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Antidepressant-Like Effects of Sarsasapogenin from Anemarrhena asphodeloides BUNGE (Liliaceae)
Abstract
The aim of this study was to investigate the effects of sarsasapogenin from Anemarrhena asphodeloides BUNGE (Liliaceae) on the forced swimming test, and the central noradrenergic, dopaminergic and serotonergic activities in mice. Our results showed that sarsasapogenin treatment at 12.5, 25 and 50 mg/kg (p.o.) for 14 d significantly reduced the duration of immobility in the forced swimming test. These doses that affected the immobile response did not affect locomotor activity. In addition, the neurochemical assays showed that sarsasapogenin produced a marked increase of noradrenaline and serotonin levels at 50 mg/kg in both the hypothalamus and the hippocampus. Moreover, sarsasapogenin showed a monoamine oxidase inhibitory activity in the mouse brain. These findings suggest that the antidepressant activity of sarsasapogenin may involve the central monoaminergic neurotransmitter systems.
... Wang et al. [11]; Moon et al. [22]; Peng et al. [23]; Pan et al. [24]; Ren et al. [25]; Liu et al. [26]; Hu et al. [27]; Lim et al. [28]; Bao et al. [29]; Tang et al. [30]; Pei et al. [ ...
... Sarsasapogenin enhances memory in a memory-impaired rat model by increasing the density of acetylcholine receptors in the brain. The behavioural despair test confirmed that sarsasapogenin had antidepressant-like effects in mice [25]. The antidepressant effect of sarsasapogenin and its relation to cholinergic signalling were investigated by Feng et al. [14]. ...
... Ren et al. [25] reported that sarsasapogenin reduced the duration of immobility in a dose-dependent manner in a forced swim test. Nevertheless, since sarsasapogenin did not generate hyperlocomotion in the open-field test, its antidepressant effect cannot be attributed to an increase in motor activity. ...
Sarsasapogenin is a natural steroidal sapogenin molecule obtained mainly from Anemarrhena asphodeloides Bunge. Among the various phytosteroids present, sarsasapogenin has emerged as a promising molecule due to the fact of its diverse pharmacological activities. In this review, the chemistry, biosynthesis and pharmacological potentials of sarsasapogenin are summarised. Between 1996 and the present, the relevant literature regarding sarsasapogenin was obtained from scientific databases including PubMed, ScienceDirect, Scopus, and Google Scholar. Overall, sarsasapogenin is a potent molecule with anti-inflammatory, anticancer, antidiabetic, anti-osteoclastogenic and neuroprotective activities. It is also a potential molecule in the treatment for precocious puberty. This review also discusses the metabolism, pharmacokinetics and possible structural modifications as well as obstacles and opportunities for sarsasapogenin to become a drug molecule in the near future. More comprehensive preclinical studies, clinical trials, drug delivery, formulations of effective doses in pharmacokinetics studies, evaluation of adverse effects and potential synergistic effects with other drugs need to be thoroughly investigated to make sarsasapogenin a potential molecule for future drug development.
... Reference literature on Helleborus niger (Ren et al., 2006(Ren et al., , 2007 proves an in vivo antidepressant effect of sarsasapogenin contained in the Helleborus niger leaf and stem as glycosylated saponin (see Fig. 3 and 4, Table 1; Karle & Karle, 1966;Linde et al., 1971;Mariezcurrena et al., 1972;Martinek, 1973Martinek, , 1974Canonica et al., 1974;Bonora et al., 1987;Liedtke et al., 1997;Mimaki et al., 2003;Vitalini, Braca, & Fico, 2011;. Sarsasapogenin performed equally to the reference selective serotonin re-uptake inhibitor (SSRI) drug fluoxetine in vivo (Ren et al., 2006(Ren et al., , 2007. ...
... Reference literature on Helleborus niger (Ren et al., 2006(Ren et al., , 2007 proves an in vivo antidepressant effect of sarsasapogenin contained in the Helleborus niger leaf and stem as glycosylated saponin (see Fig. 3 and 4, Table 1; Karle & Karle, 1966;Linde et al., 1971;Mariezcurrena et al., 1972;Martinek, 1973Martinek, , 1974Canonica et al., 1974;Bonora et al., 1987;Liedtke et al., 1997;Mimaki et al., 2003;Vitalini, Braca, & Fico, 2011;. Sarsasapogenin performed equally to the reference selective serotonin re-uptake inhibitor (SSRI) drug fluoxetine in vivo (Ren et al., 2006(Ren et al., , 2007. The concentrations of the monoamine neurotransmitters serotonin, noradrenaline (norepinephrine), and dopamine were increased by sarsasapogenin treatment in mouse brain hypothalamus and hippocampus, comparable in effect to the in vivo treatment with fluoxetine (Ren et al., 2006). ...
... Sarsasapogenin performed equally to the reference selective serotonin re-uptake inhibitor (SSRI) drug fluoxetine in vivo (Ren et al., 2006(Ren et al., , 2007. The concentrations of the monoamine neurotransmitters serotonin, noradrenaline (norepinephrine), and dopamine were increased by sarsasapogenin treatment in mouse brain hypothalamus and hippocampus, comparable in effect to the in vivo treatment with fluoxetine (Ren et al., 2006). Moreover, sarsasapogenin showed monoamine oxidase A (MAO-A) and B (MAO-B) inhibitory action in mouse brains, whereas the control drug fluoxetine did not (Ren et al., 2006). ...
Melampus is a seer-healer of Greek myth attributed with having healed the young princesses of Argos of madness. Analysis of this legend and its sources sheds light on the early stages of the “medicalizing” shift in the history of ancient Greek medicine. Retrospective psychological diagnosis suggests that the descriptions of the youths’ madness rose from actual observation of behavioral and mental disorders. Melampus is credited with having healed them by administering hellebore. Pharmacological analysis of botanical specimens proves that Helleborus niger features actual neurological properties effective in the treatment of mental disorders. The discussion aims at examining the rational aspects of the treatment of mental conditions in Greco-Roman antiquity.
... Moreover, sarsasapogenin inhibited MAO in the mouse brain. The authors therefore hypothesized that the antidepressant-like activity of sarsasapogenin involves the central monoaminergic neurotransmitter systems [64,65]. ...
... The results gave a positive result, with the mechanism being attributed to an increase in monoamine turnover. The alkaloids in the extracts were identified as anonaine (63), liriodenine (64), nornuciferine (65), and 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-3,8,9,10-tetraol (66) (see Fig. 7S, Supplementary Information) [72]. Annona coriacea was also evaluated, as well as caffeic acid (48, Fig. 6S, Supplementary Information), the major phenolic present in the extract. ...
Medicinal plants and their extracts are natural remedies with enormous potential for treating various diseases, including depression and anxiety. In the case of depression, hundreds of plants have traditionally been used in folk medicine for generations. Different plant extracts and natural products have been analyzed as potential antidepressant agents with validated models to test for antidepressant-like effects in animals, although other complementary studies have also been employed. Most of these studies focus on the possible mediators implicated in these potential effects, with dopamine, serotonin, and noradrenaline being the principal neurotransmitters implicated, both through interference with receptors and with their metabolism by monoamino oxidases, as well as through neuro-endocrine and neuroprotective effects. There are approximately 650 reports of antidepressant-like medicinal plants in PubMed; 155 of them have been compiled in this review, with a relevant group yielding positive results. Saffron and turmeric are the most relevant species studied in both preclinical and clinical studies; St. Johnʼs wort or kava have also been tested extensively. To the best of our knowledge, no review to date has provided a comprehensive understanding of the biomolecular mechanisms of action of these herbs or of whether their potential effects could have real benefits. The purpose of this narrative review is to provide an update regarding medicinal plants from the year 2000 to the present to examine the therapeutic potential of these antidepressant-like plants in order to contribute to the development of new therapeutic methods to alleviate the tremendous burden that depression causes worldwide.
... The psychotropic effects of natural products have been of interest to many clinicians and scientists due to their lack of side effects and toxicity [17,18] . Compelling research studies have shown that many types of effective components from natural products were effective agents against central nervous system diseases. ...
... Recent research suggests that timosaponin, which is derived from Rhizoma Anemarrhenae, has unique sedative action on mice with neural dysfunction caused by stress. Many preclinical studies also indicated that timosaponin may have the potential to play an essential role in both depression and anxiety treatment [18,21] . Specifically, timosaponin B-II and B-III are the two main bioactive constituents that are thought to improve learning and memory. ...
Aim:
N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice.
Methods:
NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg(-1)·d(-1)) or a positive-control drug, fluoxetine (10 mg·kg(-1)·d(-1)) for 3 weeks. Behavioral assessments were carried out every week.
Results:
In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine.
Conclusion:
YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.
... Evaluation of the possible anxiolytic effect was performed according to the previous literature [14][15][16]. Shanghai Manpu Biotechnology Co., Ltd., furnished the EPM apparatus (mode: RD1108-EPM-M), which comprised two open (30 cm × 5 cm) and two closed arms (30 cm × 5 cm × 15 cm) that extended from a common central platform (5 cm × 5 cm). To prevent mice from falling out of the maze, a ledge (2 mm H) surrounded the open arms. ...
... In the previous pentobarbital-induced sleep test, linear regression analysis showed a correlation between asparagus saponin intake and increased sleeping time. Reports suggest that sarsasapogenin from Anemarrhena asphodeloides Bunge (Liliaceae) exile antidepressant activity by mediation of the central monoaminergic neurotransmitter systems [15,16]. The content of steroidal saponins was quantified by determination of sarsasapogenin, as an index of active constituents of asparagus. ...
... The rhizomes of Anemarrhena asphodeloides Bunge (Liliaceae) have been used as a traditional medicine for anti-diabetic, anti-phlogistic, anti-pyretic, asthma, cough, bronchosis, allergy, sedative, diuretic, and anodyne properties in Korea, China, and Japan (Duke et al., 2002). Phytochemicals present in this species include xanthones (Pardo-Andreu et al., 2006), norlignans (Iida et al., 2000;Park et al., 2003;Lim et al., 2009), and steroidal saponins (Nakashima et al., 1993;Sy et al., 2008;Ren et al., 2006;Wang et al., 2010), associated with biological activities such as anti-diabetic (Nakashima et al., 1993), anti-cancer (Sy et al., 2008), antioxidant (Pardo-Andreu et al., 2006), antifungal (Iida et al., 2000;Park et al., 2003), anti-depressant (Ren et al., 2006), anti-inflammatory (Lim et al., 2009) activity, and neuroprotective effects (Wang et al., 2010). In our previous study, nyasol and its derivatives isolated from the ethyl acetate fraction of A. asphodeloides had potent RSV inhibitory potential (Bae et al., 2007). ...
... The rhizomes of Anemarrhena asphodeloides Bunge (Liliaceae) have been used as a traditional medicine for anti-diabetic, anti-phlogistic, anti-pyretic, asthma, cough, bronchosis, allergy, sedative, diuretic, and anodyne properties in Korea, China, and Japan (Duke et al., 2002). Phytochemicals present in this species include xanthones (Pardo-Andreu et al., 2006), norlignans (Iida et al., 2000;Park et al., 2003;Lim et al., 2009), and steroidal saponins (Nakashima et al., 1993;Sy et al., 2008;Ren et al., 2006;Wang et al., 2010), associated with biological activities such as anti-diabetic (Nakashima et al., 1993), anti-cancer (Sy et al., 2008), antioxidant (Pardo-Andreu et al., 2006), antifungal (Iida et al., 2000;Park et al., 2003), anti-depressant (Ren et al., 2006), anti-inflammatory (Lim et al., 2009) activity, and neuroprotective effects (Wang et al., 2010). In our previous study, nyasol and its derivatives isolated from the ethyl acetate fraction of A. asphodeloides had potent RSV inhibitory potential (Bae et al., 2007). ...
Two known steroidal saponins, timosaponin A-III (1) and anemarsaponin B (2) were isolated from the BuOH fraction of the rhizomes of Anemarrhena asphodeloides Bunge (Liliaceae) together with the xanthone derivatives, mangiferin (3) and neomangiferin (4). Structures of the isolates were identified using 1D and 2D NMR techniques and by comparison with the published values. Timosaponin A-III (1) exhibited potent inhibitory effects on the respiratory syncytial virus (RSV), with an IC 50 value of 1.00 µM.
... Evaluation of the possible anxiolytic effect was performed according to the previous literature [14][15][16]. Shanghai Manpu Biotechnology Co., Ltd., furnished the EPM apparatus (mode: RD1108-EPM-M), which comprised two open (30 cm × 5 cm) and two closed arms (30 cm × 5 cm × 15 cm) that extended from a common central platform (5 cm × 5 cm). To prevent mice from falling out of the maze, a ledge (2 mm H) surrounded the open arms. ...
... In the previous pentobarbital-induced sleep test, linear regression analysis showed a correlation between asparagus saponin intake and increased sleeping time. Reports suggest that sarsasapogenin from Anemarrhena asphodeloides Bunge (Liliaceae) exile antidepressant activity by mediation of the central monoaminergic neurotransmitter systems [15,16]. The content of steroidal saponins was quantified by determination of sarsasapogenin, as an index of active constituents of asparagus. ...
There are few studies on the neuropharmacological properties of asparagus, which was applied in Chinese traditional medicine as a tonic and heat-clearing agent. The present study was designed to investigate the anxiolytic-like activity of the aqueous extract of asparagus stem (AEAS) using elevated plus maze (EPM) and Vogel conflict tests (VCT) in mice. AEAS significantly increased the percentage of time spent in open arms in EPM, when compared with control group. In the Vogel conflict drinking test, the numbers of punished licks increased to 177% and 174% by the treatment of AEAS at the doses of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight), compared with control group. The serum cortisol level decreased significantly, at the same time. In conclusion, these findings indicated that the aqueous extract of asparagus stem exhibited a strong anxiolytic-like effect at dose of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight) in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder.
... It has been found to improve cognition in aged rats by boosting the muscarinic receptor density [38]. Sas also has antidepressant-like characteristics, since it decreased immobility time in the FST [39]. Furthermore, Sas has been shown to reduce diabetesinduced memory loss, reduce neuroinflammation through the downregulation of the PAR-1 receptor [40] and provide neuroprotection by reducing Aβ peptide overproduction [41]. ...
... Hederagenin of Akebia quinata, showed antidepressant effect by HPA axis modulation (Jin et al., 2012). Sarsasapogenin from Anemarrhena asphodeloides possess antidepressant activity by preventing MAO-A and MAO-B activities and increasing NE and 5-HT levels of the hippocampus and hypothalamus (Ren et al., 2006). ...
Depression is a condition characterized by low mood and an aversion to activity, that causes behavioral problems, poor quality of life and limits daily life activities. It is considered as the fourth leading cause of disability worldwide. Selective Serotonin Reuptake Inhibitors (SSRIs) Monoamine Oxidase (MAO) inhibitors, Tricyclic Antidepressants (TCAs), and atypical antidepressants are some of the conventional medications used to treat depression. However, only about half of patients with major depressive disorder (MDD) respond effectively to first-line antidepressant therapy. Additionally, there are a number of drawbacks to standard antidepressants, such as anti-cholinergic side effects, drug-drug interactions, and food-drug interactions, which prompts researchers to look at alternative approaches to the treatment of depression. Medicinal plants and their metabolites are extensively tested for their efficacy against depression. Electronic databases such as Google scholar, Science Direct, SciFinder and PubMed were used to search relevant literature on the role of polyphenols in depression. Plants-derived Polyphenols represent a major class of compounds extensively distributed in plants. Number of polyphenols have demonstrated antidepressant activity, among which berberine, piperine, curcumin, naringenin, ascorbic acid and ginsenosides are extensively evaluated. The medicinal plants and their derived compounds mediated synthesized green nanoparticles have also exhibited considerable efficacy in the management of depression. The therapeutic effects of these phytochemicals is mediated via differentiation and inhibition of neuronal cell apoptosis, promotion of neuronal cell survival and modulation of key neurotransmitters. The aim of this study is to review compressively the chemical, pharmacological and neurological evidence showing the potential of polyphenols in depression.
... Figure S1G) isolated from Anemarrhena asphodeloides Bunge leaf extracts possessed MAO (MAO-A and MAO-B) inhibitory activity. It was also shown to interact with norepinephrine and serotonin (5-HT) receptor systems (Ren et al., 2006). MAO inhibitory activity was observed with piperine (Supplementary Figure S1H) and methylpiperate (Supplementary Figure S1I) isolated from the ethanolic fruit extract of Piper longum L. (Lee et al., 2005;Lee et al., 2008). ...
Depression, a neurological disorder, is a universally common and debilitating illness where social and economic issues could also become one of its etiologic factors. From a global perspective, it is the fourth leading cause of long-term disability in human beings. For centuries, natural products have proven their true potential to combat various diseases and disorders, including depression and its associated ailments. Translational informatics applies informatics models at molecular, imaging, individual, and population levels to promote the translation of basic research to clinical applications. The present review summarizes natural-antidepressant-based translational informatics studies and addresses challenges and opportunities for future research in the field.
... Intensive stimulation of the GABAergic and serotoninergic receptors induces a depressive action on the CNS (35). Some plants of the Asparagaceae family have sedative effects related to serotoninergic and noradrenergic mechanisms (36,37), by facilitating monoaminergic transmission (38), or even by activating the Shp-2, ErK1/2 and Akt signaling pathways (39). A. amoena extracts exert a sedative and analgesic action, probably by agonistic action on GABA and serotonin receptors, facilitating the appearance of their biological effects. ...
Introduction: Albuca amoena is a Moroccan-Algerian endemic medicinal plant with various implications. The aim of this study is to identify phytochemical compounds of the plant, check its acute toxicity, and test its anti-depressive, anxiolytic, and analgesic effects on the central nervous system (CNS). Methods: The estimation of chemical compounds was carried out according to coloring and precipitation reactions. The Organization of Economic Cooperation and Development guidelines 423 and 402 made it possible to verify the acute toxicity of the plant orally and dermally. The sedative activity was performed according to 4 tests: rotarod, hole-board, traction, and chimney tests. The anti-depressive, anxiolytic, and analgesic effects were evaluated by forced swimming, light/dark, and writhing tests, respectively. Results: The phytochemical analysis showed that A. amoena contained a mixture of phytochemical compounds like terpenes, alkaloids, and polyphenols. According to the acute toxicity tests, the lethal dose of 50% (LD50) of A. amoena hydroalcoholic extract was between 300 and 2000 mg/kg orally and higher than 2000 mg/kg dermally. Moreover, the result of the behaviour tests of sedative and analgesic activities revealed that A. amoena hydroalcoholic extract exerted positive effects on the CNS. Conclusion: These results show the anti-depressive, anxiolytic, and analgesic effects of the bioactive substances present in A. amoena on the CNS and provide access to further investigations to highlight the main compounds of this plant and their mechanisms of actions.
... Sarsasapogenin can instantly increase the oxidative stress in the mitochondria of tumor cells and induce the apoptosis of tumor cells [1]. At the same time, sarsasapogenin can significantly increase the levels of norepinephrine and serotonin in the hypothalamus and hippocampus and can also inhibit the activity of monoamine oxidase, which indicates that it has the potential to treat depression [34]. Thus, the metabolites produced by intestinal flora are likely the sources of diverse pharmacological activities of timosaponin BII. ...
Timosaponin BII is one of the most abundant Anemarrhena saponins and is in a phase II clinical trial for the treatment of dementia. However, the pharmacological activity of timosaponin BII does not match its low bioavailability. In this study, we aimed to determine the effects of gut microbiota on timosaponin BII metabolism. We found that intestinal flora had a strong metabolic effect on timosaponin BII by HPLC-MS/MS. At the same time, seven potential metabolites (M1-M7) produced by rat intestinal flora were identified using HPLC/MS-Q-TOF. Among them, three structures identified are reported in gut microbiota for the first time. A comparison of rat liver homogenate and a rat liver microsome incubation system revealed that the metabolic behavior of timosaponin BII was unique to the gut microbiota system. Finally, a quantitative method for the three representative metabolites was established by HPLC-MS/MS, and the temporal relationship among the metabolites was initially clarified. In summary, it is suggested that the metabolic characteristics of gut microbiota may be an important indicator of the pharmacological activity of timosaponin BII, which can be applied to guide its application and clinical use in the future.
... Protocatechuic acid * 24,200,218,24 7,289,338,374, 462,487,488,5 38-542] Quercetin [218,298,338,5 44-551] Rosarin * R. rosea [552,553] Rosmarinic acid * [24,248,253,34 5,426,556-563] Safranal * C. sativus [369,576] Schisandrin B * S. chinensis [93,594] Tannic acid * T. chebula [333,369,[595][596][597][598] Tanshinone I * S. miltiorrhiza [24,[599][600][601]603] Tanshinone IIB * S.miltiorrhiza ...
Late-life mild cognitive impairment and dementia represent a significant burden on healthcare systems and a unique challenge to medicine due to the currently limited treatment options. Plant phytochemicals have been considered in alternative, or complementary, prevention and treatment strategies. Herbals are consumed as such, or as food supplements, whose consumption has recently increased. However, these products are not exempt from adverse effects and pharmacological interactions, presenting a special risk in aged, polymedicated individuals. Understanding pharmacokinetic and pharmacodynamic interactions is warranted to avoid undesirable adverse drug reactions, which may result in unwanted side-effects or therapeutic failure. The present study reviews the potential interactions between selected bioactive compounds (170) used by seniors for cognitive enhancement and representative drugs of 10 pharmacotherapeutic classes commonly prescribed to the middle-aged adults, often multimorbid and polymedicated, to anticipate and prevent risks arising from their co-administration. A literature review was conducted to identify mutual targets affected (inhibition/induction/substrate), the frequency of which was taken as a measure of potential interaction. Although a limited number of drugs were studied, from this work, interaction with other drugs affecting the same targets may be anticipated and prevented, constituting a valuable tool for healthcare professionals in clinical practice.
... Anemarrhena asphodeloide (AA), a traditional Chinese medicine, has the effects on clearing heat and purging fire, nourishing yin and moisturizing, quenching thirst and removing annoyance. Timosaponin AIII (TAIII), a steroidal saponin, is a major active component of AA (King et al., 2009), which exerts various pharmacological activities including antipyretic, anti-inflammatory (Lim et al., 2015), antidiabetic (Kimura et al., 1996), antidepressive (Ren et al., 2006), and improvement of learning and memory (Hu et al., 2005). Recently, TAIII has showed potent anti-tumor activity against various cancers in vivo and in vitro, such as gastric cancer, cervical cancer, colorectal cancer, breast cancer, acute leukemia, non-small cell lung cancer, melanoma, liver cancer, and pancreatic cancer, etc (Takeda et al., 2001;Sy et al., 2008;Tsai et al., 2013;Huang et al., 2015;Jung et al., 2016;Wang et al., 2017). ...
Timosaponin AIII (TAIII), a steroidal saponin, exerts potent anti-tumor activity in various cancers, especially breast cancer. However, the concrete molecular mechanisms of TAIII against breast cancer are still unclear. Here, we find that TAIII triggers DNA damage, leads to G2/M arrest, and ultimately induces apoptosis in breast cancer both in vitro and in vivo . TAIII induced G2/M phase arrest and apoptosis in MDA-MB-231 and MCF7 cells accompanied with down-regulation of CyclinB1, Cdc2 and Cdc25C. Further data showed that the ATM/Chk2 and p38 pathways were activated representing by up-regulated levels of p-H2A.X and p-p38, which indicated an induction of DNA damage by TAIII, leading to cell cycle arrest and apoptosis. The effects of TAIII were further confirmed by employing inhibitors of ATM and p38 pathways. In vivo , TAIII suppressed the growth of subcutaneous xenograft tumor without obvious toxicity, which indicated by Ki67 and TUNEL analysis. Data also showed that TAIII stimulated the ATM/Chk2 and p38 MAPK pathways in vivo , which in consistent with the effects in vitro . Hence, our data demonstrate that TAIII triggers DNA damage and activates ATM/Chk2 and p38 MAPK pathways, and then induces G2/M phase arrest and apoptosis in breast cancer, which provide theoretical evidence for TAIII utilized as drug against breast cancer.
... In addition, they have neuroprotective, immune-adjuvant, anti-anxiety, cardio-protective, anti-bacterial and anti-diarrhoeal properties [10]. SRS, the steroidal sapogenin from A. racemosus has been shown to possess anti-depressant properties though it has not been evaluated for factors implicated in AD [11]. ...
... [3] Phytochemical investigations have revealed that compounds isolated from AR include steroidal saponins, flavonoids, lignans, and fatty acids. [4] Recent pharmacological studies showed that constituents of AR, such as mangiferin, timosaponin BII, timosaponin BIII, and timosaponin AIII, exhibited various biological activities, including antidiabetic, [5] antidementia, [6] antidepressant, [7] anti-inflammatory, [8] and antioxidant activities. [9] Thus, they were considered the principal components responsible for the main pharmacological activities of AR; in addition, timosaponin BII and mangiferin were selected as the marker components for quality control of AR in the Chinese pharmacopeia. ...
... (1) CHM could enhance monoamine transmission systems (Viana et al., 2005;Ren et al., 2006;Zhu et al., 2006). The antidepressant effect of Xiaochaihu decoction was related with the promotion of 5-hydroxytryptamine (5-HT) release or inhibition of reuptake (Su et al., 2014); Jiaotai pill can efficaciously elevated the content of 5-HT and suppressed the consumption of norepinephrine (NE) level in the prefrontal cortex in lipopolysaccharide (LPS)-treated mice (Qian et al., 2016); (2) CHM could down-regulate hypothalamic-pituitary-adrenal (HPA) axis activity (Xu et al., 2008;Ye et al., 2012). ...
Objective:
To conduct a systematic review to assess the current evidence available for the effectiveness and safety of Chinese herbal medicine (CHM) for depression.
Methods:
An electronic search was conducted in eight databases from inception until April 2018. Randomized controlled trials with risk of bias (RoB) score ≥ 4 according to the Cochrane RoB tool were included for analyses. The primary outcome was the severity of depression. The secondary outcomes were total effective rate (TER) and adverse events. The minimally important difference (MID) of the severity of depression was a reduction in the Hamilton Rating Scale for Depression 17 items (HAMD-17) scores by 4. RevMan 5.3 Software was used for data analyses. GRADE system was used to assess the certainty of evidence.
Results:
A total of 40 eligible studies with 3549 subjects were identified. Meta-analyses showed that CHM monotherapy had better clinically effects than placebo according to HAMD-17 score (Mean Difference (MD) = -4.53, 95% CI (-5.69, -3.37), P < 0.00001; Certainty of evidence: Moderate) and TER (Risk Ratio (RR) = 2.15, 95% CI (1.61, 2.88), P < 0.00001, Certainty of evidence: Low). Meta-analyses showed that CHM was as effective as western conventional medications (WCM) in TER (RR = 0.99, 95% CI (0.95, 1.02), P = 0.41, Certainty of evidence: High) and in reducing HAMD-17 score (MD = 0.44, 95% CI (-0.11, 0.99), P = 0.12, Certainty of evidence: Moderate). Meta-analyses showed that CHM in combination with WCM was better than WCM in TER (RR = 1.16, 95% CI (1.07, 1.27), P = 0.0004, Certainty of evidence: High), while had comparable clinically effects with WCM according to HAMD-17 score (MD = -2.51, 95% CI (-3.24, -1.77), P < 0.00001, Certainty of evidence: Moderate). In additional, CHM were associated with less adverse events than WCM, and adding CHM to WCM reduced adverse events.
Conclusion:
The findings of present systematic review, at least to a certain extent, provided supporting evidence for the routine use of CHM for depression.
... Microdialysis studies later showed that administration of hederagenin from fruit extract of F. akebiae sig- nificantly increased extracellular concentrations of serotonin, nor- epinephrine and dopamine in the frontal cortex region in rats [86]. Ren et al. showed the anti-depressant effects of sarsasapogenin from Ane- marrhena asphodeloides wherein sarsasapogenin produced a marked increase in noradrenaline and serotonin levels in the hypothalamus and hippocampus, as well as, showed MAO inhibitory activity in the mouse brain [87]. Compounds isolated from Cayratia japonica such as api- genin, luteolin, flavonol and quercetin showed potent anti-depressant inhibitory effects against MAO activity. ...
Stress renders an individual to experience mental pressure and exhaustion which brings about feelings of anxiety, depression, anger and/or other negative emotions. Depression affects a person's state of mind, behaviour, health and is often associated with suicide. The use of anti-depressant drugs as therapeutic agents is associated with symptoms such as, delayed onset of action, side-effects, drug-drug and dietary interactions, sexual dysfunction, cardiac toxicity, etc. Thus, there is need to target these issues and improve current treatment options. Medicinal plants have long been used in discovering novel treatment strategies and compounds with promising roles in treating various disease conditions. There has been an increase, worldwide, in the use of medicinal plants and herbs for developing nutraceuticals for treatment of depression and other psychiatric disorders. Medicinal plants in their natural forms are valuable as they are rich in various phytochemical compounds. These phytochemical compounds have pharmacological roles in treating various diseases conditions; apart from being widely available in nature and commercially beneficial. The phytochemical compounds in plants are constantly being explored through various experimental studies to determine the molecular basis of how medicinal plants work in relation to drugs and diseases and to develop neutraceuticals for improving conditions. This review summarizes 110 medicinal plants and their phytochemical constituents that have been shown to possess anti-depressant activity. This review also highlights the various mechanisms of anti-depressant action of some of these plants and their plant parts like roots, stem, leaves, flowers, fruit or whole plant; phytochemical compounds showing anti-depressant activity such flavanoids, steroids, saponins, sugars, lectins, alkaloids, etc.; and various anti-depressant screening models used such as tail suspension test, forced swim test, chronic unpredictable stress test, sucrose preference test, monoamine oxidase inhibition assay, learned helplessness test, open field test, hole board test, etc. However, mechanistic evaluation of many of these plants still needs to be investigated and explored.
... Another dihydroflavone isolated from Gentiana macrophylla, kurarinone, could also inhibit the growth of C. albicans [155]. Nyasol ((Z)-1,3-bis(4-hydroxyphenyl)-1,4-pentadiene), isolated from the herbal plant Anemarrhena asphodeloides Bunge (Liliaceae) which has been used in Chinese traditional medicine as antipyretic, anti-inflammatory, antidiabetic, and antidepressant agent [156], exhibits antifungal activity against C. albicans alone or in synergy with azoles [157,158]. This compound also has activity against other fungal pathogens such as A. flavus, Fusarium oxysporum, Pythium ultimum, and Rhizoctonia solani, to name a few [158,159]. ...
Infections caused by Candida albicans , often refractory and with high morbidity and mortality, cause a heavy burden on the public health while the current antifungal drugs are limited and are associated with toxicity and resistance. Many plant-derived molecules including compounds isolated from traditional Chinese medicine (TCM) are reported to have antifungal activity through different targets such as cell membrane, cell wall, mitochondria, and virulence factors. Here, we review the recent progress in the anti- Candida compounds from TCM, as well as their antifungal mechanisms. Considering the diverse targets and structures, compounds from TCM might be a potential library for antifungal drug development.
... Furthermore, the expected effects of FLX in Porsolt test were absent even after the intraperitoneal injection or the housing of the male Swiss mice in standard or inverted light/dark cycle. Present data were surprising because previous studies have shown that oral treatment with antidepressants reduced the immobility time of Swiss mice in the Porsolt test in a variety of experimental conditions (19,20,(27)(28)(29)(30)(31). A paper reporting conditions similar to those here (Swiss mice, oral treatment, behavioural testing in the afternoon, blinding, and randomisation) found an effect size above 60% for FLX treatment on immobility time (29). ...
Objective
The aims of this study were to replicate previously published experiments and to modify the protocol to detect the effects of chronic antidepressant treatment in mice.
Methods
Male Swiss mice ( n =6–8/group) housed in reversed light/dark cycle were randomly assigned into receive vehicle (10% sucrose), sub-effective doses (1 and 3 mg/kg) or effective doses (10 and 30 mg/kg) of bupropion, desipramine, and fluoxetine and a candidate antidepressant, sodium butyrate (1–30 mg/kg) per gavage (p.o.) 1 h before the forced swim test (FST). Treatments continued daily for 7 and 14 days during retests 1 and 2, respectively. In an additional experiment, mice received fluoxetine (20 mg/kg) or vehicle (10% sucrose or 0.9% saline) p.o. or i.p. before the FST. Mice housed in reversed or standard light/dark cycles received fluoxetine (20 mg/kg) prior FST. Video recordings of behavioural testing were used for blind assessment of the outcomes.
Results
According to the expected, doses of antidepressants considered sub-effective failed to affect the immobility time of mice in the FST. Surprisingly, acute and chronic treatment with the high doses of bupropion, desipramine, and fluoxetine or sodium butyrate also failed to reduce the immobility time of mice in the FST. Fluoxetine 20 mg/kg was also ineffective in the FST when injected i.p. or in mice housed in normal light/dark cycle.
Conclusion
Data suggest the lack of efficacy of orally administered bupropion, desipramine, fluoxetine in the FST in Swiss mice. High variability, due to high and low immobility mice, may explain the limited effects of the treatments.
... SA possessed a variety of biological and pharmaceutical activities, such as protecting effects against impaired vascular responsiveness in streptozotocin-induced diabetic rats, the cardioprotective effects on animal models of heart hypoxia/reoxygenation injury, the antiplatelet and antithrombotic activities in an arterio-venous shunt model and protective effects against carbon tetrachloride or concanavalin A-induced acute liver damage [20][21][22][23][24]. Total flavonoids (TFA) were extracted from the rhizome of Anemarrhena asphodeloides (Zhimu) used as an antipyretic, anti-inflammatory, anti-diabetic and antidepressant in traditional Chinese medicine [25]. TFA is composed of 16 flavonoid compounds, including xanthones, mangiferin, ismangiferin, neomangiferin and 1,4,5,6,-tetrahydroxyxanthone. ...
Sulfur mustard (SM) is a vesicating chemical warfare agent used in numerous military conflicts and remains a potential chemical threat to the present day. Exposure to SM causes the depletion of cellular antioxidant thiols, mainly glutathione (GSH), which may lead to a series of SM-associated toxic responses. MSTF is the mixture of salvianolic acids (SA) of Salvia miltiorrhiza and total flavonoids (TFA) of Anemarrhena asphodeloides. SA is the main water-soluble phenolic compound in Salvia miltiorrhiza. TFA mainly includes mangiferin, isomangiferin and neomangiferin. SA and TFA possess diverse activities, including antioxidant and anti-inflammation activities. In this study, we mainly investigated the therapeutic effects of MSTF on SM toxicity in Sprague Dawley rats. Treatment with MSTF 1 h after subcutaneous injection with 3.5 mg/kg (equivalent to 0.7 LD50) SM significantly increased the survival levels of rats and attenuated the SM-induced morphological changes in the testis, small intestine and liver tissues. Treatment with MSTF at doses of 60 and 120 mg/kg caused a significant (p < 0.05) reversal in SM-induced GSH depletion. Gene expression profiles revealed that treatment with MSTF had a dramatic effect on gene expression changes caused by SM. Treatment with MSTF prevented SM-induced differential expression of 93.8% (973 genes) of 1037 genes. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 36 pathways, such as the MAPK signaling pathway, pathways in cancer, antigen processing and presentation. These data suggest that MSTF attenuates SM-induced injury by increasing GSH and targeting multiple pathways, including the MAPK signaling pathway, as well as antigen processing and presentation. These results suggest that MSTF has the potential to be used as a potential therapeutic agent against SM injuries.
... Hederagenin, the aglycone of triterpenoid saponins of Akebia quinata, exhibited antidepressant effect by modulation of the HPA axis . Sarsasapogenin, a hexacyclic steroidal sapogenin, from Anemarrhena asphodeloides increased 5-HT and NE levels of the hypothalamus and hippocampus as well as inhibited both MAO-A and MAO-B activity (Ren et al., 2006). Oleanolic acid could increase BDNF and NE levels without any effect on DA level. ...
Depression is a major mental disease that is ranked as the fourth leading cause of disability. In order to avoid unwanted adverse reactions, as well as improve efficacy, current researches are seeking alternatives to conventional antidepressants. Phytochemicals provide an extensive research area in antidepressant therapies. The aim of the present study is to comprehensively review neurological evidences demonstrating the efficacy of phytochemicals in depression. For this purpose, electronic databases were searched to collect all data on the antidepressant mechanisms of phytochemicals from 1966 up to 2015. Plant metabolites from different categories including polyphenols (flavonoids, phenolic acids, lignanes, coumarins), alkaloids, terpenes and terpenoids, saponins and sapogenins, amines, and carbohydrates were found to possess antidepressant activity. Naringenin, quercetin derivatives, eugenol, piperine, diterpene alkaloids, berberine, hyperforin, riparin derivatives, ginsenosides, as well as β-carboline alkaloids are among the most relevant ones. Naringenin has represented its antidepressant effect by elevation of serotonin (5-HT), norepinephrine, brain-derived neurotrophic factor (BDNF), and glucocorticoid receptors. Piperine demonstrated inhibition of monoamine oxidase enzymes, elevation of brain 5-HT and BDNF levels, and modulation of the hypothalamus-pituitary-adrenal axis. The serotonergic, noradrenergic, and dopaminergic effect of berberine has been proven in several studies. Quercetin derivatives have revealed antidepressant potential via elevating pro-opiomelanocortin and neuroprotective properties, as well as reduction of proinflammatory cytokines. Assessing the structure-activity relationship of highly potent antidepressant phytochemicals is suggested to find future natural, semisynthetic, or synthetic antidepressants. Further clinical studies are also necessary for confirmation of natural antidepressant efficacy and completion of their safety profile.
... Stilbenoids isolated from methanolic extract of rhizomes and roots of Veratrum taliense Loes have been shown to have MAO-A inhibitory activity [191]. Sarsasapogenin a steroidal sapogenin as a potent isolated compound from Anemarrhena asphodeloides Bunge, also has been shown to have antidepressant like effects in behavioral mouse models like despair test and force swim test [192].Curcumin a diarylheptanoid from Curcuma longa L. proved its antidepressant efficacy primarily by inhibiting MAO-A, whereas it inhibited MAO-B solitary at high dose [193]. Extracts of different plants such as Areca catechu, Piper nigrum L., Asparagus racemosus Willd, Rhazya stricta Decne, Melissa officinalis L., Origanum vulgare L., have been reported to demonstrate significant antidepressant activity probably mediated via the monoaminergic system [194][195][196][197][198][199][200][201]. ...
Monoamine oxidases A and B (MAO-A and B) play a critical role in the metabolism of intracellular neurotransmitters of the central nervous system. For decades, MAO inhibitors have proven their clinical efficacy as potential drug targets for several neurological and neurodegenerative diseases. Use of first generation non selective MAO inhibitors as neuropsychiatric drugs elicited several side effects like hypertensive crisis and cheese reaction. Therefore their use is now limited due to non-selectivity towards MAO isoforms and inhibition of metabolizing enzymes like cytochrome P450. Development of selective and specific MAO inhibitors like moclobemide, toloxatone improves their efficacy as disease-modifying effects in monotherapy as well as adjunctive therapy. Recently a lot of research has been done to elucidate the pharmacological potential of medicinal plants and their isolated bioactive constituents having MAO inhibitory activity. Herbs containing MAO inhibitors extensively used for the development of potent synthetic drugs and as safe and effective alternatives to the available synthetic drugs in the treatment of neurodegenerative diseases such as depression, Parkinson and Alzheimer's. In several diseases like Parkinson natural MAO inhibitors prevented the neuron denaturalization by their dual action via enhancing neurotransmission of dopamine as well as lowering the generation of free radicals and toxins. Currently development of selective MAO inhibitors is still under study to achieve more effective therapies by using Computer Aided Drug Designing, Ligand-based models and structure-activity hypothesis. These approaches also facilitate understanding the interaction of newly designed molecule with MAO enzymes and the rationalization of probable mechanisms of action.
... We also evaluated fluoxetine and a new antidepressant, YY-23, which is a new compound derived from the traditional antidepressant Chinese medicine Rhizoma anemarrhenae. Although the sarsasapogenin from Rhizoma anemarrhenae has been proved to have antidepressant-like effects in some depressive animal models (Matsuda et al., 2001;Ren et al., 2006), the mechanisms of the antidepressant-like effects of YY-23 are not known. Brain-derived neurotrophic factor (BDNF), as a biomarker of depression, was also examined in the PFC to understand the deficits in CMS-induced depressive-like behaviors and the pharmacodynamics of antidepressants. ...
Major depressive disorder (MDD) is one of the leading causes of morbidity worldwide. Several antidepressants have been widely prescribed to treat patients with MDD. However, neuronal changes in brain function remain poorly understood. Based on the standard chronic mild stress (CMS) model of depression in mice, we investigated the neuronal mechanisms of the classic antidepressant, fluoxetine, and a new compound (termed YY-23 in this study) derived from furostanol saponin. The results showed that both fluoxetine and YY-23 normalized CMS-induced depressive-like behaviors. YY-23 caused antidepressant-like behaviors with a faster action than fluoxetine. In terms of in vivo neuronal activities, a CMS-induced decrease in spontaneous firing in burst of medial prefrontal cortex pyramidal neurons rather than ventral tegmental area (VTA) was reversed by the chronic administration of fluoxetine and YY-23. We also found that CMS-induced deficits in the expression of prefrontal brain-derived neurotrophic factor (BDNF) were also restored by chronically administering YY-23 and fluoxetine. In addition, chronic administration of fluoxetine rather than YY-23 resulted in an improvement of antidepressive-like behavior and a change of burst firing of VTA in control-housed animals, indicating that the pharmacological effects of YY-23 were specific to CMS-treated animals. Together, these data suggest that the burst-firing patterns of pyramidal cells may be a neural biomarker of depressive-like mice and antidepressant action. Furthermore, synaptic transmission and BDNF may contribute to the rapid antidepressant-like effects on depression.
... In two neurode-generation rat models, SAR significantly raised the density of total Muscarinic receptors and its M1 subtype toward normal control levels [6] . Moreover, SAR exhibits antidepressant activity [7] . ...
To generate a polyclonal antibody against sarsasapogenin and to develop an indirect competitive enzyme-linked immunosorbent assay (IC-ELISA) method for the pharmacokinetic study of Sarsasapogenin in rats.
The antigen of sarsasapogenin was produced using an active ester method and subsequently used for raising polyclonal antibodies in rabbits. The specificity and sensitivity of the antibody were measured by IC-ELISA. Using the ELISA method, sarsasapogenin levels were measured in the serum of rats after an oral dose of 100 mg/kg.
Polyclonal antibodies raised against sarsasapogenin-bovine serum albumin were generated and showed a high reactivity to sarsasapogenin. The antibodies exhibited minor cross-reactivity to ruscogenin (23%), diosgenin (22%), 25 (R, S) ruscogenin l-O-[beta-D-glucopyranosyl (1-->2)][beta-D-xylopyranosyl (1-->3)]-beta-D-fucopyranoside (26%) and no cross-reactivity to diammonium glycyrrhizinate and notoginseng R1. The detection range of sarsasapogenin by this ELISA method was approximately 2.4-760 ng/mL. The recovery rates of 10 ng/mL, 100 ng/mL, and 500 ng/mL were in the range of 91.0%-96.2% for intra-assay and 89.0%-92.0% for inter-assay. The coefficients of variation (CV%) for intra- and inter-assays at the three different sarsasapogenin levels were 3.1%-8.3% (n=6) and 6.0%-14.1% (n=6), respectively.
The IC-ELISA method is a sensitive test for the determination of sarsasapogenin concentration in rat plasma and for pharmacokinetic (PK) studies.
... This sub-additive effect is difficult to explain; however, the existence of triterpene saponins has been reported in other species of Ternstroemia genus (Shin et al., 2003). It is known that these kinds of compounds have activity in the central nervous system (Ren et al., 2006), and also that they are able to modify the activity of some isoforms of cytochrome P450 enzymes (Henderson et al., 1999), thereafter the ethanol metabolism alteration should not be discarded as a possible explanation in the attenuation of the sedative effect of ethanol observed by the co-administration of Ternstroemia pringlei extract. This observation requires experimental support to give a convincing explanation of these facts. ...
The decoction of dried fruits of Ternstroemia pringlei (Rose) Standl. (Theaceae), commonly known as "Flor de Tila", is used in the Mexican traditional medicine to diminish insomnia and fear.
To examine the sedative effects of the dried fruits of Ternstroemia pringlei and investigate a possible synergistic pharmacodynamic interaction between the sedative effect of aqueous extract of this plant and six central nervous system (CNS) depressant drugs.
The sedative effect was performed using the exploratory cylinder test in ICR mice. The extracts and drugs were intraperitoneally administered 30 min before testing in different doses, with exception of ethanol and buspirone which were administered 5 and 20 min before testing, respectively. An isobolographic analysis was used to characterize the interaction between Ternstroemia pringlei extract and six CNS depressant drugs.
The intraperitoneal administration of the hexane, dichloromethane, methanol and aqueous extracts of Ternstroemia pringlei showed a dose-dependent sedative effect. Ternstroemia pringlei aqueous extract combined with buspirone, diazepam, diphenhydramine, haloperidol or pentobarbital exerted a super-additive (synergistic) sedative interaction. Whereas the combination Ternstroemia pringlei extract plus ethanol resulted in a sub-additive (attenuate) sedative interaction.
These findings are in agreement with the traditional use of Ternstroemia pringlei in the treatment of insomnia, however it is a plant that interacts in a complex form with CNS depressant drugs. It may represent an advertence on the use of this plant concomitantly with other neuroactive drugs.
Natural flavone and isoflavone analogs such as 3 ,4 ,7-trihydroxyflavone (1), 3 ,4 ,7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer's and Parkinson's disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC 50 value: 7.57 ± 0.14 µM) and 3 as a competitive inhibitor of hMAO-B with an IC 50 value of 7.19 ± 0.32 µM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD 4 R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD 4 R antagonist effect, respectively, for neuroprotection. The route of administration should be considered.
Objective: To provide a new idea for the treatment of depression by summarizing the antidepressant effect and mechanism of active ingredients in functional food, and medicine and food homologous products. Methods: The literature related to the antidepressant of functional food or medicine and food homologous products from September 25, 1996 to September 5, 2022 was collected through PubMed, Google Academic, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. After that, their antidepressant active ingredients and mechanism of action were systematically summarized and analyzed. Results: A total of 146 pieces of literature were involved in the study, including 67 plant-derived functional foods or medicine and food homologous products, 32 antidepressant extracts (including 8 flavonoid extracts), and 87 antidepressant active ingredients. The 87 antidepressant active ingredients include 7 terpenes, 22 saponins, 15 flavonoids, 11 phenylpropanoids, 7 phenols, 6 sugars, 8 alkaloids, and 11 others. Conclusion: The study summarized and analyzed the active ingredients and mechanisms of antidepressants in functional foods and medicine and food homologous products, which provides a new vision for the development of new antidepressants and a potential alternative treatment for patients with depression.
Central nervous system (CNS) disorders and diseases are expected to rise sharply in the coming years, partly because of the world’s aging population. Medicines for the treatment of the CNS have not been successfully made. Inadequate knowledge about the brain, pharmacokinetic and dynamic errors in preclinical studies, challenges with clinical trial design, complexity and variety of human brain illnesses, and variations in species are some potential scenarios. Neurodegenerative diseases (NDDs) are multifaceted and lack identifiable etiological components, and the drugs developed to treat them did not meet the requirements of those who anticipated treatments. Therefore, there is a great demand for safe and effective natural therapeutic adjuvants. For the treatment of NDDs and other memory-related problems, many herbal and natural items have been used in the Ayurvedic medical system. Anxiety, depression, Parkinson’s, and Alzheimer’s diseases (AD), as well as a plethora of other neuropsychiatric disorders, may benefit from the use of plant and food-derived chemicals that have antidepressant or antiepileptic properties. We have summarized the present level of knowledge about natural products based on topological evidence, bioinformatics analysis, and translational research in this review. We have also highlighted some clinical research or investigation that will help us select natural products for the treatment of neurological conditions. In the present review, we have explored the potential efficacy of phytoconstituents against neurological diseases. Various evidence-based studies and extensive recent investigations have been included, which will help pharmacologists reduce the progression of neuronal disease.
Ethnopharmacological relevance
Depression, one of the most common psychiatric disorders, is the fourth leading cause of long-term disability worldwide. A series of causes triggered depression, including psychological stress and conflict, as well as biological derangement, among which stress has a pivotal role in the development of depression. Traditional herbal medicine has been used for the treatment of various disorders including depression for a long history with multi-targets, multi-levels and multi-ways, attracting great attention from scholars. Recently, natural products have been commercialized as antidepressants which have become increasingly popular in the world health drug markets. Major research contributions in ethnopharmacology have generated and updated vast amount of data associated with natural products in antidepressant-like activity.
Aims of the review
This review aims to briefly discuss the pathological mechanism, animal models of stress-induced depression, traditional use of herbal medicines and especially recapitulate the natural products with antidepressant activity and their pharmacological functions and mechanism of action, which may contribute to a better understanding of potential therapeutic effects of natural products and the development of promising drugs with high efficacy and low toxicity for the treatment of stress-induced depression.
Materials and methods
The contents of this review were sourced from electronic databases including PubMed, Sci Finder, Web of Science, Science Direct, Elsevier, Google Scholar, Chinese Knowledge On frastructure (CNKI), Wan Fang, Chinese Scientific and Technological Periodical Database (VIP) and Chinese Biomedical Database (CBM). Additional information was collected from Yao Zhi website (https://db.yaozh.com/). Data were obtained from April 1992 to June 2021. Only English language was applied to the search. The search terms were ‘stress-induced depression’, ‘pathological mechanism’ in the title and ‘stress’, ‘depression’, ‘animal model’ and ‘natural products’ in the whole text.
Results
Stress-induced depression is related to the monoaminergic system, hypothalamic-pituitary-adrenal (HPA) axis, neuronal plasticity and a series of inflammatory factors. Four main types of animal models of stress-induced depression were represented. Fifty-eight bioactive phytochemical compounds, fifty-six herb medicines and five formulas from traditional Chinese medicine were highlighted, which exert antidepressant effects by inhibiting monoamine oxidase (MAO) reaction, alleviating dysfunction of the HPA axis and nerve injury, and possessing anti-inflammatory activities.
Conclusions
Natural products provide a large number of compounds with antidepressant-like effects, and their therapeutic impacts has been highlighted for a long time. This review summarized the pathological mechanism and animal models of stress-induced depression, and the natural products with antidepressant activity in particular, which will shed light on the action mechanism and clinical potential of these compounds. Natural products also have been a vital and promising source for future antidepressant drug discovery.
Depression, a well know mental disorder has global prevalence, nearly affecting 17% of population. Due to various limitations of the currently available drugs, people have been adopting traditional herbal medicines to alleviate the symptoms of depression. It is notable to mention that natural products, their derivatives, and their analogs are the main source for new drug candidates in depression. The mechanisms include interplay with γ-aminobutyric acid (GABA) receptors, serotonergic, dopaminergic noradrenergic systems, and elevation of BDNF levels. The focus of this review is to revisit the role of signalling molecules in depression and highlight the use of plant-derived natural compounds to counter depression in the CNS.
Depression is a widespread and persistent psychiatric disease. Due to various side effects and no curative treatments of conventional antidepressant drugs, botanical medicines have attracted considerable attention as a complementary and alternative approach. The pathogenesis of depression is quite complicated and unclear. Metabolomics is a promising new technique for the discovery of novel biomarkers for exploring the potential mechanisms of diverse diseases and assessing the therapeutic effects of drugs. In this article, we systematically reviewed the study of botanical medicine for the treatment of depression using metabolomics over a period from 2010 to 2019. Additionally, we summarized the potential biomarkers and metabolic pathways associated with herbal medicine treatment for depression. Through comprehensive evaluation of herbal medicine as novel antidepressants and understanding of their pharmacomechanisms, a new perspective on expanding the application of botanical medicines for the treatment of depression is provided.
Depression is a multigenetic or multifactorial syndrome. The central neuron system (CNS)-orientated, single target, and conventional antidepressants are insufficient and far from ideal. Traditional Chinese Medicine (TCM) has historically been used to treat depression up till today, particularly in Asia. Its holistic, multidrug, multitarget nature fits well with the therapeutic idea of systems medicine in depression treatment. Over the past two decades, although efforts have been made to understand TCM herbal antidepressants at the molecular level, many fundamental questions regarding their mechanisms of action remain to be addressed at the systems level in order to better understand the complicated herbal formulations in depression treatment. In this Mini Review, we review and discuss the mechanisms of action of herbal antidepressants and their acting targets in the pathological systems in the brain, such as monoamine neurotransmissions, hypothalamic–pituitary–adrenal (HPA) axis, neurotropic factor brain-derived neurotrophic factor (BDNF) cascade, and glutamate transmission. Some herbal molecules, constituents, and formulas are highlighted as examples to discuss their mechanisms of action and future directions for comprehensive researches at the systems level. Furthermore, we discuss pharmacological approaches to integrate the mechanism of action from the molecular level into the systems level for understanding of systems pharmacology of TCM formulations. Integration of the studies at the molecular level into the systems level not only represents a trend in TCM study but also promotes our understanding of the system-wide mechanism of action of herbal antidepressant formulations.
Anemarchalconyn (1) and anemarcoumarin A (2), the natural bioactive compounds isolated from the rhizomes of Anemarrhena asphodeloides Bunge (Liliaceae), were first totally synthesized using easily available materials in short, convenient routes with overall yields of 32 and 48%.
Depression is the predominant cause of illness and disability. We applied untargeted metabolomics using mass spectrometry to identify metabolic signatures associated with depression in serum and explored the antidepressant effects of Lilies and Rhizoma Anemarrhenae on an experimental model of chronic unpredictable mild stress (CUMS). Meanwhile metabolomics based on UHPLC-Q-TOF-MS, was used to study the change in metabolites in CUMS rat serum and to evaluate the effects of Anemarrhena Rhizoma, Lilies (alone and in combination). Partial least squares-discriminant analysis identified thirty metabolites as decisive marker compounds that discriminated the CUMS rats and the control rats. The majority of these metabolites were involved in amino acid metabolism, the tricarboxylic acid cycle, and phosphoglyceride metabolism. The reliability of the metabolites were evaluated by the administration of Lilies, Rhizoma Anemarrhenas, Fluoxetine, and the combination of Lilies and Rhizoma Anemarrhenas, to the CUMS rats. Behavior studies demonstrated that treatment with the combination of Lilies and Rhizoma Anemarrhenas resulted in optimal antidepressant effects. The combination treatment was almost as effective as Fluoxetine. Our results suggest that Lilies and Rhizoma Anemarrhenae demonstrate synergistically antidepressant effects in CUMS via the regulation of multiple metabolic pathways. These findings provide insight into the pathophysiological mechanisms underlying CUMS and suggest innovative and effective treatments for this disorder.
The herbal pair Zhimu-Baihe (Zhimu: Anemarrhena asphodeloides; Baihe: Lilium brownii var. viridulum) is a traditional Chinese medicament used for the treatment of depression. However, the relevant mechanisms of action has not been clarified. This study investigated the anti-depressant activity of the total saponins from Zhimu and Baihe and the mechanisms underlying using a chronic unpredictable mild stress (CUMS)-induced rat model of depression. High performance liquid chromatography with electrochemical detection (HPLC-ECD) was applied to determine the levels of three monoamine neurotransmitters, 5-hydroxytryptamine (5-HT), noradrenaline (NE) and dopamine (DA), in the rat hippocampus. Optimized pretreatment of samples and mass spectrometry conditions were used to analyse the metabonomic profile of the hippocampus. The 5-HT and NE levels in the CUMS group were reduced compared with the control group, whereas all groups had similar DA levels. The metabonomic profile of the hippocampus revealed 32 differential metabolites between the CUMS and control group, among which 18 metabolites were significantly recovered in the Anemarrhena saponins and Lilium saponins (AL) combination intervention group. These results suggested an anti-depressant effect of AL. Moreover, 24 metabolites in AL group were better recovered compared with the Anemarrhena saponins (AS) or Lilium saponins (LS) intervention groups, suggesting a synergetic effect of AS and LS in the treatment of depression. The anti-depressant effect might be related to the regulation of several metabolic pathways, including monoamine neurotransmitter synthesis (especially 5-HT and NE), and amino acid, fatty acid, and phospholipid metabolism in rats.
Although antidepressants have been widely prescribed to treat patients with major depressive disease (MDD), there is little disagreement over the need for improved antidepressant therapeutics as the typical treatments have a slow therapeutic onset and moderate efficacy. In the present study, we assessed a novel compound, YY-21, from timosaponin B-III derived from sarsasapogenin of Anemarrhenae Rhizoma. From the initial results, we found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 min as determined by excitatory postsynaptic current (EPSC) and field excitatory postsynaptic potential (fEPSP) in medial prefrontal cortex (mPFC) slices, respectively. YY-21 demonstrated anxiolytic-like effects following acute administration in naïve animals and reversed the depressive-like and anxiety phenotypes induced by chronic unpredictable mild stress (CMS) with a relatively fast therapeutic onset. Furthermore, analysis of intracellular signaling pathways showed that YY-21 normalized the CMS-induced low protein levels of GluN2B, p-mTOR, synaptic-related proteins, such as BDNF, PSD-95 and GluA1. Pre-application of the mTOR-selective inhibitor rapamycin blocked YY-21-induced long-term synaptic enhancement. These findings suggest that the activation of BDNF-dependent mTOR signaling, which produces a rapid increase in the postsynaptic protein PSD-95 and GluA1 and further triggers the long-term enhancement of synaptic neurotransmission, may be the mechanism underlying the rapid antidepressant and anxiolytic effects induced by YY-21.
Using polyclonal antibody against sarsasapogenin, an enzyme-linked immunosorbent assay (ELISA) for quantitative analysis of sarsasapogenin in Rhizoma Anemarrhenae was developed. The linear detection range of sarsasapogenin was 20-1 311 ng/mL. The lowest limit of detection (LOD) of the assay was 20 ng/mL, and the recovery rate ranged from 92.2% to 97.1%. The relative standard deviation for intra- and inter- assays were less than 14.3%. To validate the immunoassay, the sarsasapogenin content of Rhizoma Anemarrhenae from 5 different habitats were analyzed by the immunoassay and HPLC-ELSD. The results obtained by the two methods were consistent. This immunoassay is simple, sensitive and rapid, and could simplify the determination of the single components in multi-component system.
A homoisoflavanone, 7,4'-dihydroxyhomoisoflavanone (1) and a flavanone, (2S)-7,4'-dihydroxy-5- methoxyflavanone (2), were isolated from the rhizomes of Anemarrhena asphodeloides, together with 4,4'- dihydroxychalcon (3), 2'-O-methylphlorethin (4), 1,3-bis-di-p-hydroxyphenyl-4-penten-1-one (5), and 2,4'- dihydroxy-4-methoxybenzophenone (6) on the basis of spectroscopic and physicochemical analyses including 1Dand 2D- NMR techniques as well as by comparison of their data with the published values. Compounds 1 - 4 were isolated for the first time from this plant source. Among isolates, compound 2 exhibited moderate inhibitory effect on the differentiation of pre-adipocyte 3T3-L1 cells.
Abstract Depression is a serious widespread psychiatric disorder that affects approximately 17% of people all over the world. Exploring the neurological mechanisms of the antidepressant activity of plant-derived agents could have a crucial role in developing natural drugs for the management of depression. The aim of the present study is to review the neurological mechanisms of action of antidepressant plants and their constituents. For this purpose, electronic databases, including PubMed, Science Direct, Scopus, and Cochrane Library, were searched from 1966 to October 2013. The results showed that several molecular mechanisms could be proposed for the antidepressant activity of medicinal plants and their constituents. Hypericum species could normalize brain serotonin level. Liquiritin and isoliquiritin from Glycyrrhiza uralensis rhizome act via the noradrenergic system. Rosmarinus officinalis and curcumin from Curcuma longa interact with D1 and D2 receptors as well as elevate the brain dopamine level. Sida tiagii and Aloysia gratissima involve γ-aminobutyric acid and N-methyl-D-aspartate receptors, respectively. Fuzi polysaccharide-1 from Aconitum carmichaeli could affect brain-derived neurotrophic factor signaling pathways. Psoralidin from Psoralea corylifolia seed modulate the hypothalamic-pituitary-adrenal axis. The total glycosides of Paeonia lactiflora demonstrate an inhibitory effect on both subtypes of monoamine oxidase. 3,6'-Di-o-sinapoyl-sucrose and tenuifoliside A from Polygala tenuifolia exhibit cytoprotective effects on neuronal cells. Further preclinical and clinical trials evaluating their safety, bioefficacy, and bioavailability are suggested to prove the valuable role of natural drugs in the management of depressive disorders.
In this study, the antioxidant and pancreatic lipase inhibitory activities of aqueous methanolic (70% methanol) extract from the roots of Anemarrhena asphodeloides were investigated. The extracts of four solvent fractions (the n-hexane layer, EtOAc layer, n-BuOH layer, and H_2O layer) of the 70% methanol extract were also investigated. Furthermore, the total phenolic content was quantified using a spectrophotometric method. All the tested samples showed dose-dependent radical scavenging and pancreatic lipase inhibitory activities. In particular, the pancreatic lipase inhibitory activity of the ethyl acetate soluble portion (the EtOAc layer) from the rhizomes of the A. asphodeloides was higher than that of the other solvent-soluble portions. The antioxidant property of the extracts was evaluated using radical scavenging assays with DPPH and ABTS^ radicals. 1000 mg/ml of the n-BuOH layer extract showed 91.2% DPPH radical scavenging activity. The EtOAc layer extract and the n-BuOH layer extract showed $IC_{50}
Ethnopharmacological relevance:
Anemarrhena asphodeloides Bunge. (Asparagaceae) yields Anemarrhenae Rhizoma, which has a long history to be used as a traditional medicine to treat various ailments, like cold-induced febrile disease with arthralgia, hematochezia, tidal fever and night sweats by Yin deficiency, bone-steaming, cough, and hemoptysis. It is also used as an ingredient of healthy food, wine, tea, biological toothpaste. Its importance is demonstrated by large scale to treat kinds of diseases in eastern Asian countries. The aim of this review is to provide up-to-date information about phytochemistry, pharmacology, and toxicology of Anemarrhena asphodeloides based on scientific literatures. It will build up a new foundation for further study on mechanism and development of better therapeutic agent and healthy product from Anemarrhena asphodeloides.
Material and methods:
All the available information on Anemarrhena asphodeloides was collected via electronic search (using PubMed, SciFinder Scholar, CNKI, TPL (www.theplantlist.org), Google Scholar, Baidu Scholar, and Web of Science).
Results:
Comprehensive analysis of the literatures searched through sources available above confirmed that the ethnomedical uses of Anemarrhena asphodeloides had been recorded in China, Japan, and Korea for thousands of years. The phytochemical investigation revealed the presence of steroidal saponins, flavonoids, phenylpropanoids, alkaloids, steroids, organic acids, anthraquinones, and others. Crude extracts and pure compounds from Anemarrhena asphodeloides exhibited significant pharmacological effects on the nervous system and the blood system. They also showed valuable bioactivities, such as antitumor, anti-oxidation, anti-microbial, anti-virus, anti-inflammation, anti-osteoporosis, anti-skin aging and damage as well as other activities.
Conclusions:
In light of long traditional use and modern phytochemical and pharmacological studies summarized, Anemarrhena asphodeloides has demonstrated a strong potential for therapeutic and health-maintaining purposes. Both the extracts and chemical components isolated from the plant showed a wide range of biological activities. Thus more pharmacological mechanisms on main active compounds (TBII, TAIII, mangiferin and other ingredients) are necessary to be explored. In addition, as a good source of the traditional medicine, clinical studies of main therapeutic aspects (e.g. diabetes, Alzheimer׳s disease, Parkinson׳s disease, etc.), toxicity and adverse effect of Anemarrhena asphodeloides will also undoubtedly be the focus of future investigation.
Drugs of natural origin still play a major role in the treatment of many diseases and as lead structures for the development of new synthetic drug substances. This review article deals the pharmacological effects on the Central Nervous System (CNS) of some plant extracts and their isolated chemical components due to their monoamine oxidase (MAO) activity. Herbs and herbal preparations containing MAO-A inhibitors have been widely used as an effective alternative in the treatment of neuropsychiatric diseases such as depression. Inhibitors of MAO-B not only enhance dopaminergic neurotransmission but also prevent activation of toxin and free radical formation, alleviating the process of neuron denaturalization, on account of which they are used in Parkinson disease (PD). Several methods have been developed for monitoring MAO activity and its inhibitor screening of bioactive natural products.
Chronic exposure of human skin to solar ultraviolet (UV) radiation causes photoaging. Naturally occurring phytochemicals are known to have anti-photoaging effects. The present study examined the effect of mangiferin isolated from Anemarrhena asphodeloides on wrinkle formation, skin thickness, and changes in collagen fibers in hairless mice. The in vitro effects and possible mechanism of mangiferin on UVB irradiation were determined in human keratinocyte (HEKa) cells. In vitro results showed that mangiferin reduced UVB-induced matrix metalloproteinase (MMP)-9 protein expression and enzyme activity and subsequent attenuation of UVB-induced phosphorylation of mitogen-activated protein kinase kinase1 (MEK) and extracellular signal-regulated kinase (ERK). In the in vivo studies, mangiferin inhibited UVB-induced mean length and mean depth of skin wrinkle based on skin replica, epidermal thickening, and damage to collagen fiber. Taken together, these results indicate that mangiferin exerts anti-photoaging activity in UVB-irradiated hairless mice by regulating MMP-9 expression through inhibition of MEK and ERK.
Dementia pathologies such as Alzheimer's disease (AD) are reaching epidemic proportions, yet they are not successfully managed by effective symptomatic treatments. Only five drugs have been developed to alleviate cognitive symptoms, and more effective and safe treatments are needed for both the cognitive symptoms and behavioural and psychological symptoms of dementia (BPSD). As two of these licensed drugs (cholinesterase inhibitors [ChEIs]) are naturally derived (galantamine and rivastigmine), the potential for plants to yield new therapeutic agents has stimulated extensive research to discover new ChEIs together with plant extracts, phytochemicals and their derivatives with other mechanistic effects relevant to dementia treatment. This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence. Those phytochemicals discussed include the alkaloid physostigmine, a ChEI from the calabar bean (Physostigma venenosum), which has been used as a template for the development of synthetic derivatives that inhibit acetylcholinesterase, including the drug rivastigmine. Also discussed are other ChEI alkaloids including huperzine A, from Huperzia serrata, and galantamine, originally from the snowdrop (Galanthus woronowii); both alkaloids improve cognitive functions in AD patients. Other phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression. The review also discusses plant extracts, and their known constituents, that have shown relevant mechanistic effects for dementia and promising clinical data, but require more evidence for their clinical efficacy and safety. Such plants include Ginkgo biloba, which has been extensively studied in numerous clinical trials, with most outcomes showing positive effects on cognitive functions in dementia patients; however, more reliable and consistent clinical data are needed to confirm efficacy. Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required. Other plants that are used in traditional practices of medicine have been suggested to improve cognitive functions (e.g. Polygala tenuifolia) or have been associated with alleviation of BPSD (e.g. the traditional prescription yokukansan); such remedies are often prescribed as complex mixtures of different plants, which complicates interpretation of pharmacological and clinical data and introduces additional challenges for quality control. Evidence for the role of natural products in disease prevention, the primary but considerably challenging aim with respect to dementia, is limited, but the available epidemiological and clinical evidence is discussed, with most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba. Challenges for the development of phytochemicals as drugs and for quality control of standardized plant extracts are also considered.
Three new phenolic compounds, (E)-4'-demethyl-6-methyleucomin (1), anemarcoumarin A (2), and anemarchalconyn (3), were isolated from an ethyl acetate extract of the rhizomes of Anemarrhena asphodeloides, together with seven known compounds (4-10). The structures of the new compounds (1-3) were determined on the basis of spectroscopic data interpretation. Compound 3 exhibited a potent inhibitory effect against the differentiation of preadipocyte 3T3-L1 cells with an IC50 value of 5.3 μM. © 2009 American Chemical Society and American Society of Pharmacognosy.
Anemarrhena asphodeloides Bunge (AA, family Liliaceae), which primarily contains xantones, such as mangiferin, and steroidal saponins, such as timosaponin AIII and sarsasapogenin, has been used as an anti-pyretic, anti-inflammatory, anti-diabetic, anti-platelet aggregation, and anti-depressant agent in traditional Chinese medicine. In the present study, the memory-enhancing effects of these saponins were investigated in scopolamine-treated mice. Among saponins, timosaponin AIII (TA3) significantly reversed the scopolamine-induced deficits in a passive avoidance test and in the Morris water maze test. TA3 also increased hippocampal acetylcholine levels in scopolamine-treated mice and dose-dependently inhibited acetylcholinesterase (AChE) activity (IC(50) value, 35.4 microM). When TA3 (50 mg/kg) was orally administered to mice and its blood concentration was measured by liquid chromatography and tandem mass spectrometry, the C(max) of TA3 occurred 4-6 h after TA3 treatment. The memory-enhancing effect of TA3 was greater when it was administered 5 h before the acquisition trial than 1 h before. Scopolamine treatment in mice increased brain levels of TNF-alpha and IL-1beta expression. However, treatment with TA3 and scopolamine inhibited the increase of TNF-alpha and IL-1beta expression. These results suggest that scopolamine may cause learning and memory deficits that are further complicated by inflammation. TA3 also inhibited the activation of NF-kappaB signaling in BV-2 microglia and in SK-N-SH neuroblastoma cells induced with TNF-alpha or scopolamine. Nevertheless, TA3 may ameliorate memory deficits, mainly by inhibiting AChE.
The aim of this study was to evaluate the effects of Anemarrhena asphodeloides BUNGE (AA) on cholinergic memory deficits in mice. This agent has previously been used as an antipyretic, anti-inflammatory, anti-diabetic, and antidepressant in traditional Chinese medicine. Mangiferin was isolated from AA and showed a dose-dependent inhibition of acetylcholinesterase (AChE) activity (IC(50) value, 62.8 microM). Cholinergic dysfunction was induced in mice by administering scopolamine, and the animals were then tested using the passive avoidance test as well as the Morris water maze test. Mangiferin (20 mg/kg, p.o.) significantly reversed scopolamine-induced deficits in the passive avoidance test, and also improved escape latencies in training trials and increased swimming times in the Morris water maze test (p<0.05). Mangiferin also reduced acetylcholine and tumor necrosis factor (TNF)-alpha levels induced by scopolamine in mice brain (p<0.05) and inhibited nuclear factor (NF)-kappaB activation in scopolamine or TNF-alpha-stimulated BV-2 microglial cells. These results suggest that mangiferin can improve long-term cholinergic memory deficits by AChE inhibition or cholinergic receptor stimulation and inhibition of NF-kappaB activation.
Sarsasapogenin is a steroidal sapogenin with antitumor properties. To explain the mechanism of its apoptotic effect, mitochondrial activity was assessed via a 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry (FCM) was used to estimate the changes in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation, and cellular-reduced glutathione (GSH) level. Laser scanning confocal microscope (LSCM) recorded instantaneous ROS burst after application of sarsasapogenin. Western blotting was used to determine the expression level and intracellular distribution of cytochrome c (cyt c). It is demonstrated that during apoptosis, ROS burst acted as an early event followed by depolarization of MMP, prolonged ROS generation, and significantly declined GSH level. Cyt c was upregulated and released from mitochondria to cytosol during the process. These findings show that a mitochondrial ROS burst is an early upstream apoptotic signal which may trigger the mitochondrial apoptotic pathway and play a vital role in sarsasapogenin-induced HepG2 cell apoptosis.
An enhancement of neurotransmission of serotonin (5-HT), noradrenaline, or both, underlies the antidepressant response associated with most agents presently available to treat major depression. With respect to the 5-HT system, antidepressant drugs exert immediate effects on some neuronal elements controlling overall transmission, but it is the gradual changes in neuronal responses to such treatments that are ultimately responsible for producing their therapeutic benefits. In major depression, an increase in 5-HT1A transmission is thought to be a crucial determinant of the antidepressant response, whereas an enhancement of 5-HT2 transmission in the orbitofrontal cortex may mediate the therapeutic effect of 5-HT reuptake inhibitors in obsessive-compulsive disorder (OCD). The doses of medication and the durations of treatment necessary to obtain these alterations in 5-HT transmission in various brain structures of laboratory animals are fully consistent with the conditions in the clinic necessary to attenuate symptoms in depression and OCD. It is also possible that the relief of chronic pain produced by some antidepressants may be mediated, in part, by the blockade of peripheral 5-HT2A receptors. These observations emphasize the notion that the 5-HT system is endowed with different adaptive properties in various parts of the body, which, in addition to the multiplicity of 5-HT receptors, makes this chemospecific network important in many disorders.
Curcuma longa (turmeric) is a well-known indigenous herbal medicine. The aqueous extracts, when administered orally to the mice from 140 to 560 mg/kg for 14 days, were able to elicit dose-dependent relation of immobility reduction in the tail suspension test and the forced swimming test in mice. The effects of the extracts at the dose of 560 mg/kg were more potent than that of reference antidepressant fluoxetine. The extracts, at the dose of 140 mg/kg or above for 14 days, significantly inhibited the monoamine oxidize A (MAO) activity in mouse whole brain at a dose-dependent manner, however, oral administration of the extract only at a dose of 560 mg/kg produced observable MAO B inhibitory activity in animal brain. Fluoxetine showed only a tendency to inhibit MAO A and B activity in animal brain in the study. Neither the extracts of C. longa nor fluoxetine, at the doses tested, produced significant effects on locomotor activity. These results demonstrated that C. longa had specifically antidepressant effects in vivo. The activity of C. longa in antidepression may mediated in part through MAO A inhibition in mouse brain.
A new steroidal saponin, timosaponin F, along with six known compounds was isolated from the rhizomes of Anemarrhena asphodeloides Bge. On the basis of chemical and spectroscopic evidence, the structure of timosaponin F was elucidated as (5beta, 25 S):-spirostan-3beta,15alpha,23alpha-triol-3-O-beta- glucopyranosyl-(1--->2)-beta-galactopyranoside. The six known compounds were anemarrhenasaponin I, anemarrhenasaponin Ia, timosaponin BI, timosaponin BII, timosaponin B, timosaponin AIII; their effects on superoxide generation are also reported.
Rats were forced to swim in a restricted space will rapidly cease apparent attempts to escape and adopt a characteristic posture which we have termed "immobility". We show in previous experiments that immobility was reduced by a variety of antidepressant agents and thus suggested that the method could serve as a screening model for antidepressants. The present experiments showed that immobility was reduced by drugs which increase central dopaminergic and alpha-adrenergic activity but was less affected by drugs which act mainly on central serotonin. Conversely, immobility could be increased by drugs which diminish central catecholamine activity but not by drugs which inhibit central serotonin. It was concluded that immobility depended primarily on the activity of central catecholamines but that caution was required before ascribing immobility exclusively to activity within a single system.
A depressed state can be induced in mice by forcing them to swim in a narrow cylinder from which they cannot escape. After a brief period of vigorous activity the mice adopt a characteristic immobile posture which is readily identifiable. Immobility was reduced by tricyclic antidepressants, monoamine oxidase inhibitors and atypical antidepressants, as well as by electroconvulsive shock. Psychostimulants also reduced immobility but in contrast to antidepressants caused marked motor stimulation. Immobility was not affected by minor or major tranquilisers. These findings, closely parallel to those we have previously reported in rats, suggest that the procedure is selectively sensitive to antidepressant treatments. The mouse procedure is, however, more rapid and less costly than that with rats and is thus more suitable for the primary screening of antidepressant drugs.
Monoamine oxidase (MAO) of porcine brain mitochondria was differentially affected by hashish components: with benzylamine as a substrate, Δ1-tetrahydrocannabinol (Δ1-THC) inhibited MAO activity markedly, while cannabidiol (CBD) was essentially innocuous at the same concentrations. When added concomitantly, CBD obviated the inhibitory effect of Δ1-THC. An extract of hashish was over 10-fold more inhibitory toward MAO than Δ1-THC on weight basis. A prior incubation of the mitochondrial preparation with the cannabis compounds was required to express the inhibitory effect. Liver mitochondrial MAO was not affected by either Δ1-THC, CBD or hashish extract, despite a prolonged preincubation period, thus demonstrating tissue selectivity with respect to the cannabinoid effect.
The forced swimming test is reviewed. This test appears to be suitable for detecting antidepressant activity in rats but not in mice. Difference in experimental procedure may account for the different sensitivity to drugs of the two animal species.
Fluoxetine at 10 and 25 mg/kg increased (167 and 205%, respectively) the extracellular dopamine concentration in the prefrontal cortex, whereas 25 (but not 10) mg/kg citalopram raised (216%) dialysate dopamine. No compound modified dialysate dopamine in the nucleus accumbens. The effect of 25 mg/kg of both compounds on cortical extracellular dopamine was not significantly affected by 300 mg/kg p-chlorophenylalanine (PCPA) (fluoxetine, saline, 235%; PCPA, 230%; citalopram, saline, 179%; PCPA, 181%). PCPA depleted tissue and dialysate serotonin by approximately 90 and 50%, respectively, and prevented the effect of fluoxetine and citalopram on dialysate serotonin (fluoxetine, saline, 246%; PCPA, 110%; citalopram, saline, 155%; PCPA, 96%). Citalopram significantly raised extracellular serotonin from 0.1 to 100 microM (251-520%), whereas only 10 and 100 microM increased dialysate dopamine (143-231%). Fluoxetine similarly increased extracellular serotonin (98-336%) and dopamine (117-318%). PCPA significantly reduced basal serotonin and the effects of 100 microM fluoxetine (saline, 272%; PCPA, 203%) and citalopram (saline, 345%; PCPA, 258%) on dialysate serotonin but did not modify their effect on dopamine (fluoxetine, saline, 220%; PCPA, 202%; citalopram, saline, 191%; PCPA, 211%). The results clearly show that the effects of fluoxetine and of high concentrations of citalopram on extracellular dopamine do not depend on their effects on serotonin.
The dichloromethane fraction from Areca catechu was found to inhibit monoamine oxidase type A isolated from the rat brain with an IC50 of 665 +/- 65.1 microg/ml. Studies with pharmacological models of depression, i.e., forced swim and tail-suspension tests, indicated that it caused significant reduction in the immobility time similar to that of moclobemide (a selective inhibitor of MAO-A) without causing a significant change in motor performance. Alkaloids such as arecaidine, arecoline, and a few other constituents, reported to be present in Areca catechu were also tested, but none of them were found to inhibit MAO. Present study suggests that the dichloromethane fraction from A. catechu possesses antidepressant property via MAO-A inhibition.
Depression is a major cause of disability worldwide, but we know little
about the underlying fundamental biology. Research is hindered by the difficulties
of modelling a disorder of higher cognitive functions in animals. Depression
can be understood as the interaction of genetic susceptibility and environmental
factors; however, current classifications are purely descriptive. The complexity
of this field is best approached by rigorous explorations of known candidate
systems in conjunction with the use of genomic tools to discover new targets
for antidepressants and to predict therapeutic outcomes.
Hypericum perforatum L. (St. John's wort) is one of the leading psychotherapeutic phytomedicines and, because of this, great effort has been devoted to clarifying its mechanism of action. Chronic effects of St. John's wort and hypericin, one of its major active compounds, on regional brain amine metabolism have not been reported yet. We used a high-performance liquid chromatography system to examine the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine, Hypericum extract or hypericin on regional levels of serotonin (5-HT), norepinephrine, dopamine and their metabolites in the rat brain. We focused our interest on the hypothalamus and hippocampus, as these brain regions are thought to be involved in antidepressant drug action. Imipramine (15 mg/kg, p.o.), Hypericum extract (500 mg/kg, p.o.), and hypericin (0.2 mg/kg, p.o.) given daily for 8 weeks significantly increased 5-HT levels in the hypothalamus (P<0.05). The 5-HT turnover was significantly lowered in both brain regions after 8 weeks of daily treatment with the Hypericum extract (both P<0.05). Consistent changes in catecholamine levels were only detected in hypothalamic tissues after long-term treatment. Comparable to imipramine, Hypericum extract as well as hypericin significantly decreased 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in the hypothalamus (P<0.01). Our data clearly show that long-term, but not short-term administration of St. John's wort and its active constituent hypericin modify levels of neurotransmitters in brain regions involved in the pathophysiology of depression.
Abstract The relationship between depression and dopamine deficiency in the mesolimbic pathway has been hypothesized for many years. The experimental studies with animal models of depression and the human studies implicate the role of the dopamine system in depression. Not only do dopaminergic receptor agonists, but also antagonists such as olanzapine exhibit antidepressant effects associated with standard antidepressants in patients with treatment-resistant depression. This paradoxical result suggests that further investigations are necessary to understand the role played by dopamine in depression.
The purpose of this paper is to study the basic pharmacological action of sarsasapogenin, a sapogenin from the Chinese medicinal herb Rhizoma Anemarrhenae, (abbreviated as ZMS in this paper), on learning ability and memory of three animal models: aged rats and two neurodegeneration models produced either by single unilateral injection of beta-amyloid 1-40 (Abeta1-40) plus ibotenic acid (Ibot A) or by bilateral injection of Ibot A alone into nucleus basalis magnocellularis. Y-maze test and step-through test revealed that learning ability and memory were impaired in the three models and were improved by oral administration of ZMS. ZMS did not inhibit acetylcholinesterase nor did it occupy the binding sites of muscarinic acetylcholine receptor (M receptor), hence it is neither an cholinesterase inhibitor nor an agonist or antagonist of M receptors. On the other hand, the densities of total M receptor and its M1 subtype in the brain of the three models were significantly lower than control rats, and ZMS significantly raised the densities of total M receptors and its M1 subtype. Linear regression revealed significant correlation between the learning ability/memory and the density of either total M receptor or its M1 subtype. Autoradiographic study with 3H-pirenzipine showed that the M1 subtype density was significantly lowered in cortex, hippocampus and striatum of aged rats, and ZMS could reverse these changes towards normal control level. Interestingly, the M1 receptor density after ZMS administration only approached but did not exceed that of normal young control rats. Therefore, ZMS seems to represent a new approach to the pharmacological regulation of learning and memory and appears to be not simply palliative but may modify the progression of the disease.
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