Article

Rhodiola rosea Extract Protects Human Cortical Neurons against Glutamate and Hydrogen Peroxide-induced Cell Death Through Reduction in the Accumulation of Intracellular Calcium

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Abstract

The aim of this study was to investigate the neuroprotective effects of a titolated extract from Rhodiola rosea L. (RrE) and of salidroside (Sa), one of the major biologically active compounds extracted from this medicinal plant, against oxidative stressor hydrogen peroxide (H₂O₂) and glutamate (GLU)-induced cell apoptosis in a human cortical cell line (HCN 1-A) maintained in culture. The results obtained indicate that exposure of differentiated HCN 1-A neurons to GLU or H₂O₂ resulted in concentration-dependent cell death. A 24 h pre-treatment with RrE significantly increased cell survival and significantly prevented the plasma membrane damage and the morphological disruption caused by GLU or H₂O₂, indicating that neurons treated with RrE were protected from the neurotoxicity induced by the oxidative stressor used. In addition, RrE significantly reduced H₂O₂ or GLU-induced elevation of intracellular free Ca²⁺ concentration. The results obtained have also shown that Sa caused similar effects in all experimental models used; however, the potency of the action was lower than that of the extract containing corresponding quantities of Sa. These findings indicate that RrE has a neuroprotective effect in cortical neurons and suggest that the antioxidant activity of the RrE, due to the structural features of the synergic active principles they contain, may be responsible for its ability to stabilize cellular Ca²⁺ homeostasis.

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... In vitro studies were only included if they considered a direct effect of L-Glu on human neurons. A number of different neuronal models were considered: human neuroblastoma cells (SH-SY5Y) (n = 15) [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66], SK-N-BE (n = 1) [67], IMR-32 (n = 1) [68], HCN-1A human cortical neurons (n = 2) [69,70], human embryonic stem cell (HESC) line H9 (n = 1) [71], HB1.F3 human neural stem cells (NSCs) (n = 1) [72], and primary human fetal brain tissue (14-to 18-week aborted foetuses) (n = 2) [73,74], with studies listed in chronological order (Table 1). Studies utilised L-Glu directly or as MSG with concentrations ranging from 1.6 µM to 100 mM. ...
... Human fetal neurons displayed progressive loss throughout 6 d after L-Glu, as evidenced by microscopic examination [73]. For other primary fetal cortical neurons and stem cells, a significant reduction of cell viability was only observed in older cultures [71,74], as well as in HCN-1A and IMR-32 cell lines for which a significant loss of viability was observed after a 24 h incubation [68,70]. ...
... L-Glu caused a loss of neuronal membrane integrity and release of cytosolic lactate dehydrogenase (LDH) into the cell culture medium as an alternative means to quantify cell viability. L-Glu at a concentration range of 0.06 to 10 mM significantly increased LDH release in primary or neuronal cell lines [51,59,64,67,68,70,73]. An L-Glu concentration range from 0.8 to 50 mM applied to human neural stem cells caused significant LDH leakage in a concentration-dependent way and was maximal at 12.5 mM, indicative of saturation of cytotoxicity [72]. ...
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L-glutamate (L-Glu) is a nonessential amino acid, but an extensively utilised excitatory neurotransmitter with critical roles in normal brain function. Aberrant accumulation of L-Glu has been linked to neurotoxicity and neurodegeneration. To investigate this further, we systematically reviewed the literature to evaluate the effects of L-Glu on neuronal viability linked to the pathogenesis and/or progression of neurodegenerative diseases (NDDs). A search in PubMed, Medline, Embase, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between L-Glu and pathology for five NDDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Together, 4060 studies were identified, of which 71 met eligibility criteria. Despite several inadequacies, including small sample size, employment of supraphysiological concentrations, and a range of administration routes, it was concluded that exposure to L-Glu in vitro or in vivo has multiple pathogenic mechanisms that influence neuronal viability. These mechanisms include oxidative stress, reduced antioxidant defence, neuroinflammation, altered neurotransmitter levels, protein accumulations, excitotoxicity, mitochondrial dysfunction, intracellular calcium level changes, and effects on neuronal histology, cognitive function, and animal behaviour. This implies that clinical and epidemiological studies are required to assess the potential neuronal harm arising from excessive intake of exogenous L-Glu.
... Rhodiola rosea extract also increased in a time-and dose-dependent manner the activity of transplasma membrane oxidoreductase according to an indirect evaluation of the intracellular redox status in keratinocytes [39]. Rhodiola rosea extract and salidroside protected human cortical neurons from oxidative stress and prevented glutamate-induced cell apoptosis in a human cortical cell line (HCN 1-A) [40]. Aqueous and alcoholic extracts of Rhodiola rhizomes were observed to inhibit apoptosis and tert-butyl hydroperoxide (tert-BHP)-induced free radical production and to restore the antioxidant levels of U-937 human macrophages [41]. ...
... Protection against neuron and central neuron system disorders A titolated extract from Rhodiola rosea and salidroside protected human cortical cells (HCN 1-A) from oxidative stressors such as H 2 O 2 and glutamate-induced cell apoptosis [40]. Pretreatment with Rhodiola rosea extract significantly increased cell survival and prevented plasma membrane damage and morphological disruption caused by glutamate or H 2 O 2 , indicating that Rhodiola rosea extract protects neurons from oxidative-stress-induced disorders [40]. ...
... Protection against neuron and central neuron system disorders A titolated extract from Rhodiola rosea and salidroside protected human cortical cells (HCN 1-A) from oxidative stressors such as H 2 O 2 and glutamate-induced cell apoptosis [40]. Pretreatment with Rhodiola rosea extract significantly increased cell survival and prevented plasma membrane damage and morphological disruption caused by glutamate or H 2 O 2 , indicating that Rhodiola rosea extract protects neurons from oxidative-stress-induced disorders [40]. In addition, Rhodiola rosea extract significantly reduced oxidative-stress-induced elevation of intracellular free Ca 2þ concentrations [40]. ...
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Rhodiola is a genus of medicinal plants that originated in Asia and Europe and are used traditionally as adaptogens, antidepressants, and anti-inflammatory remedies. Rhodiola plants are rich in polyphenols, and salidroside and tyrosol are the primary bioactive marker compounds in the standardized extracts of Rhodiola rosea. This review article summarizes the bioactivities, including adaptogenic, antifatigue, antidepressant, antioxidant, anti-inflammatory, antinoception, and anticancer activities, and the modulation of immune function of Rhodiola plants and its two constituents, as well as their potential to prevent cardiovascular, neuronal, liver, and skin disorders.
... Preclinical studies have reported that RRE has anti-stress, neuropsychotropic, anxiolytic, antidepressant and neuroprotective effects [17,18]. In addition, Rhodiola rosea extract has antioxidant and anti-inflammatory effects [19,20]. No information was found in the literature about the effects of RRE in the treatment of stress-induced infertility and pathologies affecting reproductive processes. ...
... The benefit of Rhodiola rosea extract in the treatment of various psychological disorders is well known [17,18]. In addition, RRE has been shown to have antioxidant and anti-inflammatory effect, and inhibitory effect on IL-1β, TNF-α and IL-6 production [19,20,42]. Data showing that psychological disorders negatively affect duration of conception are available in the literature [43]. ...
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Purpose: The aim of the study was to examine the possible effect of Rhodiola rosea root extract (RRE) on ovarian damage, infertility (IF), delay in conception (DC), decrease in the number of offspring (NO) in female rats that have been stressed with compulsory immobilization method (CIM) and on retardation of intrauterine physical development (IPD) in offspring. Materials and methods: Female Albino Wistar rats were divided like: healthy (HG), stress-induced control (SC), and stress + 50 mg/kg RRE (S + REG) groups including sixteen rats in each group. Six rats from each group were killed for conducting biochemical and histopathological examinations in ovarian tissues and others were observed for IF, DC, NO, and IPD. Results: It was found that RRE significantly prevented the increase in oxidative parameters and proinflammatory cytokine levels in ovarian tissue of animals stressed with CIM. RRE suppressed the increase in IF rate and DC whereas caused a decrease in NO and in IPD retardation. Conclusion: These results suggested RRE may have beneficial effects in the treatment of stress induced reproductive dysfunction. Content: The effect of RRE on oxidative and inflammatory changes in ovarian tissue and reproductive changes of animals exposed to stress with compulsory immobilization method.
... Clinical studies have indicated beneficial effects of Rhodiola rosea extracts (including the WS®1375 extract) in stress and fatigue management as well as in building resilience [5][6][7][8][9][10][11][12][13]. RRE has also shown antioxidant, antiinflammatory, and neuroprotective effects in animal [14][15][16][17] and cellular models [18]. Phytochemically, extracts of Rhodiola rosea roots and rhizomes contain mainly six classes of compounds: flavonoids, phenolic acids, phenylethanoloids, phenylpropanoids, monoterpenes, and triterpenes. ...
... Both, salidroside and tyrosol, abolished the H 2 O 2 -induced oxidative damage in rat cortical neurons by decreasing the expression of Bax (a proapoptotic protein) with tyrosol being more effective possibly due to its position of the glycosyl group [56]. RRE pretreatment protected human cortical cells (HCN 1-A) against H 2 O 2 -and glutamate-induced cell apoptosis by normalizing the stress-induced increase in intracellular calcium concentration [18]. Salidroside exerted the same effects but in a lower extent than the extract indicating that the neuroprotective effect of RRE is a result of synergistic effect of its compounds. ...
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Background: Sustained stress with the overproduction of corticosteroids has been shown to increase reactive oxygen species (ROS) leading to an oxidative stress state. Mitochondria are the main generators of ROS and are directly and detrimentally affected by their overproduction. Neurons depend almost solely on ATP produced by mitochondria in order to satisfy their energy needs and to form synapses, while stress has been proven to alter synaptic plasticity. Emerging evidence underpins that Rhodiola rosea, an adaptogenic plant rich in polyphenols, exerts antioxidant, antistress, and neuroprotective effects. Methods: In this study, the effect of Rhodiola rosea extract (RRE) WS®1375 on neuronal ROS regulation, bioenergetics, and neurite outgrowth, as well as its potential modulatory effect on the brain derived neurotrophic factor (BDNF) pathway, was evaluated in the human neuroblastoma SH-SY5Y and the murine hippocampal HT22 cell lines. Stress was induced using the corticosteroid dexamethasone. Results: RRE increased bioenergetics as well as cell viability and scavenged ROS with a similar efficacy in both cells lines and counteracted the respective corticosteroid-induced dysregulation. The effect of RRE, both under dexamethasone-stress and under normal conditions, resulted in biphasic U-shape and inverted U-shape dose response curves, a characteristic feature of adaptogenic plant extracts. Additionally, RRE treatment promoted neurite outgrowth and induced an increase in BDNF levels. Conclusion: These findings indicate that RRE may constitute a candidate for the prevention of stress-induced pathophysiological processes as well as oxidative stress. Therefore, it could be employed against stress-associated mental disorders potentially leading to the development of a condition-specific supplementation.
... R. rosea increase in time and dose-dependent manner of plasma membrane oxidoreductase to the intracellular redox status in keratinocytes. R. rosea extract and salidroside protects the human cortical neurons from oxidative stress and prevents the glutamate-induced cell apoptosis in human cortical cell line (Palumbo DR et al., 2012) [41] . R. rosea aglycone, tyrosol has various biological properties such as cancer preventive and anti-inflammatory properties and prevent oxidative-stressrelated disorders (Tuck KL et al., 2002;Ko RK et al., 2011) [42,43] . ...
... R. rosea increase in time and dose-dependent manner of plasma membrane oxidoreductase to the intracellular redox status in keratinocytes. R. rosea extract and salidroside protects the human cortical neurons from oxidative stress and prevents the glutamate-induced cell apoptosis in human cortical cell line (Palumbo DR et al., 2012) [41] . R. rosea aglycone, tyrosol has various biological properties such as cancer preventive and anti-inflammatory properties and prevent oxidative-stressrelated disorders (Tuck KL et al., 2002;Ko RK et al., 2011) [42,43] . ...
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Rhodiola rosea L. is also called Golden root, Arctic root or Rose root. Its roots are act as adaptogens to help our body adapt to resist physical, chemical and environmental stress. Rhodiola rosea are rich in polyphenols, salidroside, tyrosol and other primary bioactive compounds. This review gives the information about the bioactivities it includes in anti-depressant, Anti-oxidant, Antifatique, Adaptogenic, anticancer activities and its current and future medical applications.
... Normally, the intracellular concentration of Ca 2+ keeps balance, and the significant changes in Ca 2+ may result in a series of physiological diseases (Echeverry et al., 2015). It has been reported that one possible mechanism for the cell apoptosis induced by H 2 O 2 is an increased concentration of Ca 2+ in cytoplasm (Palumbo, Occhiuto, Spadaro, & Circosta, 2012). As shown in Fig. 4e, the Ca 2+ concentration in LO2 cells was increased to 165% of the control value after exposure of H 2 O 2 . ...
... As shown in Fig. 4e, the Ca 2+ concentration in LO2 cells was increased to 165% of the control value after exposure of H 2 O 2 . This observation was consistent with the report in the literature, i.e.ÁH 2 O 2 induced an increase in Ca 2+ concentration in the cytoplasm (Palumbo et al., 2012;Shen et al., 2011). However, unlike the markedly decreased Ca 2+ concentration in PC12 cells with pre-incubation of fungal polysaccharides found in the literature (Shen et al., 2011), pretreatment of LO2 cells with 100 kGy-KGM did nothing to prevent the increased concentration of Ca 2+ induced by H 2 O 2 (Fig. 4f). ...
Article
Konjac glucomannan (KGM) is an important functional polysaccharide in food research. However, unstable dispersibility of KGM inhibits its in-depth study and wide application. In this study, a degraded KGM (100 kGy-KGM), which showed excellent dispersibility and specific physicochemical properties, were obtained by γ-irradiation in a dosage of 100 kGy. We investigated the protective effect of 100 kGy-KGM against H2O2 induced oxidative damage in LO2 cells. Our results demonstrated that pretreatment of LO2 cells with 100 kGy-KGM not only significantly increased cellular survivals and activities of GSH-Px and CAT, but also reduced levels of LDH, MDA and intracellular accumulation of ROS. The marked protective effect against oxidative damage and excellent dispersibility in 100 kGy-KGM allowed its possible use as an antioxidant. Our study provided fundamental knowledge to understand the structure-functions relationships of degraded-KGM, which could result in a theoretical guidance for the future application of KGM.
... Chronic exposure to low dose of the metal was shown to cause reduction in Ca 2+ -dependent glutamate and -aminobutyric acid (GABA) release in the hippocampus and overall presynaptic neuron dysfunction in rats [48,49]. The freely diffusible and stable ROS, H 2 O 2 , could induce oxidative stress by promoting calcium influx and interacting with iron or copper to generate toxic ROS, including the highly potent hydroxyl radical which can result in neuronal cell death [50,51]. H 2 O 2 has been postulated to be involved in neurodegenerative disease and the neuronal injury and death induced by amyloid beta protein and glutamate [51]. ...
... The freely diffusible and stable ROS, H 2 O 2 , could induce oxidative stress by promoting calcium influx and interacting with iron or copper to generate toxic ROS, including the highly potent hydroxyl radical which can result in neuronal cell death [50,51]. H 2 O 2 has been postulated to be involved in neurodegenerative disease and the neuronal injury and death induced by amyloid beta protein and glutamate [51]. Excessive calcium and lead could facilitate the generation of reactive oxygen species in biological systems. ...
... Chronic exposure to low dose of the metal was shown to cause reduction in Ca 2+ -dependent glutamate and -aminobutyric acid (GABA) release in the hippocampus and overall presynaptic neuron dysfunction in rats [48,49]. The freely diffusible and stable ROS, H 2 O 2 , could induce oxidative stress by promoting calcium influx and interacting with iron or copper to generate toxic ROS, including the highly potent hydroxyl radical which can result in neuronal cell death [50,51]. H 2 O 2 has been postulated to be involved in neurodegenerative disease and the neuronal injury and death induced by amyloid beta protein and glutamate [51]. ...
... The freely diffusible and stable ROS, H 2 O 2 , could induce oxidative stress by promoting calcium influx and interacting with iron or copper to generate toxic ROS, including the highly potent hydroxyl radical which can result in neuronal cell death [50,51]. H 2 O 2 has been postulated to be involved in neurodegenerative disease and the neuronal injury and death induced by amyloid beta protein and glutamate [51]. Excessive calcium and lead could facilitate the generation of reactive oxygen species in biological systems. ...
... Chronic exposure to low dose of the metal was shown to cause reduction in Ca 2+ -dependent glutamate and -aminobutyric acid (GABA) release in the hippocampus and overall presynaptic neuron dysfunction in rats [48,49]. The freely diffusible and stable ROS, H 2 O 2 , could induce oxidative stress by promoting calcium influx and interacting with iron or copper to generate toxic ROS, including the highly potent hydroxyl radical which can result in neuronal cell death [50,51]. H 2 O 2 has been postulated to be involved in neurodegenerative disease and the neuronal injury and death induced by amyloid beta protein and glutamate [51]. ...
... The freely diffusible and stable ROS, H 2 O 2 , could induce oxidative stress by promoting calcium influx and interacting with iron or copper to generate toxic ROS, including the highly potent hydroxyl radical which can result in neuronal cell death [50,51]. H 2 O 2 has been postulated to be involved in neurodegenerative disease and the neuronal injury and death induced by amyloid beta protein and glutamate [51]. Excessive calcium and lead could facilitate the generation of reactive oxygen species in biological systems. ...
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Objective: Methanolic leaf extracts of Parkia biglobosa, PBE, and one of its major polyphenolic constituents, catechin, were investigated for their protective effects against neurotoxicity induced by different agents on rat brain hippocampal slices and isolated mitochondria. Methods: Hippocampal slices were preincubated with PBE (25, 50, 100, or 200 µg/mL) or catechin (1, 5, or 10 µg/mL) for 30 min followed by further incubation with 300 µM H2O2, 300 µM SNP, or 200 µM PbCl2 for 1 h. Effects of PBE and catechin on SNP- or CaCl2-induced brain mitochondrial ROS formation and mitochondrial membrane potential (ΔΨm) were also determined. Results: PBE and catechin decreased basal ROS generation in slices and blunted the prooxidant effects of neurotoxicants on membrane lipid peroxidation and nonprotein thiol contents. PBE rescued hippocampal cellular viability from SNP damage and caused a significant boost in hippocampus Na(+), K(+)-ATPase activity but with no effect on the acetylcholinesterase activity. Both PBE and catechin also mitigated SNP- or CaCl2-dependent mitochondrial ROS generation. Measurement by safranine fluorescence however showed that the mild depolarization of the ΔΨm by PBE was independent of catechin. Conclusion: The results suggest that the neuroprotective effect of PBE is dependent on its constituent antioxidants and mild mitochondrial depolarization propensity.
... 6 R. rosea exerts antioxidant effects and thereby reduced tissue injury, resulting from oxidative stress. 7,8 However, the efficacy of R. rosea in renal tissue damage after ureter obstruction has not been investigated. In the present study, we assessed the efficacy of R. rosea at alleviating the renal damage induced by unilateral ureter obstruction (UUO) in rats. ...
... 7 Palumbo et al. reported that R. rosea had antioxidant properties and acted as a neuroprotector of cortical neurons. 8 Our results also indicate that R. rosea possesses antioxidant activity. R. rosea may alleviate the renal damage induced by UUO through its antioxidant effects. ...
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Purpose: To evaluate the efficacy of Rhodiola rosea extract in terms of alleviating the renal damage induced by unilateral ureter obstruction (UUO) in rats. Material and methods: Thirty Wistar albino male rats were divided into five groups: (I) Control, (II) UUO 7 days, (III) UUO 7 days+extract,(IV) UUO 14 days, and (V) UUO 14 days+extract. Seven or 14 days after the initiation of the experimental procedure, the left kidneys of rats in all five groups were removed for histological examination, and their blood was drawn for biochemical measurements. Result: Median malondialdehyde (MDA) and glutathione peroxidase (GPx) levels were, respectively, 39.4 (5.04) nmol/mL and 25.8 (8.01) nmol/minute/mL in group I, 77.9 (12.38) nmol/mL and 5.8 (1.95) nmol/minute/mL in group II, 48.7 (12.1) nmol/mL and 9.1 (2.3) nmol/minute/mL in group III, 58.5 (23.83) nmol/mL and 8.4 (2.1) nmol/minute/mL in group IV, and 44.8 (4.97) nmol/mL and 13.8 (3.73) nmol/minute/mL in group V. There was a statistically significant difference among the groups in terms of MDA and GPx levels (p<0.05 for both). The median numbers of apoptotic cells were 1 (1), 8 (2.25), 3 (1.25), 23.5 (9), and 7 (I) in groups I, II, III, IV, and V, respectively. There was a statistically siginificant difference among the groups in terms of apoptotic cell number (p<0.05). Conclusion: R. rosea extract was shown to alleviate the renal damage induced by UUO through its antioxidant effects. The mechanism by which R. rosea extract causes these effects merits further investigation.
... Clinical studies have shown that RW preparations can reduce the symptoms of AP, heart failure and other heart diseases, have antioxidant and antiinflammatory effects, and reduce hypoxia-induced cellular oxidative stress (6,7). Moreover, modern pharmacological researches have revealed multiple bioactivities of RW plants, such as antioxidative (8,9), immunomodulatory (10), anti-Inflammatory (11), antidiabetic (12,13), antihypertensive and neuroprotective (14,15) antistress and antidepressant (16)(17)(18), anti-altitude sickness (19,20), antifatigue (21,22), and anticancer (23,24) activities. The relationship between the chemical profile and bioactivities of RW should be established. ...
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Background Rhodiola wallichiana var. cholaensis (RW) is one of the traditional Chinese medicinal materials, which is used to treat angina pectoris (AP). However, the possible underlying mechanisms remains unclear. The aim of this study was to explore RW in the treatment of AP and to identify the potential mechanism of the core compounds. Methods In this study, systematic and comprehensive network pharmacology and molecular docking were used for the first time to explore the potential pharmacological mechanisms of RW on AP. First, the relative compounds were obtained by mining the literature, and potential targets of these compounds using target prediction were collected. We then built the AP target database using the DigSee and GeneCards databases. Based on the data, overlapping targets and hub genes were identified with Maximal Clique Centrality (MCC) algorithm in Cytoscape, cytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and protein-protein interaction (PPI) analysis were performed to screen the hub targets by topology. Molecular docking was utilized to investigate the receptor-ligand interactions on Autodock Vina and visualized in PyMOL. Results A total of 218 known RW therapeutic targets were selected. Systematic analysis identified nine hub targets (VEGFA, GAPDH, TP53, AKT1, CASP3, STAT3, TNF, MAPK1 and JUN) mainly involved in the complex treatment effects associated with the protection of the vascular endothelium, as well as the regulation of glucose metabolism, cellular processes, inflammatory responses, and cellular signal transduction. Molecular docking indicated that the core compounds had good affinity with the core targets. Conclusions The results of this study preliminarily identify the potential targets and signaling pathways of RW in AP therapy and lay a promising foundation for further experimental studies and clinical trials.
... The oxidative damage induced by exercise fatigue can be prevented by optimizing nutrition, especially by increasing the dietary antioxidant content (38). Salidroside, acting as an exogenous antioxidant, can effectively prevent and delay oxidative damage, reduce MDA levels, enhance the activities of the antioxidant enzymes SOD, CAT and GSH-Px, while maintaining its own antioxidant activity and stabilizing Ca 2+ homeostasis in cells (39). Amarkand extract is rich in polyphenols and can significantly extend swimming endurance time by mitigating oxidative stress and by improving various injuries related to fatigue, leading to an increase in the aerobic metabolism of glucose and endurance (40). ...
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Exercise fatigue can exert deleterious effects on the body. This study evaluated the effects and mechanisms by which Lonicera caerulea berry polyphenols extract (LCBP) improved the treadmill endurance of mice. Comparison was performed between the effects at 25°C and low temperatures (-5°C). Energy storage, product metabolism, and other biochemical indices were determined using vitamin C (VC) as a positive control. Co-immunoprecipitation was performed to detect the interaction between different proteins. Dietary supplementation with LCBP significantly prolonged the exhaustion time during treadmill exercise by 20.4% (25 °C) and 27.4% (-5 °C). LCBP significantly regulated the expression of antioxidant and inflammatory proteins, Bcl-2 /Bax apoptosis proteins, and the PKCα -NOx2 / Nox4 pathway proteins, and activated the expression of AMPK-PGC1α -NRF1-TFAM proteins in skeletal muscle mitochondria. The gene and protein expression of miRNA-133a/IGF-1/PI3K/Akt/mTOR in skeletal muscle cells was also activated. Molecular docking confirmed that the main components of LCBP such as cyanidin-3-glucoside, catechin, and chlorogenic acid, have strong binding affinity toward AMPKα. LCBP alleviates exercise fatigue in mice by reducing oxidative stress, inflammation, and apoptosis of skeletal muscle cells, enhances mitochondrial biosynthesis and cell proliferation, reduces fatigue, and enhances performance. These effects are also significant in a low-temperature environment (Graphical Abstract). Consequently, these results provide novel insights into the anti- fatigue roles of LCBP in exercise fatigue.
... In contrast, while caffeine inhibits phosphodiesterase, resulting in enhanced cyclic AMP concentrations, adaptogens have often been observed to reduce cyclic AMP concentrations via down-regulation of adenylate cyclase, and the up-regulation of phosphodiesterase [68]. Moreover, under many conditions, caffeine also stimulates glutamate and acetylcholine biosynthesis primarily via adenosine A1 antagonism [76,77], whereas adaptogens are associated with a reduction in glutamate excitotoxicity [78]. ...
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Using a placebo-controlled, double-blinded, within-participants, randomized, cross-over design, we examined the neurocognitive effects of a: (a) caffeine-containing, adaptogenic herbal-rich natural energy shot (e+ shot), (b) a matched caffeine-containing shot (caffeine), and, (c) a placebo. Participants (n = 30) were low consumers of caffeine without elevated feelings of energy. Before and three times after beverage consumption, a 27-min battery was used to assess motivation to perform cognitive tasks, mood, attention ((serial subtractions of 3 (SS3) and 7 (SS7), the continuous performance task (CPT), and the rapid visual input processing tasks)), heart rate (HR), blood pressure (BP), and motor coordination (nine-hole peg test) with a 10-min break between each post-consumption battery. The procedure was repeated for each beverage for each participant at least 48 h apart and within 30 min the same time of day using a random group assignment with blinding of researchers and subjects. To evaluate for changes in outcomes, a Treatment × Time analysis of covariance controlling for hours of prior night’s sleep was used. Analysis of all outcomes and all treatment comparisons indicated that compared to placebo, both e+ shot (Δ = 2.60; η2 = 0.098) and caffeine (Δ = 5.30, η2 = 0.098) increased systolic BP 30 min post consumption (still within normal healthy ranges). The caffeine beverage also led to an improvement in most cognitive measures and moods 30-min post-consumption with improvements tapering at 69 and 108 min, while e+ shot noted more steady improvements with no significant differences between beverages on most cognitive and mood measures at 69 and 108 min. However, compared to caffeine, e+ shot noted a significant increase in reaction time at 108 min, while caffeine noted a small change in the opposite direction. No side-effects were reported by any intervention. These results suggest that the specific blend of adaptogens in e+ shot may modulate the neurocognitive effects of caffeine on mood, and cognition.
... 。郁金含有挥发油、姜黄素和多糖等成分, 其中姜黄素可能通过调节AKt及其磷酸化过程,调节 PI3K/Akt途径的胰岛素信号转导通路,从而发挥神经 保护作用 [12] 。临床研究 [13] 表明:醒脑静注射液可以 通过血脑屏障直接作用于中枢神经系统,增强大脑 功能。本研究结果表明:单次通过静脉给予醒脑静 注射液能够显著缩短大鼠苏醒时间,多次给药能改 善昏迷苏醒后大鼠抓力和自主活动,提示醒脑静注射 液能明显改善脑缺血昏迷后神经功能的恢复。 Glu和DA是调节中枢神经系统重要的神经递 质。脑缺血昏迷后,Glu释放增加,Glu受体过度激活 产生兴奋性神经毒性,钙离子胞内超载、神经元凋 亡、NO及大量自由基导致炎症反应 [14] 。研究 [15][16] 量与CREB的磷酸化水平呈正比 [20][21] ...
Article
Objective: To study the protective effect of Xingnaojing Injection on early global brain ischemia-induced deep coma in rats. Methods: The deep coma model was induced by global brain ischemia by using four-vessel occlusion method in male SD rats. According to the body weight, the rats were randomly divided into 8 groups: a model control group, three different dose of Xingnaojing Injection (1.8, 3.6 and 5.4 mL.kg-1) groups, a Xingnaojing Injection (3.6 mL.kg-1) plus PI3K inhibitor group, a naloxone injection (0.04 mL.kg-1) group and a naloxone injection (0.04 mL.kg-1) plus Xingnaojing Injection (3.6 mL.kg-1) group (n=8 per group). In addition, eight animals served as the sham group were performed same operation with the model group excepting no blockage of the blood vessels. After the operation, three different doses of Xingnaojing Injection and/or naloxone injection were given intravenously once a day for three days. Ten μL PI3K inhibitor (LY294002, 10 mmol/L) was injected via anterior cerebral ventricle at once after global brain ischemia. The awakening time after the first drug treatment, the grasping power and the autonomous activity within 10 min after the last drug treatment were recorded. The levels of both dopamine (DA) and glutamate (Glu) in cerebrospinal fluid were detected by ELISA. The pathological changes were observed in brain tissue slices with HE staining and the protein levels of Akt/p-Akt and cAMP-response element binding protein (CREB)/p-CREB in hippocampus were detected by Western blotting. Results: Comparing with the model group, single administration of Xingnaojing Injection could significantly shorten the waking time (P<0.05) and continuous administration of Xingnaojing Injection for 3 d could increase grasping power, distance, frequency and duration of autonomous activities (P<0.05 or P<0.01) in the deep coma rat. Also, Xingnaojing Injection could inhibit these increases in neurotransmitters DA and Glu contents (P<0.05 or P<0.01), and improve pathological changes of hippocampal tissue. Xingnaojing Injection significantly induced protein phosphorylation of both Akt and CREB (P<0.05 or P<0.01); this effect was inhibited by PI3K inhibitor (P<0.05 or P<0.01). Moreover, the protective effects of naloxone on awakening time, grasping power, the autonomous activity and hippocampus damage in global brain ischemia-induced deep coma could be enhanced by joint use of Xingnaojing Injection (P<0.05 or P<0.01). Conclusion: Xingnaojing Injection could significantly improve deep coma induced by global brain ischemia in rat, which is related to inducing PI3K/Akt-dependent protein phosphorylation of CREB, and reducing hippocampal damage. The protective effect of Xingnaojing Injection is synergistically enhanced by naloxone.
... Hyperactivation of glutaminergic receptors leads to neuronal damage and cell death (excitotoxicity) [39].In L-glu-induced excitotoxicity model in vitro, Rhodiola rosea L. or its active compounds exert neuroprotective effects partly by stabilization of cellular Ca 2+ homeostasis. Dora Rita Palumbo et al. found that for human cortical cell line (HCN 1-A), Rhodiola rosea L. extract and salidroside increased cell survival, decreased the morphological disruption and intracellular free Ca 2+ concentration [40]. Similar results were found in PC-12 cell line (rat pheochromocytoma cell) [41]. ...
Article
Rhodiola rosea L., a worldwide botanical adaptogen, has been confirmed to possess protective effects of inflammatory injury for many diseases, including cardiovascular diseases, neurodegenerative diseases, diabetes, sepsis, and cancer. This paper is to review the recent clinical and experimental researches about the anti-inflammatory effects and the related mechanisms of Rhodiola rosea L. extracts, preparations, and the active compounds. From the collected information reviewed, this paper will provide the theoretical basis for its clinical application, and provide the evidences or guidance for future studies and medicinal exploitations of Rhodiola rosea L.
... Further investigations of R. rosea on normal melanocytes, including in vivo studies, are needed to corroborate these findings. A hydroethanolic extract of R. rosea rhizome [18] protected human brain cortical cells (HCN 1-A) against H 2 O 2 and glutamate toxicity. Thus, at concentrations ranging from 0.1-100 µg/mL, the extract enhanced cell viability and protected normal polarized morphogenesis in vitro. ...
Article
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The traditional medicines of Asia and Europe have long used various Rhodiola species, which are endemic to the subarctic areas of the northern hemisphere, as tonic, adaptogen, antidepressant, and anti-inflammatory drugs. In order to establish the therapeutic uses of these plants in modern medicine, the pharmacological effects of Rhodiola sp. have been widely studied. Indeed, the most amply researched species, Rhodiola rosea, has been shown to possess antioxidant, adaptogenic, antistress, antimicrobial, immunomodulatory, angiomodulatory, and antitumoral effects. Salidroside (p-hydroxyphenethyl-β-D-glucoside), a major compound in Rhodiola, seems to be responsible for many of the effects observed with Rhodiola extracts.The aim of this paper is to review the pharmacological effects not only of various Rhodiola species, mainly R. rosea along with Rhodiola imbricata, Rhodiola algida, and Rhodiola crenulata, but also of salidroside, focusing especially on its antioxidant, immunomodulatory, antitumoral, and antiproliferative activities, as well as to describe their therapeutic significance in disease management. Although previous pharmacological studies have established a scientific basis for possible therapeutic uses of Rhodiola extracts and salidroside, high-quality, randomized, controlled clinical trials are still needed. Georg Thieme Verlag KG Stuttgart · New York.
... ERα expression is necessary in astrocytes, but not neurons, for neuroprotection in experimental autoimmune encephalomyelitis, the most widely used mouse model of multiple sclerosis, an autoimmune disease characterized by demyelination and axonal degeneration (Spencea et al. 2011). Consequently, it can be expected that the neuroprotective effect of Rhodiola (Zhang et al. 2007(Zhang et al. , 2010Chen et al. 2009a,b;Bocharov et al. 2010;Fletcher et al. 2010;Li et al. 2011;Palumbo et al. 2012;Shi et al. 2012) must be associated with upregulation ESR1 in glia cells. Surprisingly, the results of a study we conducted are not in line with this hypothesis, because Rhodiola downregulate ERα gene expression. ...
... Exposure to H 2 O 2 resulted in 60 % cell death, while after a 24-h pretreatment, the extract prevented the reduction in neuronal viability by 55-60 %. The levels of lactate dehydrogenase (LDH) decreased by 25-50 %, compared to the H 2 O 2 -treated cells (Palumbo et al. 2012). Salidroside (10-100 lM) restored the survival of human neuroblastoma cells (SH-SY5Y) up to 76 % in comparison with the cell death (57.5 %) induced by H 2 O 2 (Zhang et al. 2007). ...
Article
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Rhodiola rosea L. is a worldwide popular plant with adaptogenic activities that have been and currently are exploited in the traditional medicine of many countries, as well as, examined in a number of clinical trials. More than 140 chemical structures have been identified which belong to several natural product classes, including phenylpropanoid glycosides, phenylethanoids, flavonoids and essential oils, and are mainly stored in the rhizomes and the roots of the plant. A number of mechanisms contribute to the adaptogenic activities of R. rosea preparations and its phytochemical constituents. Among them, the intrinsic inducible mammalian stress responses and their effector proteins, such as heat shock protein 70 (Hsp70), are the most prominent. Due to its popular medicinal use, which has led to depletion of its natural habitats, R. rosea is now considered as endangered in most parts of the world. Conservation, cultivation and micropropagation are all implemented as potential preservation strategies. A number of in vitro systems of R. rosea are being developed as sources of pharmaceutically valuable secondary metabolites. These are greatly facilitated by advances in elucidation of the biosynthetic pathways and the enzymes, which catalyse the production of these secondary metabolites in the plant. In addition, biotechnological approaches show promise towards achieving sustainable production of R. rosea secondary metabolites.
... Naïve rats treated with the extract showed the prolongation of latency of reaction of both passive avoidances compared to the control, and also the scopolamine groups -probably by non-specific mechanisms on cholinergic neurons-showing the plant extract can be a preventive agent against dementia [46]. R. rosea extract protects human cortical neurons against glutamate and hydrogen peroxide-induced cell death through reduction in the accumulation of intracellular calcium [47]. 'Fatigue index' which is an overall level of measurement of mental fatigue involving complex cognitive functions (associative thinking, calculation, concentration, speed of audio-visual perception) was found significantly enhanced in physicians on long night duty without any side effects [48]. ...
Article
Potential of the medicinal plant Rhodiola rosea belonging to the angiosperm family Crassulaceae, has been used by mankind since time immemorial. However, scientific research documentation of this medicinal plant is gradually growing in literature throughout the world. R. rosea plant is known for its astonishing capacity in rejuvenation of life, cellular longevity, antioxidant capacity, and cardio-protective as well as neuroprotective nature; and over all, its central role as a powerful adaptogen, which is now being commercially exploited to prevent fatigues, illness, and even death in harsh climatic conditions. Its protective role in Cognitive Biology is pharmacologically proved. In this review paper, biology of the plant, medicinal properties, and pharmacological formulations have been structured. The cellular and molecular mechanisms, metabolic cross-talk, and regulation of gene expressions by plant formulations during prevention of human sufferings have also been reviewed.
... Naïve rats treated with the extract showed the prolongation of latency of reaction of both passive avoidances compared to the control, and also the scopolamine groups -probably by non-specific mechanisms on cholinergic neurons-showing the plant extract can be a preventive agent against dementia [46]. R. rosea extract protects human cortical neurons against glutamate and hydrogen peroxide-induced cell death through reduction in the accumulation of intracellular calcium [47]. 'Fatigue index' which is an overall level of measurement of mental fatigue involving complex cognitive functions (associative thinking, calculation, concentration, speed of audio-visual perception) was found significantly enhanced in physicians on long night duty without any side effects [48]. ...
Article
Potential of the medicinal plant Rhodiola rosea belonging to the angiosperm family Crassulaceae, has been used by mankind since time immemorial. However, scientific research documentation of this medicinal plant is gradually growing in literature throughout the world. R. rosea plant is known for its astonishing capacity in rejuvenation of life, cellular longevity, antioxidant capacity, and cardio-protective as well as neuroprotective nature; and over all, its central role as a powerful adaptogen, which is now being commercially exploited to prevent fatigues, illness, and even death in harsh climatic conditions. Its protective role in Cognitive Biology is pharmacologically proved. In this review paper, biology of the plant, medicinal properties, and pharmacological formulations have been structured. The cellular and molecular mechanisms, metabolic cross-talk, and regulation of gene expressions by plant formulations during prevention of human sufferings have also been reviewed.
... Naïve rats treated with the extract showed the prolongation of latency of reaction of both passive avoidances compared to the control, and also the scopolamine groups -probably by non-specific mechanisms on cholinergic neurons-showing the plant extract can be a preventive agent against dementia [46]. R. rosea extract protects human cortical neurons against glutamate and hydrogen peroxide-induced cell death through reduction in the accumulation of intracellular calcium [47]. 'Fatigue index' which is an overall level of measurement of mental fatigue involving complex cognitive functions (associative thinking, calculation, concentration, speed of audio-visual perception) was found significantly enhanced in physicians on long night duty without any side effects [48]. ...
Article
Potential of the medicinal plant Rhodiola rosea belonging to the angiosperm family Crassulaceae, has been used by mankind since time immemorial. However, scientific research documentation of this medicinal plant is gradually growing in literature throughout the world. R. rosea plant is known for its astonishing capacity in rejuvenation of life, cellular longevity, antioxidant capacity, and cardio-protective as well as neuroprotective nature; and over all, its central role as a powerful adaptogen, which is now being commercially exploited to prevent fatigues, illness, and even death in harsh climatic conditions. Its protective role in Cognitive Biology is pharmacologically proved. In this review paper, biology of the plant, medicinal properties, and pharmacological formulations have been structured. The cellular and molecular mechanisms, metabolic cross-talk, and regulation of gene expressions by plant formulations during prevention of human sufferings have also been reviewed.
... Furthermore, R. rosea helps balance the stressresponse system by preventing excessive release of stress hormones like cortisol (Panossian et al., 2010). Salidroside, an important neuroprotective constituent of R. rosea blocks apoptosis in rat neuronal cells (Cai et al. 2008), attenuates glutamate-induced apoptosis in primary hippocampal neurons (Chen et al. 2008), protects neuronal PC12 cells against amyloid peptide cytotoxicity (Jang et al. 2003) and protects human cortical cells against oxidative injury (Palumbo, Occhiuto, Spadaro, & Circosta, 2012). R. rosea extracts alone, salidroside, and a combination of R. rosea, Schizandra chinensis, and Eleutherococcus senticosus (Adapt232, Swedish Herbal Institute) exhibit metabolic and transcriptional effects on mediators of the stress response, homeostasis, energy metabolism, and the neuroendocrine-immune system . ...
Article
Background: Complementary and alternative medicine (CAM) in psychiatry or integrative psychiatry covers a wide range of biological, psychological and mind-body treatments that enhance standard medical practices and patient outcomes. While CAM approaches are popular amongst patients in their practice as well as in self-report because of their ease of use, health professionals have received limited education in these interventions and often are unaware of their patients' use of CAM treatments. Method: This overview highlights evidence-based CAM treatments for attention deficit hyperactivity disorder (ADHD) including dietary interventions, phytomedicines, mind-body practices and neurofeedback. Results: While conventional treatments are the mainstays for ADHD, there are a large number of available treatments that can be used to enhance treatment response. Conclusion: With improved education and further scientific and clinical research, validated integrative treatments will provide more effective, lower risk and lower cost care for patients with ADHD.
... degeneration (Spencea et al., 2011). Consequently, it can be expected that neuroprotective effect of adaptogens (Kim et al., 2004;Bu et al., 2005;Chen et al., 2009a;Qu et al., 2009;Bocharov et al., 2010;Zhang et al., 2007Zhang et al., , 2010Li et al., 2011;Lee et al., 2012a,b;Palumbo et al., 2012;Shi et al., 2012;Zeng et al., 2012) must be associated with up-regulation ESR1 in glia cells. Surprisingly, the results of our study are not in line with this anticipation because adaptogens down-regulate ERα gene expression. ...
Conference Paper
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Gene expression profiling was conducted on the human neuroglial cell line, T98G, after treatment with either a complex herbal formulation (ADAPT-232) or its constituents, which included extracts of Eleutherococcus senticosus root, Schisandra chinensis berry, and Rhodiola rosea root or several individual constituents, including eleutheroside E, schizandrin B, salidroside, triandrin, and tyrosol. The concentration at which the compounds were tested strongly influenced both the intensity of the cellular response and the profile of differentially expressed genes. Combining two or more active substances in one mixture significantly changed deregulated gene profiles: synergetic interactions resulted in activation of genes that none of the individual substances affected; antagonistic interactions resulted in suppression of some genes that had been activated by the individual substances. These interactions may influence transcriptional control of metabolic regulation, on both the cellular and the whole organism levels. This study was the first to demonstrate that combining active substances with different deregulated gene array profiles and intracellular networks could produce a new substance with unique pharmacological characteristics. Thus, the mixture of two chemical substances could produce a qualitatively new substance, biologically different from its constituents. Presumably, this phenomenon could be used to eliminate undesirable effects (e.g. toxic effects) and increase the selectivity of pharmacological interventions.
... Hippocampal sections of Rr group (GIII) stained with anti-CASP 3 antibody revealed no immunoreactivity in all layers of DG. This was in accordance with Palumbo et al. (18) who showed the neuroprotective effect of Rr in cortical neurons. It significantly increased cell survival, decreased apoptosis and significantly prevented the plasma membrane damage and the morphological disruption caused by oxidative stress. ...
Article
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Depression is one of the most prevalent psychiatric disorders. Endogenous neural stem cells (NSCs) could replace damaged Hippocampal neurons in depression. This work was planned to evaluate Rhodiola rosea (Rr) extract possible role in stimulation of NSCs proliferation and in depression improvement. Thirty adult male albino rats were divided into three groups; control, untreated depressed model and Rr model. After depression induction by chronic mild stress, rats received Rr extract 1.5 g/kg/day for three weeks. The sucrose preference test (SP) was done before, after depression induction and 3 weeks after supplementation of Rr. The brain was removed and processed for H&E and immunohistochemical staining for caspase 3, glial fibrillary acid protein (GFAP) and proliferating cell nuclear antigen (PCNA). Rr group revealed improved sucrose preference, increased undamaged neurons and decreased dark neurons. Moreover, Caspase 3 +ve cells were not detected, GFAP +ve cells increased and PCNA +ve cells were detected only in Rr group. This work points to the role of Rr in depression improvement and in stimulation of NSCs proliferation.
... Salidroside is reported to inhibit the proliferation of cancer cells [40], but there are as much reports that show an antiapoptotic effect [41] and pro-proliferative effect especially on fibroblasts [42,43]. Furthermore, salidroside attenuates the level of intracellular calcium [44], resulting in a support of keratinocyte proliferation. Supernatants might relate to the increased cell number particularly with regard to the unaltered reduction of MTT and WST-1 test compared to untreated cells. ...
Article
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Methanolic avocado (Persea americana Mill., Lauraceae) seed extracts were separated by preparative HSCCC. Partition and HSCCC fractions were principally characterized by LC-ESI-MS/MS analysis. Their in vitro influence was investigated on proliferation, differentiation, cell viability, and gene expression on HaCaT and normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF). The methanol-water partition (M) from avocado seeds and HSCCC fraction 3 (M.3) were mostly composed of chlorogenic acid and its isomers. Both reduced NHDF but enhanced HaCaT keratinocytes proliferation. HSCCC fraction M.2 composed of quinic acid among chlorogenic acid and its isomers inhibited proliferation and directly induced differentiation of keratinocytes as observed on gene and protein level. Furthermore, M.2 increased NHDF proliferation via upregulation of growth factor receptors. Salidrosides and ABA derivatives present in HSCCC fraction M.6 increased NHDF and keratinocyte proliferation that resulted in differentiation. The residual solvent fraction M.7 contained among low concentrations of ABA derivatives high amounts of proanthocyanidins B1 and B2 as well as an A-type trimer and stimulated proliferation of normal cells and inhibited the proliferation of immortalized HaCaT keratinocytes.
... γ-amino butyric acid larly in improving memory and concentration, alleviating depression, and improving mental performance under stressful conditions [10]. The Eurasian variety of R. rosea has neuroprotective [12,13], antidepressant [14], and stress-reducing activities [15]. ...
Article
Rhodiola rosea is a medicinal plant used by the indigenous Inuit people of Nunavik and Nunatsiavut, Eastern Canada, as a mental and physical rejuvenating agent. This traditional use led to the present investigation of R. rosea in the context of anxiety disorders. An alcohol extract of R. rosea roots was characterized phytochemically and orally administered for three consecutive days to Sprague-Dawley rats at 8 mg/kg, 25 mg/kg, and 75 mg/kg body weight. The rats were subjected to three behavioral paradigms of anxiety, including the elevated plus maze, social interaction, and contextual conditioned emotional response tests. Rhodiola rosea showed dose-dependent anxiolytic activity in the elevated plus maze and conditioned emotional response tests, with moderate effects in the higher-anxiety SI test. The active dose varied according to the anxiety test. In order to elucidate a mechanism, the extract was further tested in an in vitro GABAA-benzodiazepine receptor-binding assay, where it demonstrated low activity. This study provides the first comparative assessment of the anxiolytic activity of Nunavik R. rosea in several behaviour models and suggests that anxiolytic effects may be primarily mediated via pathways other than the GABAA-benzodiazepine site of the GABAA receptor.
... However, in several cellular experimental paradigms, it has been observed that tyrosol shows potent biological activities regardless of its weak anti-oxidative strength (Giovannini et al., 1999;Samuel, Thirunavukkarasu, Penumathsa, Paul, & Maulik, 2008;Sun et al., 2012). Moreover, many foods, such as virgin olive oil, wine and natural extracts containing tyrosol as a major constituent have shown great protection against many pathological conditions (Bertelli et al., 2002;Palumbo, Occhiuto, Spadaro, & Circosta 2012). Interestingly, Cañuelo et al. (2012) reported that tyrosol increases lifespan and stress resistance in the nematode Caenorhabditis elegans. ...
Article
Experimental evidence suggests that tyrosol [2-(4-hydroxyphenyl)ethanol] exhibits potent protective activities against several pathogeneses. In this study, we evaluated the protective effect of tyrosol against 1-methyl-4-phenylpyridinium (MPP(+))-induced CATH.a neuron cell death. Tyrosol dose-dependently protected CATH.a cells from MPP(+)-induced cell death and the protection was more apparent after prolong incubation (48h). The data showed that tyrosol treatment suppressed the reduction of phospho-tyrosine hydroxylase level in CATH.a cells. Further, the compound repressed MPP(+)-induced depletion of mitochondrial membrane potential (Δψm) and thereby maintained intracellular ATP production in the cell. The cellular signalling pathway studies revealed that tyrosol protected CATH.a cells from MPP(+)-induced apoptotic signalling, most likely via activation of PI3K/Akt signalling pathway along with up-regulation of anti-oxidative enzymes (SOD-1 and SOD-2) and DJ-1 protein in the cell. Collectively, present study demonstrates that tyrosol significantly protects dopaminergic neurons from MPP(+)-induced degradation, and reveals potential neuroprotective mechanism of tyrosol.
... degeneration (Spencea et al., 2011). Consequently, it can be expected that neuroprotective effect of adaptogens (Kim et al., 2004;Bu et al., 2005;Chen et al., 2009a;Qu et al., 2009;Bocharov et al., 2010;Zhang et al., 2007Zhang et al., , 2010Li et al., 2011;Lee et al., 2012a,b;Palumbo et al., 2012;Shi et al., 2012;Zeng et al., 2012) must be associated with up-regulation ESR1 in glia cells. Surprisingly, the results of our study are not in line with this anticipation because adaptogens down-regulate ERα gene expression. ...
Article
Full-text available
Gene expression profiling was performed on the human neuroglial cell line T98G after treatment with adaptogen ADAPT-232 and its constituents – extracts of Eleutherococcus senticosus root, Schisandra chinensis berry, and Rhodiola rosea root as well as several constituents individually, namely, eleutheroside E, schizandrin B, salidroside, triandrin, and tyrosol. A common feature for all tested adaptogens was their effect on G-protein-coupled receptor signaling pathways, i.e., cAMP, phospholipase C (PLC), and phosphatidylinositol signal transduction pathways. Adaptogens may reduce the cAMP level in brain cells by down-regulation of adenylate cyclase gene ADC2Y and up-regulation of phosphodiesterase gene PDE4D that is essential for energy homeostasis as well as for switching from catabolic to anabolic states and vice versa. Down-regulation of cAMP by adaptogens may decrease cAMP-dependent protein kinase A activity in various cells resulting in inhibition stress-induced catabolic transformations and saving of ATP for many ATP-dependant metabolic transformations. All tested adaptogens up-regulated the PLCB1 gene, which encodes phosphoinositide-specific PLC and phosphatidylinositol 3-kinases (PI3Ks), key players for the regulation of NF-κB-mediated defense responses. Other common targets of adaptogens included genes encoding ERα estrogen receptor (2.9–22.6 fold down-regulation), cholesterol ester transfer protein (5.1–10.6 fold down-regulation), heat shock protein Hsp70 (3.0–45.0 fold up-regulation), serpin peptidase inhibitor (neuroserpin), and 5-HT3 receptor of serotonin (2.2–6.6 fold down-regulation). These findings can be reconciled with the observed beneficial effects of adaptogens in behavioral, mental, and aging-associated disorders. Combining two or more active substances in one mixture significantly changes deregulated genes profiles: synergetic interactions result in activation of genes that none of the individual substances affected, while antagonistic interactions result in suppression some genes activated by individual substances. These interactions can have an influence on transcriptional control of metabolic regulation both on the cellular level and the level of the whole organism. Merging of deregulated genes array profiles and intracellular networks is specific to the new substance with unique pharmacological characteristics. Presumably, this phenomenon could be used to eliminate undesirable effects (e.g., toxic effects) and increase the selectivity of pharmacological intervention.
... Apart from these Heo et al., 2012 reported that hippocampal cells (HT22) undergo apoptosis which was ascribed to the misbalance in calcium homeostasis that leads to oxidative burst. These finds have also been supported by the fact that some protective agents may regulate calcium homeostasis in H 2 O 2 induced cell death in human cortical neurons (Palumbo et al., 2012) since H 2 O 2 induces free intra-cellular calcium flux. In PC-12 cells, Nrf2/ARE signalling pathway has been used as a rescue strategy in the protection from H 2 O 2 mediated acute cell death (Lou et al., 2012). ...
Article
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Adaptogens comprise a category of herbal medicinal and nutritional products promoting adaptability, resilience, and survival of living organisms in stress. The aim of this review was to summarize the growing knowledge about common adaptogenic plants used in various traditional medical systems (TMS) and conventional medicine and to provide a modern rationale for their use in the treatment of stress-induced and aging-related disorders. Adapto-gens have pharmacologically pleiotropic effects on the neuroendocrine-immune system, which explain their traditional use for the treatment of a wide range of conditions. They exhibit a biphasic dose-effect response: at low doses they function as mild stress-mimetics, which activate the adaptive stress-response signaling pathways to cope with severe stress. That is in line with their traditional use for preventing premature aging and to maintain good health and vitality. However, the potential Med Res Rev. 2020;1-74. wileyonlinelibrary.com/journal/med | 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Rhodiola rosea L. (R. rosea) is one of the most beneficial medicinal plants and it is studied as an adaptogen. This study aims to evaluate the neuroprotective activity of compounds extracted from the root of R. rosea against methylglyoxal (MG)-induced apoptosis in neuro-2A (N2A) cells. The root of R. rosea was extracted with ethanol and partitioned with water, ethyl acetate, and n-butanol fractions to evaluate acetylcholinesterase (AChE) inhibitory activity and neuroprotective activity. The ethyl acetate fraction exhibited the highest values of AChE inhibitory activity (49.2% ± 3%) and cell viability (50.7% ± 4.8%) for neuroprotection. The structure identification of the most potential fraction (ethyl acetate fraction) revealed 15 compounds, consisting of three tannins, five flavonoids, and seven phenolics by infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All compounds were evaluated for their neuroprotective activity. Salidroside had the most potential neuroprotective activity. Gallic acid and methyl gallate had potential cytotoxicity in N2A cells. This study showed that R. rosea might have potential neuroprotective activities.
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Tibetan medicine (TM), the second largest traditional Chinese medicine system in China, boasts a long history and an integrated theoretical system. It abounds with classical medical works constituing a unique corpus of Tibetan materia medica (TMM). China has now conceived a modern education system of TM, and Tibetan medical hospitals at different levels have been set up. Many enterprises are granted the privileges to produce preparations of TM in compliance with Good Manufacturing Practices (GMP) regulations. However, there still exist unsolved issuess in TMM research as to the mechanism of action and the active constituents of TMM which are now been tackled through pharmacology and modern science and technology. Up till now, the mechanism of action and the active constituents of 141 medicines as well as 230 preparations of TM have been preliminarily revealed. This paper reviews in detail the development of TM and the status quo of TM's pharmacological research, in hope of serving a reference value for the promotion of the modernization of TM and understanding of TM among the medical scholars.
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Over the past three decades, the knowledge gained about the mechanisms that underpin the potential use of Rhodiola in stress- and ageing-associated disorders has increased, and provided a universal framework for studies that focused on the use of Rhodiola in preventing or curing metabolic diseases. Of particular interest is the emerging role of Rhodiola in the maintenance of energy homeostasis. Moreover, over the last two decades, great efforts have been undertaken to unravel the underlying mechanisms of action of Rhodiola in the treatment of metabolic disorders. Extracts of Rhodiola and salidroside, the most abundant active compound in Rhodiola, are suggested to provide a beneficial effect in mental, behavioral, and metabolic disorders. Both in vivo and ex vivo studies, Rhodiola extracts and salidroside ameliorate metabolic disorders when administered acutely or prior to 2 experimental injury. The mechanism involved includes multi-target effects by modulating various synergistic pathways that control oxidative stress, inflammation, mitochondria, autophagy, and cell death, as well as AMPK signaling that is associated with possible beneficial effects on metabolic disorders. However, evidence-based data supporting the effectiveness of Rhodiola or salidroside in treating metabolic disorders is limited. Therefore, a comprehensive review of available trials showing putative treatment strategies of metabolic disorders that include both clinical effective perspectives and fundamental molecular mechanisms is warranted. This review highlights studies that focus on the potential role of Rhodiola extracts and salidroside in type 2 diabetes and atherosclerosis, the two most common metabolic diseases.
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Rhodiola species, belonging to the family Crassulaceae, have long been used as an adaptogen, tonic, antidepressant, and antistress medicine or functional food in Asia and Europe. Due to the valuable application, the growing demand of Rhodiola species has led to a rapid decrease in resource content. This review aims to summarize the integrated research progress of seven mainstream Rhodiola species. We first outline both traditional and current use of Rhodiola for the treatment of various diseases. A detailed summary and comparison of chemical, pharmacological, toxicological, and clinical studies of various Rhodiola species highlight recent scientific advances and gaps, which gives insights into the understanding of Rhodiola application and would be helpful to improve the situation of biological resources and diversities of Rhodiola plants.
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Roseroot (Rhodiola rosea L.) belongs to plants revealing adaptogenic properties, which are attributed to the presence of specific phenolic compounds and are reflected mainly as antioxidant activity. The aim of the present study was to determine the antioxidant and antibacterial activity of various products obtained from R. rosea (underground organs as well as their aqueous and ethanolic dry extracts) in relation to the chemical profiles of phenolic and essential oil compounds. The chemical profiles were determined by High-performance Liquid Chromatography with a diode-array detector (HPLC-DAD) and Gas chromatography-mass spectrometry (GC-MS), antioxidant activity by (1,1-Diphenyl-2-picrylhydrazyl) Scavenging Capacity Assay (DPPH), (2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)) Scavenging Capacity Assay (ABTS) and Ferric Reducing Antioxidant Power Assay (FRAP) and antimicrobial properties were expressed as minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) values following the broth microdilutions method. The results show that the investigated samples differed in terms of their chemical compositions and biological activities. The extracts were more abundant in phenolic compounds (salidroside, tyrosol, and rosavin derivatives) in comparison to dried underground organs. The content of the determined phenolics in the analyzed extracts was affected by the solvent used for extraction. The ethanolic extract was characterized by the highest content of these substances in comparison to the aqueous one and the dried raw material, especially with regard to rosavin (969.71 mg/100 g). In parallel, this extract showed the strongest antioxidant and antibacterial activity. However, dried R. rosea underground organs also revealed strong antibacterial effects against, for example, Staphylococcus strains.
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Bisabololoxide A (BSBO), main constituents in German chamomile extract, is responsible for antipruritic effect. In previous study, the incubation with 30-100 μM BSBO for 24 h exerted cytotoxic and proapoptotic effects on rat thymocytes. To further characterize BSBO cytotoxicity, the effect on the cells suffering from calcium overload by calcium ionophore A23187 was examined. A23187 induced Ca(2+) -dependent cell death. Contrary to our expectation, 1-10 μM BSBO inhibited A23187-induced increase in cell lethality of rat thymocytes. BSBO attenuated A23187-induced increases in populations of shrunken living cells, phosphatidylserine-exposed living cells, and dead cells, without affecting the increase in intracellular Ca(2+) concentration and the Ca(2+) -dependent hyperpolarization. The effect of BSBO on A23187-treated cells may be unique because the activation of Ca(2+) -dependent K(+) channels is required for cell shrinkage, externalization of phosphatidylserine, and cell death in some cells. The cell death induced by A23187 was not inhibited by Z-VAD-FMK, a pan-inhibitor of caspases. Thus, the cell death may be a necrosis with some features observed during an early stage of apoptosis. These results suggest that BSBO at low micromolar concentrations is cytoprotective against calcium overload. Copyright © 2013 John Wiley & Sons, Ltd.
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In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta- amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1–38 or 25–35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. beta APs alone had no effect on neuronal survival during a 4 d exposure period. beta APs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of beta APs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The beta APs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that beta APs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that beta APs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta APs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the beta APs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., increased staining with tau and ubiquitin antibodies). Taken together, these data suggest that beta-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.
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Mutations in DJ-1 cause an autosomal recessive, early onset familial form of Parkinson disease (PD). However, little is presently known about the role of DJ-1 in the more common sporadic form of PD and in other age-related neurodegenerative diseases, such as Alzheimer disease (AD). Here we report that DJ-1 is oxidatively damaged in the brains of patients with idiopathic PD and AD. By using a combination of two-dimensional gel electrophoresis and mass spectrometry, we have identified 10 different DJ-1 isoforms, of which the acidic isoforms (pI 5.5 and 5.7) of DJ-1 monomer and the basic isoforms (pI 8.0 and 8.4) of SDS-resistant DJ-1 dimer are selectively accumulated in PD and AD frontal cortex tissues compared with age-matched controls. Quantitative Western blot analysis shows that the total level of DJ-1 protein is significantly increased in PD and AD brains. Mass spectrometry analyses reveal that DJ-1 is not only susceptible to cysteine oxidation but also to previously unsuspected methionine oxidation. Furthermore, we show that DJ-1 protein is irreversibly oxidized by carbonylation as well as by methionine oxidation to methionine sulfone in PD and AD. Our study provides new insights into the oxidative modifications of DJ-1 and indicates association of oxidative damage to DJ-1 with sporadic PD and AD.
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In the course of examining the effects on cells of polyamines, their metabolites, and polyamine analogs, it is often necessary to make some measure of cellular activity as an indicator of cell damage or cytotoxicity. One of the simplest assays utilizes 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT), a water-soluble yellow dye that is readily taken up by viable cells and reduced by the action of mitochondrial dehydrogenases (1). The reduction product is a water-insoluble blue formazan, that must then be dissolved for calorimetric measurement. Ethanol or propanol (2), acid-isopropanol (0.04M HCl in propan-2-ol) (3), acid-isopropanol plus 10% Triton X-100 (4), mineral oil (unspecified), or dimethyl sulfoxide (DMSO) (5) have all been suggested. In the author’s hands DMSO was found to be the most satisfactory (Fig. 1). Fig. 1.Effect of solvent on formazan absorbance. EtOH, ethanol, PrOH, propanol, iPrOH, 2-propanol, iPrOH/HCl, 0.04M HCl in 2-propanol; iPrOH/HCl/TX, 0.04M HCl in 2-propanol plus 10% Triton X-100; DMSO, dimethyl sulfoxide (error bars show S.D., n = 5).
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Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases such as Alzheimer's disease and Parkinson's. Using the Alzheimer's disease-associated hydrogen peroxide (H2O2), we investigated the neuroprotective efficacy of a natural mixture of phytoestrogenic isoflavones (genistein, daidzein, biochanin A and formononetin) from Trifolium pratense L. (Red clover) against oxidative stress-induced cell death in human cortical cell line HCN 1-A maintained in culture. Neuronal viability was determined by MTT or trypan blue test and neuronal integrity by morphological analysis. The results obtained indicate that exposure of HCN 1-A cell cultures to hydrogen peroxide resulted in a concentration-dependent decrease in neuron viability. Concentration of H2O2 ranging from 50 to 200 µg/ml were toxic to these cultures. A 24-hour pretreatment with 0.5, 1 and 2 µg/ml isoflavones extract significantly increased cell survival as evidenced by MTT or trypan blue test and significantly prevented the morphological disruption caused by H2O2 as shown by microscopical inspection, indicating that neurons treated with isoflavones were protected from the cell death induced by H2O2 exposure. These findings imply that the neuroprotective effect of isoflavones extract is partly associated with its antioxidant activity. Further, results of these investigations indicate that although isoflavones extract exert a neuroprotective effect, it do not promoted cortical neuron process outgrowth. Copyright
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In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta-amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. beta APs alone had no effect on neuronal survival during a 4 d exposure period. beta APs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of beta APs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The beta APs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that beta APs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that beta APs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta APs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the beta APs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., increased staining with tau and ubiquitin antibodies). Taken together, these data suggest that beta-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.
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This study reports the use of lactate dehydrogenase release to monitor changes in culture viability in flask culture and fixed bed, porosphere bioreactor systems. Lactate dehydrogenase release shows good agreement with increase in non-viable cell numbers and decline in glucose utilisation in flask cultures. Studies with the immobilised system show that lactate dehydrogenase release can detect loss of viability which is not always indicated by a decrease in glucose utilisation. The data show that culture viability in a repeated-feed-and-harvest system is influenced markedly by both a) the medium change regime itself and b) the use of an immobilised bioreactor compared to a flask system for the same medium change regime.
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A cell line has been established in continuous culture of human cerebral cortical neurons obtained from a patient with unilateral megalencephaly, a disorder associated with continued proliferation of immature neuronal cells. When differentiated in the presence of nerve growth factor, 1-isobutyl-3-methylxanthine, and dibutyryl adenosine 3',5'-monophosphate (cAMP), the cells display mature neuronal morphology with numerous long, extensively branched processes with spines and varicosities. The cells stain positively for neurofilament protein and neuron-specific enolase (selective neuronal markers) but are negative for glial markers, such as glial fibrillary acidic protein, S-100, and myelin basic protein. The cells also stain positively for the neurotransmitters gamma-aminobutyric acid (GABA), glutamate, somatostatin, cholecystokinin-8, and vasoactive intestinal polypeptide. These cells may facilitate characterization of neurons in the human central nervous system.
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Recent findings link altered processing of beta-amyloid precursor protein (beta APP) to disruption of neuronal Ca2+ homeostasis and an excitotoxic mechanism of cell death in Alzheimer's disease. A major pathway of beta APP metabolism results in the release of secreted forms of beta APP, APPss. These secreted forms are released in response to electrical activity and can modulate neuronal responses to glutamate, suggesting roles in developmental and synaptic plasticity. beta APP is upregulated in response to neural injury and APPss can protect neurons against excitotoxic or ischemic insults by stabilizing the intracellular Ca2+ concentration [Ca2+]i. An alternative beta APP processing pathway liberates intact beta-amyloid peptide, which can form aggregates that disrupt Ca2+ homeostasis and render neurons vulnerable to metabolic or excitotoxic insults. Genetic abnormalities (e.g. certain beta APP mutations or Down syndrome) and age-related changes in brain metabolism (e.g. reduced energy availability or increased oxidative stress) may favor accumulation of [Ca2+]i-destabilizing beta-amyloid peptide and diminish the release of [Ca2+]i-stabilizing, neuroprotective APPss.
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There is widespread interest in the neurotoxicity of the endogenous excitatory amino acid neurotransmitter glutamate. Excessive glutamate release or accumulation leads to neuronal injury or death in a variety of experimental models of ischemia, anoxia and hypoglycemia. This injury appears to be caused by overactivation of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors since a variety of competitive and uncompetitive NMDA antagonists can attenuate this process, sometimes in a dramatic fashion. Given the clinical context in which this form of neuronal injury occurs, it would be desirable if we could identify agents that blocked NMDA toxicity, after initial receptor binding and ion channel fluxes had transpired. Because NMDA receptor activation initiates the arachidonic acid cascade, we have recently looked at whether the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) can reduce NMDA neurotoxicity in vitro. In the concentration range 1-30 microM, NDGA diminished the death of cultured rodent hippocampal neurons produced by 100 microM NMDA. When 30 microM NDGA was present both before and after NMDA exposure, death declined by over 50%. NDGA did not block NMDA-induced inward currents in voltage-clamped neurons, so the drug is not a direct NMDA receptor antagonist. It also had no effect on the elevation in intracellular calcium produced by NMDA exposure. It is likely that NDGA acts at a site(s) distal to the NMDA receptor and the neuronal membrane to limit NMDA toxicity. We are hopeful that strategies for limiting excitotoxicity, which halt destructive intracellular events, can be developed for use in human neurological diseases linked to excessive stimulation of glutamate receptors.
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Exposure of cultured rat hippocampal neurons to glutamate resulted in accumulation of cellular peroxides (measured using the dye 2,7-dichlorofluorescein). Peroxide accumulation was prevented by an N-methyl-D-aspartate (NMDA) receptor antagonist and by removal of extracellular Ca2+, indicating the involvement of NMDA receptor-induced Ca2+ influx in peroxide accumulation. Glutamate-induced reactive oxygen species contributed to loss of Ca2+ homeostasis and excitotoxic injury because antioxidants (vitamin E, propyl gallate, and N-tert-butyl-alpha-phenylnitrone) suppressed glutamate-induced elevation of intracellular Ca2+ concentration ([Ca2+]i) and cell death. Basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF), but not ciliary neurotrophic factor, each suppressed accumulation of peroxides induced by glutamate and protected neurons against excitotoxicity. bFGF, NGF, and BDNF each increased (to varying degrees) activity levels of superoxide dismutases and glutathione reductase. NGF increased catalase activity, and BDNF increased glutathione peroxidase activity. The ability of the neurotrophic factors to suppress glutamate toxicity and glutamate-induced peroxide accumulation was attenuated by the tyrosine kinase inhibitor genistein, indicating the requirement for tyrosine phosphorylation in the neuro-protective signal transduction mechanism. The data suggest that glutamate toxicity involves peroxide production, which contributes to loss of Ca2+ homeostasis, and that induction of antioxidant defense systems is a mechanism underlying the [Ca2+]i-stabilizing and excitoprotective actions of neurotrophic factors.
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The effect of intracellular ion deregulation, particularly of [Ca2+], on the events following acute cell injury and the progression of change from initiation (reversible) to maintenance (reversible-irreversible) phases and finally to cell death has been the major thrust of experimentation in our laboratory for over 20 years. Cell death, which plays an important role in both normal and pathological phenomena, has been classified into two principal types, accidental and programmed. Recent exploration of programmed cell death (or apoptosis) has revealed extensive data showing it is an important mechanism for the normal maintenance and also differentiation of a variety of cell types and organs. From the results from our laboratory and those of others, we continue to expand and refine our working hypothesis: deregulation of [Ca2+] results in a number of phenomena from activation of signaling mechanisms and alterations in cellular structure to alterations in gene expression, all of which contribute to or play a critical role in cellular toxicity, including carcinogenesis and cell death. Therefore, although much more experimentation is needed to clarify some of these phenomena, the implications of such data for understanding the mechanisms and processes involved in carcinogenesis and the chemotherapeutic killing of cancer cells are extremely exciting. These relationships between [Ca2+], cell injury, and cell death are briefly reviewed here within the framework of our hypothesis.
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In many neurologic disorders, injury to neurons may be caused at least in part by overstimulation of receptors for excitatory amino acids, including glutamate and aspartate. These neurologic conditions range from acute insults such as stroke, hypoglycemia, trauma, and epilepsy (Table 1) to chronic neurodegenerative states such as Huntington's disease, the acquired immunodeficiency syndrome (AIDS) dementia complex, amyotrophic lateral sclerosis, and perhaps Alzheimer's disease (Table 2)1–3. Glutamate is the principal excitatory neurotransmitter in the brain, and its interactions with specific membrane receptors are responsible for many neurologic functions, including cognition, memory, movement, and sensation4. In addition, excitatory . . .
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Amyloid beta protein (A beta) is a 40-43 amino acid peptide that is associated with plaques in the brains of Alzheimer's patients and is cytotoxic to cultured neurons. Using both primary central nervous system cultures and clonal cell lines, it is shown that a number of anti-oxidants protect cells from A beta toxicity, suggesting that at least one pathway to A beta cytotoxicity results in free radical damage. A beta causes increased levels of H2O2 and lipid peroxides to accumulate in cells. The H2O2-degrading enzyme catalase protects cells from A beta toxicity. Clonal cell lines selected for their resistance to A beta toxicity also become resistant to the cytolytic action of H2O2. In addition, A beta induces the activity of NF-kappa B, a transcription factor thought to be regulated by oxidative stress. Finally, A beta-induced H2O2 production and A beta toxicity are blocked by reagents that inhibit flavin oxidases, suggesting that A beta activates a member of this class of enzymes. These results show that the cytotoxic action of A beta on neurons results from free radical damage to susceptible cells.
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Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases; one such ailment is Alzheimer's disease. Using the Alzheimer's disease-associated amyloid beta protein, glutamate, hydrogen peroxide, and buthionine sulfoximine, we investigated the neuroprotective potential of estrogen against oxidative stress-induced cell death. We show that 17-beta-estradiol, its nonestrogenic stereoisomer, 17-alpha-estradiol, and some estradiol derivatives can prevent intracellular peroxide accumulation and, ultimately, the degeneration of primary neurons, clonal hippocampal cells, and cells in organotypic hippocampal slices. The neuroprotective antioxidant activity of estrogens is dependent on the presence of the hydroxyl group in the C3 position on the A ring of the steroid molecule but is independent of an activation of estrogen receptors.
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Alzheimer's disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death and formation of amyloid plaques and neurofibrillary tangles (NFTs) NFTs are composed of hyperphosphorylated tau protein, and senile plaques contain aggregates of the β-peptide. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress during the course of the disease. Advanced glycation endproducts (AGEs), which are formed by a nonenzymatic reaction of glucose with long-lived protein deposits, are potentially toxic to the cell, are present in brain plaques in AD, and its extracellular accumulation in AD may be caused by an accelerated oxidation of glycated proteins. The microtubuli-associated protein tau is also subject to intracellular AGE formation. AGEs participate in neuronal death causing direct (chemical) radical production: Glycated proteins produce nearly 50-fold more radicals than non-glycated proteins, and indirect (cellular) radical production: Interaction of AGEs with cells increases oxidative stress. During aging cellular defence mechanisms weaken and the damages to cell constituents accumulate leading to loss of function and finally cell death. The development of drugs for the treatment of AD remains at a very unsatisfying state. However, pharmacological approaches which break the vicious cycles of oxidative stress and neurodegeneration offer new opportunities for the treatment of AD. Theses approaches include AGE-inhibitors, antioxidants, and anti-inflammatory substances, which prevent radical production. ACE inhibitors might be able to stop formation of AGE-modified β-amyloid deposits, antioxidants are likely to scavenge intracellular and extracellular superoxide radicals and hydrogen peroxide before these radicals damage cell constituents or activate microglia, and anti-inflammatory drugs attenuating microglial radical and cytokine production.
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Neuronal death underlies the symptoms of many human neurological disorders, including Alzheimer's, Parkinson's and Huntington's diseases, stroke, and amyotrophic lateral sclerosis. The identification of specific genetic and environmental factors responsible for these diseases has bolstered evidence for a shared pathway of neuronal death — apoptosis — involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases. These death cascades are counteracted by survival signals, which suppress oxyradicals and stabilize calcium homeostasis and mitochondrial function. With the identification of mechanisms that either promote or prevent neuronal apoptosis come new approaches for preventing and treating neurodegenerative disorders.
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Rhodiola rosea is a popular plant in traditional medical systems in Eastern Europe and Asian with a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, eliminating fatigue, and preventing high altitude sickness. Rhodiola rosea has been categorized as an adaptogen by Russian researchers due to its observed ability to increase resistance to a variety of chemical, biological, and physical stressors. Its claimed benefits include antidepressant, anticancer, cardioprotective, and central nervous system enhancement. Research also indicates great utility in asthenic conditions (decline in work performance, sleep difficulties, poor appetite, irritability, hypertension, headaches, and fatigue) developing subsequent to intense physical or intellectual strain. The adaptogenic, cardiopulmonary protective, and central nervous system activities of Rhodiola rosea have been attributed primarily to its ability to influence levels and activity of monoamines and opioid peptides such as beta-endorphins.
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A randomized, double-blind, placebo-controlled, parallel-group clinical study with an extra non-treatment group was performed to measure the effect of a single dose of standardized SHR-5 Rhodiola rosea extract on capacity for mental work against a background of fatigue and stress. An additional objective was to investigate a possible difference between two doses, one dose being chosen as the standard mean dose in accordance with well-established medicinal use as a psychostimulant/adaptogen, the other dose being 50% higher. Some physiological parameters, e.g. pulse rate, systolic and diastolic blood pressure, were also measured. The study was carried out on a highly uniform population comprising 161 cadets aged from 19 to 21 years. All groups were found to have very similar initial data, with no significant difference with regard to any parameter. The study showed a pronounced antifatigue effect reflected in an antifatigue index defined as a ratio called AFI. The verum groups had AFI mean values of 1.0385 and 1.0195, 2 and 3 capsules respectively, whilst the figure for the placebo group was 0.9046. This was statistically highly significant (p < 0.001) for both doses (verum groups), whilst no significant difference between the two dosage groups was observed. There was a possible trend in favour of the lower dose in the psychometric tests. No such trend was found in the physiological tests.
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The influence of four factors on the dye exclusion test for cell viability was investigated. Eosin concentration, serum concentration, cell concentration and staining time were each varied in turn to assess their effects on the number of rabbit leucocytes staining in damaged and undamaged suspensionsStained cell counts tended to be high when high concentrations of stain and/or low concentrations of serum were used, and vice versa, irrespective of whether suspensions were initially damaged or not. The stained cell counts of undamaged suspensions were not affected by staining times up to 90 min. In damaged suspensions the proportion of stained cells increased with the staining time. Stained cell counts tended to be high when very low concentrations of cells were used.
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Increasing lines of evidence indicate that estrogen acts as a neuroprotective agent through a nongenomic mechanism. We tested the hypothesis that 17beta-estradiol could rapidly attenuate glutamate-induced calcium (Ca2+) overload in rat primary hippocampal neurons via a membrane receptor-dependent mechanism. The bulk cytosolic intracellular Ca2+ level was measured in neurons with fluorescent Ca2+ probe fluo3. Preexposure of primary cultured hippocampal neurons to 17beta-estradiol for 3 min attenuated intracellular Ca2+ increase induced by glutamate in a concentration-dependent manner. The action of 17beta-estradiol was reversible after washout. Administration of membrane-impermeable 17beta-estradiol conjugated to bovine serum albumin (E2-BSA) produced the same effect, suggesting possible involvement of cell membrane receptors. ICI 182,780, a specific estrogen receptor (ER) antagonist, blocked the neuronal response to 17beta-estradiol and estradiol BSA, indicating a role of specific ERs. The present study demonstrates that 17beta-estradiol acutely reduces glutamate-stimulated intracellular Ca2+ increase via ERs probably on the cell surface of the hippocampal neurons.
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Hydrogen peroxide (H(2)O(2)) is a stable, uncharged and freely diffusable reactive oxygen species (ROS) and second messenger. The generation of H(2)O(2) in the brain is relatively high because of the high oxygen consumption in the tissue. Alzheimer's disease is a neurodegenerative disorder characterised by the appearance of amyloid-beta (Abeta)-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles. The pathology of Alzheimer's disease is also associated with oxidative stress and H(2)O(2) is implicated in this and the neurotoxicity of the Abeta peptide. The ability for Abeta to generate H(2)O(2), and interactions of H(2)O(2) with iron and copper to generate highly toxic ROS, may provide a mechanism for the oxidative stress associated with Alzheimer's disease. The role of heavy metals in Alzheimer's disease pathology and the toxicity of the H(2)O(2) molecule may be closely linked. Drugs that prevent oxidative stress include antioxidants, modifiers of the enzymes involved in ROS generation and metabolism, metal chelating agents and agents that can remove the stimulus for ROS generation. In Alzheimer's disease the H(2)O(2) molecule must be considered a therapeutic target for treatment of the oxidative stress associated with the disease. The actions of H(2)O(2) include modifications of proteins, lipids and DNA, all of which are effects seen in the Alzheimer's disease brain and may contribute to the loss of synaptic function characteristic of the disease. The effectiveness of drugs to target this component of the disease pathology remains to be determined; however, metal chelators may provide an effective route and have the added bonus in the case of clioquinol of potentially reducing the Abeta load. Future research and development of agents that specifically target the H(2)O(2) molecule or enzymes involved in its metabolism may provide the future route to Alzheimer's disease therapy.
Article
Rhodiola rosea is a medicinal plant having stimulating and adaptogenic properties, and some reports also indicate its anticancer and antimutagenic effect. However, the mechanism of its anticancer effect is unknown as there have been no cytological studies regarding cytostatics, cell cycle, induction of apoptosis or the mitotic activity of healthy and cancerous cells. In the present paper, those parameters were investigated using HL-60 cells, with flow cytometry and fluorescence microscopy. It has been found that the extract of Rhodiola rosea rhizomes inhibits division of HL-60 cells, which is preceded by an accumulation of cells at the prophase stage. This leads to induction of apoptosis and necrosis in HL-60 cells, and to marked reduction of their survival. The cells enter apoptosis from phase G2/M of the cell cycle. After treatment with the extract, no chromosome aberrations or micronuclei were observed, which indicates the mild action of the extract. The cytostatic and antiproliferative effect of the Rhodiola rosea rhizome extract, and its mild action, raises hope for its use in anticancer therapy by enhancing the effectiveness of cytostatics.
Article
The methanol extract of the underground part of Rhodiola rosea was found to show inhibitory activity against Staphylococcus aureus. Bioactivity-guided fractionation of a 95% ethanol extract from the stems of R. rosea led to the isolation of five compounds: gossypetin-7-O-L-rhamnopyranoside (1), rhodioflavonoside (2), gallic acid (3), trans-p-hydroxycinnamic acid (4) and p-tyrosol (5). Their structures were elucidated by UV, IR, MS and NMR data, as well as by comparison with those of the literature. Compounds 1 and 2 were evaluated for their antibacterial and antiprostate cancer cell activities. Compounds 1 and 2 exhibited activity against Staphylococcus aureus with minimum inhibitory concentrations of 50 microg/mL and 100 microg/mL, respectively. Cytotoxicity studies of 1 and 2 also displayed activity against the prostate cancer cell line with IC(50) values of 50 microg/mL and 80 microg/mL, respectively.
Article
Salidroside (Sald), was extracted from Rhodiola rosea L, a traditional Chinese medicine which has been used for long time for anti-aging, anti-cancer and anti-oxidative stress etc. In present experiment, salidroside could protect the PC12 cell against injuries caused by exposure of PC12 cells to 2 mmol/L glutamate for 15 min followed by incubation with serum-free medium for 24 h, which resembled the excitotoxin in vivo system. Furthermore, saldroside could decrease the [Ca2+]i of PC12 cells in Mg2+-free Hanks' solution and D-Hanks' solution but there was no effect on basal [Ca2+]i in Hanks' solution. The studies also indicated that salidroside inhibited the increases of [Ca2+]i induced by KCl and glutamate. In conclusion, salidroside may protect PC12 cell against glutamate excitotoxic damage through suppressing the excessive entry of Ca2+ and the release of the calcium stores.
Article
The endogenous steroid estrogen has been shown to affect neuronal growth, differentiation and survival. Genistein, daidzein and other isoflavones have been shown to mimic the pharmacological actions of the gonadal steroid estrogen with which they have structural similarities. Several studies have looked at the effect of isoflavones in the brain. In the present study, human cortical cell line HCN 1-A maintained in culture was used to test the neuroprotective efficacy of a natural mixture of phytoestrogenic isoflavones (genistein, daidzein, biochanin A and formononetin) from Red clover against glutamate toxicity. Neuronal viability was determined by MTT or trypan blue test and neuronal membrane damage was quantitatively measured by lactate dehydrogenase (LDH). The results obtained indicate that exposure of HCN 1-A cell cultures to glutamate resulted in concentration-dependent decreases in neuron viability. Concentration of glutamate ranging from 0.01 to 5 mM was toxic to these cultures. A 24-h pretreatment with 0.5, 1 and 2 microg/ml isoflavones enriched fraction (IEF) significantly increased cell survival and significantly decreased cellular lactate dehydrogenase release from differentiated cortical neurons, indicating that neurons treated with isoflavones were protected from the cell death induced by glutamate exposure. Moreover, the pretreatment with IEF prevented the morphological disruption caused by glutamate as shown by microscopical inspection. These findings indicate that IEF has a neuroprotective effect in human cortical neurons and that this effect might be resulted from his antioxidant and estrogenic actions.
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Antiproliferative and antimitotic effect, S phase accumulation and induction of apoptosis and necrosis after treatment of extract from Rhodiola rosea rhizomes on HL-60 cells
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Majewska A, Hoser G, Furmanova M et al. 2006. Antiproliferative and antimitotic effect, S phase accumulation and induction of apoptosis and necrosis after treatment of extract from Rhodiola rosea rhizomes on HL-60 cells. J Ethnopharmacol 103: 43–52.
Hydrogen peroxide mediates amyloid beta protein toxicity
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Apoptosis in neurodegenerative disorders
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