric method was used to measure the release of LDH (lactate dehydrogenase), the activity of SOD (superoxide dismutase), the activity of AChE (acetylcholine) and the production of MDA(malonaldehyde) in the culture medium. Results: Treatment with beta amyloid peptide 25-35 (20 μmol · L-1) for 24 h caused a significant damage in primary neurons. Timosaponin B II 10-4 10-5 mol · L-1 markedly improved neurons metabolic activity, decresed the release of LDH and the production of MDA, markedly increased the activity of SOD and decresed the activity of AChE. Conclusion: Timosaponin B II could significantly reduce the neurotoxicity induced by beta amyloid peptide 25-35 in primary neurons. The mechanism of which may be related with resisting oxidative damage and regulating the cholinergic system.
Aim: To study whether or not the green tea catechins (EGCG) has physiological benefits and the underling protective mechanism. Methods: The subunit protein levels of α4inverted commasα7 of nAChR were detected by BCA protein assay, Dot Blot assay and MTT assay. Results: The results showed that the green tea catechins can significantly reduce the subunit protein levels of nAChR and decrease the cell activity induced by Aβ 1-40. Conclusions: EGCG can provide neuroprotection in vitro by up-regulating nAChR sununit levels and inhibiting the neurotoxin of Aβ1-40.
Aim: To investigate the effects of midazolam and penehyclidine hydrochloride on learning and memory function of mice. Methods: According to stratified random block design, 80 KM mice were divided into 4 groups: midazolam 1 mg·kg -1 (group M, n = 20), penehyclidine hydrochloride 0.2 mg·kg -1 (group P, n = 20), midazolam 1 mg·kg -1 + penehyclidine hydrochloride 0.2 mg·kg -1 (group M + P, n = 20) and control group (group NS, n = 20), and 20 mice in every group were divided randomly into experiments of testing memory acquisition (n = 10) and memory consolidation (n = 10) further. To evaluate the behavioral alteration with these agents, a step-through passive avoidance test was used. Mice were administrated agents before training section for testing memory acquisition, and administrated agents immediately after training section for testing memory consolidation. The step-through latencies and the number of errors on 1,2,3,4,5,6 and 7 day after the training were recorded. Results: Midazolam impaired memory acquisition and consolidation when administrated alone or in combination with penehyclidine hydrochloride. Administration of midazolam combinated with penehyclidine hydrochloride did not worsen the effect on memory acquisition, but worsen the effect on memory consolidation obviously. Furthermore, administration of midazolam combinated with penehyclidine hydrochloride impaired memory function persisting longer than that of administration of midazolam alone. Conclusion: Administration of midazolam and penehyclidine hydrochloride would result in inhibiting learning and memory function of mice.
Aim: To investigate the antioxidant property of general cistanosides (GCs) in human HL-60 cell line. Methods: GCs was obtained from the acetonic extract of Xinjiang Cistanch salsa; its in vitro antioxidant activity was studied in human HL-60 cell line oxidation system. The generation of cellular free radical (ROS) was followed by oxidation of DCFH-DA probing into its oxidized product DCF. The Ginkgo biloba extract EGB 761 was used as positive control. Results: At the concentration of 0.25, 0.50 g·L -1 and 0.75 g·L -1,GCs inhibited the ROS formation by 56% and 62% and 67%, respectively. The ROS inhibitory activity of GCs was similar to that of EGB 761. Conclusion: GCs has relatively high antioxidant activities in human HL-60 cell line.
The genus Cistanche generally has four species in China, including C. deserticola (CD), C. tubulosa (CT), C. salsa (CS) and C. sinensis (CSN), among which CD and CT are official herbal sources of Cistanche Herba (CH). To clarify the sources of CH and ensure the clinical efficacy and safety, a multi-step IR macro-fingerprint method was developed to analyze and evaluate the ethanol extracts of the four species. Through this method, the four species were distinctively distinguished, and the main active components phenylethanoid glycosides (PhGs) were estimated rapidly according to the fingerprint features in the original IR spectra, second derivative spectra, correlation coefficients and 2D-IR correlation spectra. The exclusive IR fingerprints in the spectra including the positions, shapes and numbers of peaks indicated that constitutes of CD were the most abundant, and CT had the highest level of PhGs. The results deduced by some macroscopic features in IR fingerprint were in agreement with the HPLC fingerprint of PhGs from the four species, but it should be noted that the IR provided more chemical information than HPLC. In conclusion, with the advantages of high resolution, cost effective and speediness, the macroscopic IR fingerprint method should be a promising analytical technique for discriminating extremely similar herbal medicine, monitoring and tracing the constituents of different extracts and even for quality control of the complex systems such as TCM.
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