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Effects of tenuifolin extracted from Radix Polygalae on learning and memory: A behavioral and biochemical study on aged and amnesic mice
Abstract
Although normal cognitive changes take place when a person becomes older, aging in humans is generally associated with deterioration of cognitive performance and, in particular, of learning and memory. These cognitive deficits can cause debilitating consequences due to aging. There are a number of herbal medicines which are reported to improve brain function including intelligence. In the present study, improving effects of tenuifolin, extracted from Radix Polygalae (RP), on learning and memory in aged and dysmnesia mice were determined using step-down type passive avoidance test or Y type maze trial. Oral administration of tenuifolin (0.02, 0.04, 0.08 g/kgd(-1), for 15 d) evidently improved the latency and number of errors in aged and dysmnesia mice. The levels of cortical acetylcholine esterase (AChE) activity and hippocampal neurotransmitters in aged mice given tenuifolin (0.02, 0.04, 0.08 g/kgd(-1), for 15 d) were also investigated, and increased levels of norepinephrine (NE), dopamine (DA), decreased activity of AChE were found. However, serotonin (5-HT) had no significant difference from that of aged mice given distilled water. The evident improvement of learning and memory of aged mice is carried out by the effects of tenuifolin on the three stages of memory process, that is, acquisition, consolidation and retrieval. This may do so by relatively increasing the levels of NE, DA in the hippocampus and by decreasing the activity of AChE in the cortex.
... TEN has been reported to have various biological and pharmacological activities such as antioxidation, anti-inflammation, antidementia, and anti-aging. [11,12] Pharmacological data indicate that TEN could suppress secretion of Aβ in SH-SY5Y APP 695 cells [13] and protect SH-SY5Y cells against the injury induced by 6-OHDA. [14] Our previous study has shown that TEN could improve the proliferation and differentiation of hippocampal neural stem cells in vitro. ...
... TEN, a major active component of the Chinese herb Yuanzhi, has been described as having a wide range of activities on the pathological state of the organism by many studies. [11][12][13][14][15] Recently, our laboratory has demonstrated that TEN has significant protective effects against the neurotoxicity induced by methylglyoxal in cultured hippocampal neural stem cells. [16] Hence, the present study was designed to explore the neuroprotective effect of TEN on STZ-induced cognitive decline in a model of sporadic AD. ...
BACKGROUND
Tenuigenin (TEN), a major active component of the Chinese herb Polygala tenuifolia root, has been used to improve memory and cognitive function in Traditional Chinese Medicine for centuries.
PURPOSE
The present study was designed to explore the possible neuroprotective effect of TEN on the streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD).
METHODS
STZ was injected twice intracerebroventrically (3 mg/kg, ICV) on alternate days (day 1 and day 3) in Rats. Daily treatment with TEN (2, 4, and 8 mg/kg) starting from the first dose of STZ for 28 days. Memory-related behaviors were evaluated using the Morris water maze test. Hyperphosphorylation of tau proteins in hippocampus were measured by western blot assay. Superoxide dismutase activities, malondialdehyde, glutathione peroxidase and 4-hydroxy-2-nonenal adducts contents were also measured in the hippocampus.
RESULTS
Treatment with TEN significantly improved STZ-induced cognitive damage, markedly reduced changes in malondialdehyde and 4-hydroxy-2-nonenal adducts, and significantly inhibited STZ-induced reduction in superoxide dismutase and glutathione peroxidase activities in the hippocampus. In addition, TEN decreased hyperphosphorylation of tau resulting from intracerebroventricular STZ (ICV-STZ) injection, and Nissl staining results showed that TEN has protective effects on hippocampal neurons.
CONCLUSION
These results provide experimental evidence demonstrating preventive effect of TEN on cognitive dysfunction, oxidative stress, and hyperphosphorylation of tau in ICV-STZ rats. This study indicates that TEN may have beneficial effects in the treatment of neurodegenerative disorders such as AD.
... Radix polygalae (RP) (Yuan zhi) is commonly prescribed in many classical decoctions such as "Kai Xin San" [388], and "Ding Zhi Wan" [389] for the treatment of forgetfulness [390], anxiety [391], insomnia or depression [392]. Recent pharmacological studies have also reported the sedative-hypnotic [391], memory improving [390], cognitive recognition enhancing [393], antidepressant [392] and neuroprotective effects [170] of RP. ...
... Radix polygalae (RP) (Yuan zhi) is commonly prescribed in many classical decoctions such as "Kai Xin San" [388], and "Ding Zhi Wan" [389] for the treatment of forgetfulness [390], anxiety [391], insomnia or depression [392]. Recent pharmacological studies have also reported the sedative-hypnotic [391], memory improving [390], cognitive recognition enhancing [393], antidepressant [392] and neuroprotective effects [170] of RP. RP was reported to inhibit the phosphatidylinositol 3-kinase (PI3K)/Akt or activate the N-methyl-D-aspartate (NMDA) signaling pathways [394,395]. ...
Autophagy is a universal catabolic cellular process for quality control of cytoplasm and maintenance of cellular homeostasis upon nutrient deprivation and environmental stimulus. It involves the lysosomal degradation of cellular components such as misfolded proteins or damaged organelles. Defects in autophagy are implicated in the pathogenesis of diseases including cancers, myopathy, neurodegenerations, infections and cardiovascular diseases. In the recent decade, traditional drugs with new clinical applications are not only commonly found in Western medicines, but also highlighted in Chinese herbal medicines (CHM). For instance, pharmacological studies have revealed that active components or fractions from Chaihu (Radix bupleuri), Hu Zhang (Rhizoma polygoni cuspidati), Donglingcao (Rabdosia rubesens), Hou po (Cortex magnoliae officinalis) and Chuan xiong (Rhizoma chuanxiong) modulate cancers, neurodegeneration and cardiovascular disease via autophagy. These findings shed light on the potential new applications and formulation of CHM decoctions via regulation of autophagy. This article reviews the roles of autophagy in the pharmacological actions of CHM and discusses their new potential clinical applications in various human diseases.
... Deciphering the complexities of AD stands at the forefront of neuroscience, with extensive research efforts demonstrating that Aβ is neuro-and synapto-toxic in both in vitro and in vivo experiments. Various research models have employed the use of the Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) peptide, which retains the toxic properties of the full length peptide (39)(40)(41)(42)(43), to test the pathogenic mechanisms of Aβ, making it a desirable model for testing AD, and thus chosen for the present study to examine its toxicity in a neuronal cell line. ...
... Biochemical analysis has ascertained that the active components of P. tenuifolia are primarily saponins that are derivatives of presenegenin. Current research efforts directed towards elucidating the therapeutics of P. tenuifolia have shown that it possesses both neuroprotective and nootropic activity, exemplified in its ability to effectively attenuate scopolamine-induced memory impairments [36,37], decrease Aβ secretion [38,39], up regulate neurotransmitters [40], and increase NGF secretion is cultured astrocytes [41]. In addition, P. tenuifolia has been shown to promote the proliferation of hippocampal stem cells and neurite outgrowth [42], demonstrating that it's a promising agent in the amelioration of neurodegeneration. ...
Background:
Improved therapeutics aimed at ameliorating the devastating effects of neurodegenerative diseases, such as Alzheimer's disease (AD), are pertinent to help attenuate their growing prevalence worldwide. One promising avenue for such therapeutics lies in botanical medicines that have been efficaciously employed in the likes of traditional medicine doctrines for millennium. Integral to this approach is the necessity of neuritogenesis and/or neuroprotection to counterbalance the deleterious effects of amyloid-β (Aβ) proteins. Senegenin, a principle saponin of Polygala tenuifolia Willd., which has empirically shown to improve cognition and intelligence, was chosen to evaluate its cytoprotective potential and possible neuritogenic and neuroprotective effects.
Methods:
The purpose of the present study was then to analyze morphological changes in neurite development and altered protein expression of two proteins requisite to neuritogenesis, growth associated protein 43 (Gap-43) and microtubule-associated protein 2 (MAP2) in PC 12 cells. Neuritogenic analysis was conducted with immunofluorescence after incubation with Aβ (25-35) peptide, and to deduce information on cell viability and mitochondrial functionality MTT (3,(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) was employed.
Results:
This study found that cells pre-incubated with senegenin for 24 h (40 μg and 20 μg/ml) before introducing Aβ attenuated Aβ-cytotoxicity, and significantly increased cell viability by 23 % and 34 % (P < 0.001), respectively. In neurite outgrowth experiments, Aβ was compared to NGF positive control and senegenin treated groups which showed a drastic decrease in the quantity, average length and maximum length of neurites (P < 0.001). At concentrations of 1 μg/ml (P < 0.01) and 5 μg/ml (P < 0.05) senegenin triggered neuritogenesis with significant increases in total neurite number, average length and maximum length. This was additionally shown through the augmented expression of MAP2 and Gap-43.
Conclusions:
These results suggest that senegenin possesses cytoprotective properties, can moderate neurite outgrowth and augment MAP2 and Gap-43, thus suggesting a potential therapeutic value for Polygala tenuifolia in neurodegenerative disorders.
... Onjisaponin B has been shown to strengthen cholinergic neurons and to increase the expression of ChAT (Yabe et al., 2003). Research on tenuifolin indicates that it not only reduces cortical AChE activity but also elevates the expression levels of NE and DA in the hippocampus, although it does not affect the regulation of 5-HT (Zhang et al., 2008). Additionally, NE serves as an antiinflammatory agent by regulating microglia, astrocytes, and proinflammatory factors, thereby reducing brain inflammation (O'Donnell et al., 2012), which underscores tenuifolin's potential anti-inflammatory effects. ...
Objective
This study aims to elucidate the intervention effects of saponin components from Polygala tenuifolia Willd (Polygalaceae) on dementia, providing experimental evidence and new insights for the research and application of saponins in the field of dementia.
Materials and Methods
This review is based on a search of the PubMed, NCBI, and Google Scholar databases from their inception to 13 May 2024, using terms such as “P. tenuifolia,” “P. tenuifolia and saponins,” “toxicity,” “dementia,” “Alzheimer’s disease,” “Parkinson’s disease dementia,” and “vascular dementia.” The article summarizes the saponin components of P. tenuifolia, including tenuigenin, tenuifolin, polygalasaponins XXXII, and onjisaponin B, as well as the pathophysiological mechanisms of dementia. Importantly, it highlights the potential mechanisms by which the active components of P. tenuifolia prevent and treat diseases and relevant clinical studies.
Results
The saponin components of P. tenuifolia can reduce β-amyloid accumulation, exhibit antioxidant effects, regulate neurotransmitters, improve synaptic function, possess anti-inflammatory properties, inhibit neuronal apoptosis, and modulate autophagy. Therefore, P. tenuifolia may play a role in the prevention and treatment of dementia.
Conclusion
The saponin components of P. tenuifolia have shown certain therapeutic effects on dementia. They can prevent and treat dementia through various mechanisms.
... Honokiol was found effective in PS1V97L Tg mice, with a potential mechanism of up-regulating peroxisome proliferator-activated receptor γ and peroxisome proliferator-activated receptor-γ coactivator-1α through SIRT3 pathway, thus improving mitochondrial function and apoptosis, and promoting microglial phagocytic function Li et al., 2021b). Tenuifolin (Zhang et al., 2008), ginsenoside , cryptotanshinone (Mei et al., 2009) and carnosic acid (Yi-Bin et al., 2022) were found effective in APP/PS1 mice, with potential mechanisms of anti-neuroinflammation and anti-oxidative stress through Nrf2/NF-κB and CEBPβ-NFκB signaling pathways, reducing tau phosphorylation, synaptoprotection and mitoprotection via PI3K/Akt/GSK3β pathway and regulating NMDAR2B downstream cascades (Chen and Jia, 2020;Chen et al., 2022;Jiao and Jia, 2022;Liu et al., 2023;Lyu and Jia, 2022). In addition, butylphthalide and lycium barbarum extract were found effective in 3×Tg and/or APP/PS1 mice, with potential mechanisms of reducing tau phosphor-ylation, reducing AβO-induced inflammatory reactions, synapse stabilization, anti-oxidation and anti-apoptosis through CaMKⅡα pathway Liu et al., 2021a;Peng et al., 2010;Sun et al., 2022;Zhang et al., 2016). ...
Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease (AD). AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD. Each transgenic model has its unique behavioral and pathological features. This review summarizes the research progress of transgenic mouse models, and their progress in the unique mechanism of amyloid-β oligomers, including the first transgenic mouse model built in China based on a single gene mutation (PSEN1 V97L) found in Chinese familial AD. We further summarized the preclinical findings of drugs using the models, and their future application in exploring the upstream mechanisms and multitarget drug development in AD.
... The suppressing effects of OB on neuroinflammation, apoptosis, oxidative stress and Aβ pathology may relate to NF-κB/p65, Nrf-2/HO-1, Bcl-2/ Bax/caspase-9 signaling pathways [22,23,51]. TEN is a metabolite of OB [26], and oral administration of TEN markedly increased the learning and memory ability in AD animals by anti-apoptosis [27], anti-neuroinflammation [28] and reduction of Aβ secretion [16,[52][53][54]. The activities of anti-apoptosis, anti-neuroinflammation, anti-oxidative stress, anti-Aβ pathology are beneficial for hippocampal neurogenesis, however, there is little literature about whether these compounds could rescue the damages of hippocampal neurogenesis in APP/PS 1 mice. ...
Background
Alzheimer’s disease (AD) is the most common dementia worldwide, and there is still no satisfactory drug or therapeutic strategy. Polygala tenuifolia is a traditional Chinese medicine with multiple neuroprotective effects. In present study, we investigated the effects of three active constituents [3,6′-disinapoyl sucrose (DISS), onjisaponin B (OB) and tenuifolin (TEN)] of Polygala tenuifolia (PT) on the proliferation and differentiation of neural stem cells (NSCs) to identify the potential active constituent of PT promoting hippocampal neurogenesis.
Methods
NSCs were isolated from hippocampi of newborn C57BL/6 mice, and transfected with mutant amyloid precursor protein (APP) gene to establish an AD cell model (APP-NSCs). 3-(4,5- Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays were performed, and the proliferation and differentiation of NSCs were assessed by neurosphere formation assay, 5-bromo-2′-deoxyuridine (BrdU) incorporation assay and immunofluorescence (IF) staining analysis. APP/PS1 transgenic mice were administrated with the potential active constituent DISS for 4 weeks. Morris water maze (MWM), Nissl staining assay and IF staining assays were carried out to evaluate the cognitive function, neural damages and hippocampal neurogenesis, respectively.
Results
DISS exerted the optimal ability to strengthen APP-NSCs proliferation and neuronal differentiation, followed by OB and TEN. Furthermore, DISS treatment for 4 weeks strikingly rescued the cognitive deficits, neuronal injures, and neurogenesis disorder in adult APP/PS1 transgenic mice.
Conclusions
Our findings demonstrated that DISS is the constituent of PT that triggers the most potent increase of hippocampal neurogenesis in our mouse model of AD.
... As shown in Fig. 4A, a significant increase in DA was observed in response to RR, PR, CUP, and SF. These findings are also consistent with previous studies that showed inhibition of DA-metabolizing enzymes in response to PR and CUP (Yamada et al. 2018 (Zhang et al. 2008), and that SF and its ingredients improve scopolamine-induced memory impairment. (Han et al. 2019) (Song et al. 2017), Because previous reports have shown improved spatial memory due to increased DA in mouse models for Alzheimer's disease (Ambrée et al. 2009), our findings for these components may be due to increased DA signaling. ...
Dementia is exacerbated by loss of appetite and amotivation, recent studies have indicated that ninjin'yoeito improves anorexia and amotivation. Previous studies suggest that ninjin'yoeito inhibits dopamine-metabolizing enzymes and enhances dopamine signaling. However, whether ninjin'yoeito increases dopamine content in living cells remains unclear. Here, PC12 cells were used to examine whether ninjin'yoeito affects the dopamine metabolic pathway. Dopamine content significantly increased 3 h after treatment ninjin'yoeito extract. Concomitantly, the levels of 3-methoxytyramine and 3,4-dihydroxyphenylacetic acid was significantly reduced. The effects of components of ninjin'yoeito on the dopamine metabolic pathway were also assessed. Treatment with onjisaponin B, nobiletin, and schisandrin, the ingredients of Polygalae Radix, Citri Unshiu Pericarpium, and Schisandrae Fructus increased dopamine content and decreased its metabolite content in the culture media. Our findings suggest that ninjin'yoeito improves anorexia and amotivation by inhibiting metabolic enzyme and increasing the dopamine content in cells.
... The method described by Zhang et al 23 Mice's memory ability was tested 24 h after training using the following method: record the number of correct responses and take the correct rate as the testing score (correct number/10×100%). Higher accuracy rate means better memory ability for mice. ...
Introduction
Vascular dementia (VaD), one of the brain injuries, is difficult to be cured, so it is important to take active neuroprotective treatment after its occurrence. Many studies have shown that apoptosis serves an important role in VaD occurrence; therefore, inhibition of apoptosis may contribute to the recovery of neurological function after VaD occurrence. Cerebroprotein hydrolysate-I (CH-I), a neuropeptide preparation which consists of several amino acids and small molecular peptides as the main active constituent, is extracted using a method similar to cerebrolysin (CBL) which has neuroprotective and neurotrophic effects.
Methods
In the present study, a VaD model which was constructed using bilateral common carotid artery occlusion (BCCAO) in Kunming mice was applied to examine the neuroprotective effects of CH-I.
Results
The results show that CH-I treatment could attenuate the decrease of learning and memory ability, cell apoptosis in the hippocampal CA1 region and inhibit the activation of caspase-3 and caspase-9 in VaD mice. Furthermore, CH-I treatment could also upregulate Bcl-2 protein levels and activate PI3K and Akt.
Discussion
We speculate that CH-I may induce a neuroprotective effect activating PI3K/Akt signaling pathway in VaD mice.
... Among these compounds, paeoniflorin reduces COX-2 expression and inflammatory reactions both in vivo and in vitro (37,38). Previous studies demonstrated that tenuifolin not only showed inhibitory activity on Aβ synthesis but also exhibited nootropic activity through inhibiting AChE and promoting norepinephrine and dopamine production (39)(40)(41). The main herb of RSYR, ginseng, has ginsenosides, saponins, flavonoids, polyphenols and other compounds. ...
... Place discrimination and reversal learning assessed in the IntelliCage system are affected by pharmacological or genetic manipulation of various neural circuits such as dopaminergic, cholinergic, and serotonergic pathways (Sekiguchi et al., 2011;Macpherson et al., 2016;Pelsoczi and Levay, 2017;Marwari and Dawe, 2018;Marwari and Dawe, 2019). Among these neurotransmitters, DA signaling is of particular interest, as tenuifolin, an ingredient of Polygalae Radix (PR), was shown to elevate DA levels in the hippocampus of aged and dysmnesia mice alongside improving impaired learning performance (Zhang et al., 2008). In addition, several ingredients of PR have inhibitory activities against DA transporter and DA metabolism-related enzymes, including monoamine oxidase B and catechol-Omethyltransferase (Yamada et al., 2018). ...
The cognitive and psychological domains of frailty in the elderly have drawn increasing attention given the aging of society. However, therapeutics to treat minor deficits in cognition and mental state in the elderly remain an unmet need. Kamikihito (KKT), a traditional Japanese Kampo medicine indicated for neuroses, anxiety, and insomnia, is effective for treating cognitive dysfunction and depressive-like behaviors in animal models, suggesting that it may have therapeutic potential for treating cognitive and/or mental frailty. In this study, we first validated the known anxiolytic effects of KKT in a conventional maze test. We then introduced an automated behavioral assay system, IntelliCage, to evaluate the therapeutic potential of KKT for age-related and diverse central functions by performing sequential behavioral tasks in young and aged mice to assess basal activities, cognitive functions, perseveration, and hedonic-related behaviors. Although young mice treated with KKT did not exhibit changes in diurnal variation, KKT-administered aged mice exhibited an accelerated decline in voluntary activity during the early part of the light period, implying that KKT may promote sleep onset in aged mice. Neither place learning acquisition for gaining rewards nor subsequent behavioral flexibility performance was altered by KKT in the young group, whereas the aged KKT group exhibited significantly enhanced performance in both phases of learning relative to age-matched controls. Conversely, perseverative nose-pokes (NPs) to gain rewards observed during place learning, indicative of compulsivity, were attenuated by KKT in both age groups. Regarding hedonic processing, aged mice exhibited a decreased preference for sweet solutions compared to young mice, which was effectively reversed by KKT treatment. Furthermore, KKT elevated high-effort choices for high-value reward in an effort-based decision-making paradigm in both age groups, implying augmentation of motivational behaviors by KKT. Collectively, KKT exerted various beneficial effects in cognitive and emotional domains, several of which were more evident in aged mice than in young mice, suggesting the potential of KKT for treating cognitive and mental frailty.
... belongs to Polygalaceae family and is a typical herbal medicine and has been extensively used for the treatment of dementia. Radix Polygalae plays an important role in most nootropics prescriptions (Zhang et al., 2008;Wang et al., 2015a;Wang et al., 2015b). Onjisaponin B reduces Ab production without directly inhibiting of BACE1 and g-secretase activities, promoting APP degradation (Li et al., 2016b) (Table 1). ...
Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The major characteristics of AD are amyloid β plaques, apoptosis, autophagy dysfunction, neuroinflammation, oxidative stress, and mitochondrial dysfunction. These are mostly used as the significant indicators for selecting the effects of potential drugs. It is imperative to explain AD pathogenesis and realize productive treatments. Although the currently used chemical drugs for clinical applications of AD are effective in managing the symptoms, they are inadequate to achieve anticipated preventive or therapeutic outcomes. There are new strategies for treating AD. Traditional Chinese Medicine (TCM) has accumulated thousands of years of experience in treating dementia. Nowadays, numerous modern pharmacological studies have verified the efficacy of many bioactive ingredients isolated from TCM for AD treatment. In this review, representative TCM for the treatment of AD are discussed, and among these herbal medicines, the Lamiaceae family accounts for the highest proportion. It is concluded that monomers and extracts from TCM have potential therapeutic effect for AD treatment.
... Thus, the neuroprotective effects of PYEDE involved modulation of the activities of enzymes related to neurotransmitter metabolism. Numerous studies have also shown that improvements in learning and memory of aged mice were achieved by increasing NE and DA levels and decreasing the activity of AchE (53)(54)(55) . The polysaccharides of PYEDE might have played a role in the neuroprotective effects, and this is supported by previous studies (56) that found that oligosaccharides or sulphated oligosaccharides extracted from seaweed, such as GV-971, captured Aβ at multiple sites, and inhibited Aβ fibrils formation, and improved cognitive impairment. ...
This study investigated the effects of Porphyra yezoensis enzyme degradation extract (PYEDE) on the brain injuries and neurodegenerative diseases due to oxidative stress. We used in vitro antioxidant systems to verify the antioxidant potential of PYEDE. The results indicated that PYEDE alleviated weight loss and organ atrophy, reduced the levels of lipid peroxidation and protein carbonylation, and elevated glutathione (GSH) content in the serum and brains of the D-gal-induced aging model mice. PYEDE also renewed the glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and total anti-oxidant capability (T-AOC) activities, downregulated the inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) levels, normalized the hippocampal neurons, and modulated multiple neurotransmitter systems by inhibiting the activities of acetylcholinesterase (AchE) and monoamine oxidase (MAO) in the upregulation of acetylcholine (Ach), dopamine (DA) and norepinephrine (NE) levels. Overall, PYEDE is a promising supplement for the alleviation of oxidative stress and age-associated brain diseases.
... The reduction of this fear response was not due to the lack of contextual memory because the working memory and spatial memory were not affected, but rather improved. This is consistent with previous findings that RP prevented the spatial memory impairment in scopolamine-treated rats [2] and that RP components showed improvement in hippocampus-dependent learning and age-related memory loss [14]. Increased spontaneous locomotion activities can be misinterpreted as an improved memory in the Morris water maze and Ymaze task, as well as a reduced fear memory in conditioned fear . ...
Radix Polygalae (RP) has been used to relieve psychological stress in traditional oriental medicine. Recently, cell protective, antiamnestic and antidepressant-like effects were disclosed but the possible application of RP to post-traumatic stress disorder, in which exaggerated fear memory persists, has not yet been explored. For this purpose, the effects of RP on fear behavior was examined in a mouse model of single prolonged stress and conditioned fear (SPS-CF), previously shown to mimic key symptoms of post-traumatic stress disorder. Male mice received daily oral dose of RP extract or vehicle during the SPS-CF procedure. Then fear-related memory (cohort 1, n=25), non-fear-related memory (cohort 2, n=38) and concentration-dependent effects of RP on fear memory (cohort 3, n=41) were measured in 3 separate cohort of animals. Also working memory and anxiety-like behaviors were measured in cohort 1. RP-treated SPS-CF mice exhibited attenuated contextual but not cued freezing and no impairments in the working memory and spatial reference memory performances relative to vehicle-treated SPS-CF controls. RP-treated SPS-CF and naive mice also demonstrated no difference in anxiety-like behavior levels relative to vehicle-treated SPS-CF and naive controls, respectively. In the hippocampus of SPS-CF mice, expression of BAG1, which regulates the activity of GR, was decreased, whereas RP increased expression of BAG1 in naïve and SPS-CF mice. These results suggest that RP exerts some symptomatic relief in a mouse with exaggerated fear response. RP and its molecular components may thus constitute valuable research targets in the development of novel therapeutics for stress-related psychological disorders.
... The method described by Zhang et al. (2008a) served as the reference. The Y-maze apparatus had a conductive grid floor and consisted of three identical arm boxes (40 × 10 × 20 cm 3 ) made of dark, opaque Plexiglas that were symmetrically opposed 120°to each other. ...
Chemical communication plays a key role in mammalian reproductive and social behaviour. The chemical constituents of urine are the main signal resource that can encode sex, quality and social status. In order to investigate the role of urine in the reproductive biology of Tupaia belangeri, the volatile components of urine were analysed by gas chromatography-mass spectrometry, and the behaviour of the tree shrew in response to urinary odour was investigated in a Y-maze test. The results show that hydrocarbons were the major components of urine in wild, acclimated and laboratory-breeding animals. The concentrations of the chemical components in urine from individuals in the wild population were higher than those in the acclimated and breeding animals. Tupaia belangeri showed significant differences in reactions of individuals and urinary odour. Males and females had different components in their urine. The stay duration of male tree shrews to the urinary odour of females in oestrus or lactating was significantly longer than that to the odour of pregnant females. The chemical components were different at different reproductive stages. Taken together, these results suggest that the odour of urine can encode female reproductive status and gender. Tupaia belangeri relies on these odours to recognise sex and choose a mate. Chemical communication based on signals in urine plays an important role in the reproduction of T. belangeri.
... As neurodegeneration is a complicated and multifactorial disease, Chinese medicine offers the advantage of modulating the systemic organs via synergetic effects of different compositions within a single herb. For example, the well-known TCMs such as Yuanzhi (Radix Palygalae) [31], Renshen (Radix Ginseng) [32], and Hehuanpi (Cortex Albiziae) [33] are prescribed to ameliorate memory loss; Gouqi (Fructus Lycii), Fuling (Poria), Gancao (Radix Glycyrrhizae), and Shichangpu (Rhizoma Acori Tatarinowii) are used to improve the cognitive function [34]. In addition, traditional herbal formulations such as "Kaixinsan" which are composed of 4 herbs, Radix Ginseng, Radix Polygalae, Rhizoma Acori Tatarinowii, and Poria, is a famous TCM formula for the treatment of mental disorders, forgetfulness, and depression possibly via the pCREB pathways [35]. ...
With the increase in the proportion of aged population due to the rapid increase of life expectancy, the worldwide prevalence rate of multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease has been increased dramatically. The demographic trend toward an older population has drawn the attention to new drug discovery and treatment on age-related diseases. Although a panel of drugs and/or therapies are currently available for treating the neurodegenerative diseases, side effects or insufficient drug efficacy have been reported. With the long history in prescription of Chinese medicine or natural compounds for modulating aged-related diseases, emerging evidence was reported to support the pharmacological role of Chinese medicine in ameliorating the symptoms, or interfering with the pathogenesis of several neurodegenerative diseases. This review brings evidence about today's trends and development of a list of potential neuroprotective herbal compounds from both the traditional and modern pharmacological point of view. With future projections, the potential hope and implication of using Chinese medicine as an alternative source for novel drug discovery for neurodegenerative diseases is proposed.
... Onjisaponins, 3-6′-disinapoyl sucrose (DISS), and 3,4,5-trimethoxycinnamic acid (TMCA) are the main components of RP extract. Among these, tenuifolin, which is the chemical backbone of onjisaponins, increased the synaptic level of dopamine and norepinephrine in the hippocampus (9). Also, antidepressant-like effect of DISS was related to the regulation of hypothalamuspituitary-adrenal (HPA) axis and monoamine oxidase-B activity (10). ...
The therapeutic goal for the treatment of posttraumatic stress disorder (PTSD) is to promote extinction and to prevent the relapse of fearful memories. Research has identified pharmacological treatments that may regulate the formation and extinction of fear memories, but not many reagents that block the relapse of extinguished fear are known. Radix Polygalae (RP) is an Asian herb used for sedation, and its ingredients have anxiolytic and antidepressant properties. As various neurological effects have been identified, we tested whether RP affects the relapse of fear. Freezing in response to a conditioned context and cues was used to measure the effects of RP in mice. In cohort 1 (n = 30), consolidation, extinction, and reinstatement were tested during the course of 18 days of treatment. In cohort 2 (n = 30), consolidation, extinction, and renewal were tested during 10 days of treatment. The consolidation, extinction, reinstatement, and possibly the renewal of context-induced freezing were inhibited due to the administration of RP in animal subjects. However, the effects of RP on the freezing responses of subjects elicited by conditioned auditory cues were less obvious. Because it effectively suppresses the consolidation of fear memories, RP may be used for primary and secondary prevention of symptoms in PTSD patients. Additionally, because it effectively suppresses the reinstatement and renewal of fear memories, RP may be applied for the prevention of fear relapse in PTSD patients who have undergone exposure therapy.
... A modern population pharmaco epidemiology survey of Chinese herbs for treating insomnia reported that RP has been a common individual Chinese herb prescribed for insomnia till now ( Chen et al., 2011 ). Accumulating evidence shows that RP possesses sleep-promoting, antidepressant, antipsychotic effects and cognitive improvement and the possible mechanism may be tightly related to regulating the central neurotransmitters ( Cheng et al., 2006;Chung et al., 2002;Lee et al., 2013;Zhang et al., 2008 ). Animal studies showed that polygalasaponins, one of the main constituents of RP, exhibited the sedative-hypnotic effects on pentobarbital-induced sleep by prolonging the sleep duration and shortening the sleep latency ( Yao et al., 2010 ). ...
... Compound has been tested at 0.02, 0.04 and 0.08 mg/kg conc., and proved its anti-AChE activity in Male Kunming mice which is in good correlation with behavioural studies Age [57] When the compound was tested in C57BL/6J mice, they relieved from AZ symptoms but mechanism of action precisely not described [59] It was proved to prevent pathologic morphological changes in the synapse and NADPH-d neurons through oral administration for a period of 4 weeks in Female Chinese kunmig mice Ovirectomy [60] Thymoquinon e ...
Ayurvedic medicine is a system of traditional medicine, which is native to India, and Ayurvedic practitioners have developed a number of medicinal preparations and surgical procedures for the treatment of various ailments. Till date we don't have, effective therapy to successfully prevent neuronal cell death in neurodegenerative diseases, for which currently no curative treatment is available and research focuses on drugs for slowing disease progression or providing prophylaxis. However, Ayurveda has numerous plants with amazing and outstanding properties even though few actions of herbs that are described in Ayurveda are quite new to the conventional medicine. Polyphenolic compounds, found in various types of plant parts like fruits, dry fruits, plant extracts, wine, and tea, that are antioxidant by nature having useful prophylactic properties for the treatment of excitotoxic and oxidative cell death. As an additive to various excellent reviews, which explains and highlight the therapeutic effect/efficacy of herbals as potent neuro modulators, here with we have given various phyto-constituents that can drag the attention to treat AZ. Even though there are many herbal constituents which have been proved to increase cognitive abilities here we have included the constituents that have been tested against AZ insult.
... The extract of Rhodiola rosea L. has been used as memory enhancer in Asia for thousands of years. Various animal models have demonstrated that RRLE could improve brain functions [15]. In the present study, the memory-enhancing effects of RRLE on the normal aged mice were investigated by using open-field test. ...
Purpose: The memory-enhancing effects of Rhodiola rosea L. extract (RRLE) on normal aged mice were assessed. Methods: In the open-field test, the effect of RRLE (150 and 300 mg/kg) on mouse locomotive activities was evaluated by investigating the extract’s influence on CAT and AchE activities in the brain tissue of mice. Results: Compared with aged group, high dose of RRLE reduced the total distance (3212.4 ± 123.1 cm, p < 0.05) significantly, increased catalase (CAT) activity (101.4 ± 12.2 U/mg pro, p < 0.05), and inhibited acetyl cholinesterase (AChE) activity (0.94 ± 0.12 U/mg pro, p < 0.05) in the brain tissue of aged mice. Conclusion: The results show that RRLE improves the memory functions of aged mice probably by increasing CAT activity while decreasing AChE activity. © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved.
... Traditional Chinese medicine has long been used to treat dementia [20][21][22][23]. Among those historically used herbal drugs, Radix Polygalae (RAPO) has been demonstrated to exhibit nootropic activity [20,24,25]. Moreover, our previous data regarding the "Smart soup" containing Rhizoma Acori Tatarinowii, Poria cum Radix Pini and Radix Polygalae showed systematic beneficial effects against AD and RAPO function to decrease Aβ production [24,26]. ...
Decline of cognitive function is the hallmark of Alzheimer's disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the β- amyloid (Aβ) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Aβ production without direct inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Aβ pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery. © 2016 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Neurocognitive disorders are characterized by a decline in various components of cognitive function, resulting in a high rate of morbidity and mortality. Despite multiple efforts, there is still a lack of practical preventive and therapeutic approaches for these diseases, and current pharmaceuticals have failed to manage their progression. Consequently, this chapter aims to provide a concise overview of the existing preclinical and clinical evidence that explores the impact of plant-based therapies on the prevention and treatment of neurocognitive disorders.
We thoroughly searched different web databases to identify preclinical and clinical studies that investigate the effect of plant-based medicines on cognitive function in animal models, as well as individuals who are healthy, those with mild cognitive decline, or those with Alzheimer’s disease. We included studies that examined plant extracts, multi-component herbal preparations, and phytochemicals such as Nigella sativa Linn., Rosmarinus officinalis L., Ginkgo biloba, and Melissa officinalis. The neuroprotective effects of these plants were associated with their anticholinesterase, anti-inflammatory, and antioxidative activities. None of the included studies reported severe adverse reactions.
In conclusion, the results of the preclinical and clinical studies indicate the potential benefits of plant-based therapies on neurocognitive disorders. However, more extended and comprehensive clinical studies must confirm these findings thoroughly.
Osteoporosis (OP) is closely related to iron overload. Bajitianwan (BJTW) is a traditional Chinese medicine formulation used for treating senile diseases such as dementia and osteoporosis. Modern pharmacological researches have found that BJTW has beneficial effect on bone loss and memory impairment in aging rats. This paper aimed to explore the role and mechanism of BJTW in ameliorating iron overload-induced bone loss. Furthermore, BJTW effectively improved the bone micro-structure of the femur in mice, and altered bone metabolism biomarkers alkaline phosphatase (ALP) and osteocalcin (OCN) in serum, as well as oxidative indexes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) glutathione (GSH) and malondialdehyde (MDA) in liver. As for network pharmacology, 73 components collected from BJTW regulated 99 common targets merged in the BJTW and OP. The results of RNA-seq indicated that there were 418 potential targets in BJTW low dose group (BJTW-L) and 347 potential targets in BJTW high dose group (BJTW-H). Intriguingly, both PI3K-AKT signaling pathway and the AGEs-RAGE signaling pathway were contained in the KEGG pathways enrichment results of network pharmacology and transcriptomics, which were considered as the potential mechanism. Additionally, we verified that BJTW regulated the expression of related proteins in RAGE/PI3K-AKT pathways in MC3T3-E1 cells. In summary, BJTW has potent effect on protecting against iron overload-induced OP, and its mechanism may be related to the activation of the RAGE/PI3K-AKT signaling pathways.
Alzheimer's Disease (AD) is a global public health priority characterized by high mortality rates in adults and an increasing prevalence in aging populations worldwide. Despite significant advancements in comprehending the pathogenesis of AD since its initial report in 1907, there remains a lack of effective curative or preventive measures for the disease. In recent years, natural compounds sourced from diverse origins have garnered considerable attention as potential therapeutic agents for AD, owing to their anti-inflammatory, antioxidant, and neuroprotective properties. This review aims to consolidate the therapeutic effects of natural compounds on AD, specifically targeting the reduction of β-amyloid (Aβ) overproduction, anti-apoptosis, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Notably, the identified compounds exhibiting these effects predominantly originate from plants. This review provides valuable insights into the potential of natural compounds as a reservoir of novel therapeutic agents for AD, thereby stimulating further research and contributing to the development of efficacious treatments for this devastating disease.
Medicinal plants are being used from time immemorial for their therapeutic benefits and have immense value in the therapy of neurodegenerative disorders. One of the most important neurological disorders is Alzheimer’s disease (AD) which is a major contributor to dementia and is accompanied by abundant oxidative stress in the brain tissue. A critical pathway to target the increased oxidative stress is to administer agents with antioxidant potential. Despite currently available clinical treatments to treat AD such as cholinesterase inhibitors or NMDA antagonists which address only the symptoms and cannot hamper disease progression, no efficient available clinical treatment can break the vicious cycle of oxidative stress and neurodegeneration till date. The main objective of presenting this review is that traditional Chinese medicine (TCM) acts as a promising candidate in breaking this vicious cycle and improves the quality of life of the debilitating patients. The active constituents of various herbs in TCM including Angelica sinensis, Radix polygalae, Polygala tenuifolia, and members of the Lamiaceae family have acquired experience of managing oxidative stress as indicated in the review for more than a thousand years now, and the preclinical and clinical evidence of their therapeutic potential has been highlighted in the review. Most importantly, Chinese herbs provide a multiple-target approach rather than a single-target approach and thus can target multiple pathways involved in AD at once. The Chinese herbs can definitely untangle the issues in the current therapy regimen of AD.
Tenuifolin (TEN), a natural neuroprotective compound obtained from the Polygala tenuifolia Willd plant, has improved cognitive symptoms. However, the impact of TEN on memory impairments caused by sleep deprivation (SD) is unclear. Accordingly, the objective of this study was to investigate the mechanisms behind the preventative benefits of TEN on cognitive impairment caused by SD. TEN (10 and 20 mg/kg) and Huperzine A (0.1 mg/kg) were given to mice through oral gavage for 28 days during the SD process. The results indicate that TEN administrations improve short‐ and long‐term memory impairments caused by SD in the Y‐maze, object identification, and step‐through tests. Moreover, TEN stimulated the generation of anti‐inflammatory cytokines (interleukin‐10), lowered the production of pro‐inflammatory cytokines (interleukin‐1β, interleukin‐6, and interleukin‐18), and activated microglia, improving antioxidant status in the hippocampus. TEN treatments significantly boosted the expression of nuclear factor erythroid 2‐related factor 2 and heme oxygenase‐1 while considerably decreasing the expression of NOD‐like receptor thermal protein domain associated protein 3 and caspase‐1 p20. Additionally, TEN restored the downregulation of the brain‐derived neurotrophic factor signaling cascade and the impaired hippocampal neurogenesis induced by SD. When considered collectively, our data suggest that TEN is a potentially effective neuroprotective agent for cognition dysfunction.
Xiaoer Huanglong Granule is the only Chinese Patent Medicine widely used for treating attention deficit hyperactivity disorder. However, not much is known on the bioactive components and pharmacokinetics of Xiaoer Huanglong Granule even after it was successfully introduced into clinical use. This study analyzed the components in the medication and rat plasma after oral administration with the help of UNIFI platform and Masslynx. A total of 119 and 37 components were detected in the medication and plasma, respectively, using ultra performance liquid chromatography ‐ tandem mass spectrometer. We established a rapid and sensitive simultaneous determination of 1 triterpene saponin, 3 monoterpene glycosides, and 3 lignans in rat plasma by solid‐phase extraction. The determination was accomplished within 7.50 min via gradient elution. The values of lower limit of quantification were validated at 0.08 ng/mL for tenuifolin, 0.8 ng/mL for lactiflorin, 1.828 ng/mL for albiflorin, 2 ng/mL for paeoniflorin, gomisin B, and gomisin D, 10 ng/mL for schisandrin. The results from validations of other methods were all acceptable (RSD ≤ 14.94%). This is the first report on the identification and pharmacokinetics studies of components in Xiaoer Huanglong Granule. Moreover, the pharmacokinetic behavior of lactiflorin was studied for the first time. This article is protected by copyright. All rights reserved
The general consensus is that stress affects the central nervous system and can lead to cognitive problems. The root of Polygala tenuifolia (P. tenuifolia) is a well‐known traditional Chinese medicine used for improving brain function. Tenuifolin (TEN) is the major constituent of P. tenuifolia and has a promising neuroprotective property. The purpose of this study was to investigate the alleviating effect of TEN on cognitive impairment induced by chronic restraint stress (CRS) and its mechanism. Our results showed that CRS exposure resulted in impaired cognitive performance in C57BL/6J mice, as indicated by decreased responses in Y‐maze, novel objects recognition, and step‐through passive avoidance tests. TEN treated daily orally (10 and 20 mg/kg) for 30 days reversed these behavior changes. Meanwhile, TEN could significantly regulate interleukin (IL)‐6 and IL‐10 levels in the hippocampus. TEN inhibited the toll‐like receptor 4/nuclear factor‐kappa B‐mediated inflammation, as well as adrenocorticotropic hormone and corticosterone levels in serum. Most importantly, we found that TEN also upregulated the expressions of brain‐derived neurotrophic factor, tropomyosin kinase B, glucocorticoid receptor, glutamate receptor 1, and synapse‐associated proteins. Collectively, these data suggest that TEN has a potential improvement effect on memory loss caused by CRS.
Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.
Coronavirus Disease-2019 (COVID-19), an infectious disease associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global emergency with high mortality. There are few effective treatments, and many severe patients are treated in an intensive care unit (ICU). The purpose of this study was to evaluate whether the Japanese Kampo medicine ninjin'yoeito (NYT) is effective in treating ICU patients with COVID-19.
Nine patients with confirmed SARS-CoV-2 infection admitted to the ICU were enrolled in this study. All patients underwent respiratory management with invasive mechanical ventilation (IMV) and enteral nutrition. Four patients received NYT (7.5 g daily) from an elemental diet tube. We retrospectively examined the prognostic nutritional index (PNI), length of IMV, length of ICU stay, length of hospital stay, rate of tracheostomy, and mortality rate.
The median age of the enrolled participants was 60.0 years (4 men and 5 women). The median body mass index was 27.6. The most common comorbidity was diabetes (4 patients, 44%), followed by hypertension (3 patients, 33%) and chronic kidney disease (2 patients, 22%). The median length of IMV, ICU stay, and hospital stay were all shorter in the NYT group than in the non-NYT group (IMV; 4.0 days vs 14.3 days, ICU; 5.3 days vs 14.5 days, hospital stay; 19.9 days vs 28.2 days). In the NYT and non-NYT groups, the median PNI at admission was 29.0 and 31.2, respectively. One week after admission, the PNI was 30.7 in the NYT group and 24.4 in non-NYT group. PNI was significantly (p = 0.032) increased in the NYT group (+13.6%) than in the non-NYT group (−22.0%).
The Japanese Kampo medicine NYT might be useful for treating patients with severe COVID-19 in ICU. This study was conducted in a small number of cases, and further large clinical trials are necessary.
With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. Progressive neuroinflammation contributes to aging, cognitive malfunction, and neurodegenerative diseases. However, precise mechanisms or drugs targeting aged-related neuroinflammation and cognitive impairment remain un-elucidated. Traditional herbal plants have been prescribed in many Asian countries for anti-aging and the modulation of aging-related symptoms. In general, herbal plants' efficacy is attributed to their safety and polypharmacological potency via the systemic manipulation of the body system. Radix polygalae (RP) is a herbal plant prescribed for anti-aging and the relief of age-related symptoms; however, its active components and biological functions remained un-elucidated. In this study, an active methanol fraction of RP containing 17 RP saponins (RPS), was identified. RPS attenuates the elevated C3 complement protein in aged mice to a level comparable to the young control mice. The active RPS also restates the aging gut microbiota by enhancing beneficial bacteria and suppressing harmful bacteria. In addition, RPS treatment improve spatial reference memory in aged mice, with the attenuation of multiple molecular markers related to neuroinflammation and aging. Finally, the RPS improves the behavior and extend the lifespan of C. elegans, confirming the herbal plant's anti-aging ability. In conclusion, through the mouse and C. elegan models, we have identified the beneficial RPS that can modulate the aging process, gut microbiota diversity and rectify several aging-related phenotypes.
Over the last decades a decrease in mortality has paved the way for late onset pathologies such as cardiovascular, metabolic or neurodegenerative diseases. This evidence has led many researchers to shift their focus from researching ways to extend lifespan to finding ways to increase the number of years spent in good health; “healthspan” is indeed the emerging concept of such quest for ageing without chronic or disabling diseases and dysfunctions. Regular consumption of natural products might improve healthspan, although the mechanisms of action are still poorly understood. Since preclinical studies aimed to assess the efficacy and safety of these compounds are growing, we performed a systematic review and meta-analysis on the effects of natural products on healthspan in mouse and rat models of physiological ageing. Results indicate that natural compounds show robust effects improving stress resistance and cognitive abilities. These promising data call for further studies investigating the underlying mechanisms in more depth.
Context
Sibiricose A5 (A5), sibiricose A6 (A6), 3,6′-disinapoyl sucrose (DSS), tenuifoliside A (TFSA) and 3,4,5-trimethoxycinnamic acid (TMCA) are the main active components of Polygala tenuifolia Willd. (Polygalaceae) (PT) that are active against Alzheimer's disease.
Objective
To compare the pharmacokinetics and bioavailability of five active components in the roots of raw PT (RPT), liquorice-boiled PT (LPT) and honey-stir-baked PT (HPT).
Materials and methods
The median lethal dose (LD50) was evaluated through acute toxicity test. The pharmacokinetics of five components after oral administration of extracts of RPT, LPT, HPT (all equivalent to 1.9 g/kg of RPT extract for one dose) and 0.5% CMC-Na solution (control group) were investigated, respectively, in Sprague-Dawley rats (four groups, n = 6) using UHPLC-MS/MS. In addition, the absolute bioavailability of A5, A6, DSS, TFSA and TMCA after oral administration (7.40, 11.60, 16.00, 50.00 and 3.11 mg/kg, respectively) and intravenous injection (1/10 of the corresponding oral dose) in rats (n = 6) was studied.
Results
The LD50 of RPT, LPT and HPT was 7.79, 14.55 and 15.99 g/kg, respectively. AUC0-t of RPT, LPT and HPT were as follows: A5 (433.18 ± 65.48, 680.40 ± 89.21, 552.02 ± 31.10 ng h/mL), A6 (314.55 ± 62.73, 545.76 ± 123.16, 570.06 ± 178.93 ng h/mL) and DSS (100.30 ± 62.44, 232.00 ± 66.08, 197.58 ± 57.37 ng h/mL). The absolute bioavailability of A5, A6, DSS, TFSA and TMCA was 3.25, 2.95, 2.36, 1.17 and 42.91%, respectively.
Discussion and conclusions
The pharmacokinetic and bioavailability parameters of each compound can facilitate future clinical studies.
Background:
Inflammation and oxidative stress are believed to play an important role in the pathogenesis of Alzheimer's disease (AD). Tenuifolin (TEN) is a natural neuroprotective compound extracted from Polygala tenuifolia Willd, which may improve cognitive symptoms.
Objective:
This study was designed to evaluate the protective effect of TEN on inflammatory and oxidative stress induced by amyloid-β (Aβ)42 oligomers in BV2 cells, and to explore the underlying mechanisms.
Methods:
We conducted cell viability assays to estimate drug toxicity and drug effects on cells. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were performed to detect the release of inflammatory factors. Nitric oxide (NO) assays were used to measure the degree of oxidative stress. Western blot and immunofluorescence analysis were used to explore the influence of TEN on the nuclear factor-κB (NF-κB) pathway.
Results:
Pretreatment of BV2 microglial cells with TEN inhibited the release of tumor necrosis factor-α, interleukin-6, and interleukin-1β, alleviated NO-induced oxidative stress by inhibiting the expression of inducible nitric oxide synthase and cyclo-oxygenase-2, and protected SH-SY5Y cells from the toxicity induced by the medium conditioned by BV2 cells previously exposed to Aβ42 oligomers. Moreover, TEN suppressed upstream activators of NF-κB, as well as NF-κB translocation to the nucleus in BV2 microglial cells.
Conclusion:
This study demonstrates that TEN can protect SH-SY5Y cells from Aβ42 oligomer-induced microglia-mediated inflammation, and oxidative stress by downregulating the NF-κB signaling pathway.
The root of plant Polygala arillata has been used in the Oriental medicine as a tonic and for the treatment of certain diseases. Our current research on phytochemical profile of the roots of P. arillata led to the isolation of a new oligosaccharide ester (1, polygaloside), a new glucose ester (7, arillatoside), along with five known sucrose esters (2–6). Their structures were elucidated on the basis of extensive chemical and spectroscopic methods as well as comparison with those reported in the literature. The occurence of various oligosaccharide esters in P. arillata including unique compounds plays taxonomical impact and suggests potential in medicinal uses of the title plant.
Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease causing progressive degeneration of motor neurons, ultimately resulting in death. Till now, no medicinal strategy has been proved to be completely successful in ameliorating the disease’s symptoms, except riluzole that only has a moderate effect. A limited therapeutic intervention of ALS encourages patients to opt for alternative medicine and therapies. Traditional Chinese herbal medicines (TCM) have been shown to overcome neuroinflammation, excitatory amino acid toxicity, oxidative stress, apoptosis and autophagy. In this regard, Chinese herbal medicines (CHMs) have been explored as a therapeutic option to manage clinical manifestations of ALS and other neurological diseases. In this review, we summarize the therapeutic benefits of CHMs on various neurodegenerative disorders, particularly ALS. The mechanistic details of various Chinese herbs along with their active molecules that delay the disease onset have also been discussed.
https://www.crcpress.com/Terpenoids-Against-Human-Diseases/Roy/p/book/9780815370666
Frailty and sarcopenia have recently gained considerable attention in terms of preventive care in Japan, which has an ever-increasing aging population. Sarcopenia is defined as atrophy of skeletal muscles caused by the age-related decrease in growth hormone/insulin-like growth factor and sex hormones. The Japanese Ministry of Health, Labor and Welfare reports that frailty can lead to impairment of both mental and physical functioning. Chronic diseases such as diabetes and dementia may underlie frailty. It is important to prevent progression of frailty and extend the healthy lifespan. In herbal medicine practice, including Japanese Kampo medicine, “Mibyo,” a presymptomatic state, has long been recognized and may be applicable to frailty. Kampo medicines may include several medicinal plants and are thought to have the potential to improve symptoms of frailty, such as loss of appetite and body weight, fatigue, and sarcopenia, as well as anxiety, depression, and cognitive decline. Ninjin'yoeito (Ren Shen Yang Ying Tang) is the most powerful Kampo medicine and has been widely applied to palliative care of cancer patients. This review includes recent anti-aging studies and describes the effects and mechanisms of Ninjin'yoeito (Ren Shen Yang Ying Tang) when used for frailty or to extend a healthy life expectancy.
Background:
Traditional Chinese herbal medicine (TCHM) is widely used for treating vascular dementia (VaD) in China. Recent studies of a number of TCHMs have demonstrated in vitro biological activity and therapeutic effects in animals, but the published clinical evidence has not been systematically appraised.
Objectives:
To evaluate the efficacy and safety of TCHMs listed in either the Chinese Pharmacopoeia (CP) or the Chinese National Essential Drug List (NEDL) that are used to treat VaD. A secondary aim was to identify promising TCHMs for further clinical research.
Search methods:
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's Specialised Register (on 14 March 2018) and also several Chinese biomedical databases: the Chinese Biological Medicine Database (January 1979 to May 2015), Wanfang database (January 1998 to May 2015), Chongqing VIP Information Co. Ltd or Weipu (January 1998 to May 2015) and the Chinese National Knowledge Infrastructure (January 1979 to May 2015).
Selection criteria:
We included randomised controlled trials (RCTs) of TCHMs compared to placebo, to Western medicine (WM) or to routine therapy for VaD risk factors. Eligible participants were men and women aged 18 years and above, diagnosed with VaD by any of the following four criteria: (1) Diagnostic and Statistical Manual of Mental Disorders (DSM) versions III, III-R, IV, IV-TR; (2) National Institute of Neurological Disorders and Stroke (NINDS-AIREN); (3) International Classification of Diseases 9 or 10; (4) the Hachinski or the Modified Hachinski Ischaemic Score. We required the use of an imaging technique to differentiate VaD from other dementias. We excluded (1) trials with participants diagnosed with mixed dementia or those that did not use an imaging technique to ascertain VaD; (2) trials of NEDL-listed Gingko biloba or Huperzine A as experimental interventions, to avoid duplication of existing Cochrane Reviews; (3) trials using acupuncture alone as the experimental intervention; (4) trials using another CP- or NEDL-listed TCHM (except for Huperzine A and Gingko which are popular in Western practice) as the control intervention; and (5) trials using purely non-pharmacological interventions as the control intervention unless explicitly described as 'routine therapy for VaD risk factors'.
Data collection and analysis:
We assessed the risks of bias using the Cochrane 'Risk of bias' tool and adapted the Outcome Reporting Bias in Trials (ORBIT) classification system for outcome reporting bias. We assessed TCHM effects on five clinically important outcomes: cognition, global performance, safety, activities of daily living and behaviour and summarised the effects using mean differences for continuous outcomes and risk ratios or risk differences for binary outcomes. We stratified the studies into those that estimated the TCHM versus 'no treatment' effect and those that estimated the TCHM versus the WM effect, with further stratification by the specific TCHM tested or by one of the four modes of action. We pooled using a random-effects model. Due to substantial clinical and design heterogeneity, we did not estimate an 'overall TCHM effect'.
Main results:
We only found studies (47 studies, 3581 participants) for 18 of the 29 eligible TCHMs as defined by our inclusion criteria. All were superiority trials conducted in China between 1997 and 2013, with most employing a two-arm parallel design with sample sizes ranging from 26 to 240 and a median treatment duration of 12 weeks (range: 2 to 24 weeks).We found that reporting and trial methodology were generally poor; in particular, there was a lack of information on randomisation, an absence of blinding of participants and outcome assessors and incomplete reporting of adverse events (AEs). None of the 30 trials published from 2007 onwards adopted the CONSORT recommendations for reporting RCTs of herbal interventions.We found seven TCHMs which each had potentially large benefits in studies estimating the TCHM versus 'no treatment' effect and in studies estimating the TCHM versus the WM effect. Two TCHMs (NaoXinTong and TongXinLuo) were common to both groups. Three of these TCHMs - Nao XinTong, NaoMaiTai and TongXinLuo - had the strongest evidence to justify further research. Two TCHMs (NaoMaiTai and TongXinLuo) had a 5% or more increased risk of AEs compared to the 'no Treatment' control, but the quality of this evidence was poor.
Authors' conclusions:
We found moderate- to very low-quality evidence of benefit and harm of TCHMs for VaD. Methodological inadequacies need to be addressed by better conducted and reported trials. We identified NaoMaiTai, NaoXinTong and TongXinLuo as warranting special research priority.
As the global aged population is increasing tremendously, time has come to concentrate on tail end life stage diseases. Alzheimer's disease (AD) is one such disease whose origin is an enigmatic, impacts later stage of life drastically due to irreparable damage of cognition. The characteristic feature of the disease is the accumulation of neurotoxic amyloid-beta (Aβ) and hyper phosphorylated Tau protein as fibrillary tangles. Several research reports obtained from in vitro and in vivo studies proved the efficacy of herbals in culminating neurodegenerative changes of AD by acting through various molecular pathways at various stages. So far some AChE inhibitors and NMDA receptor antagonists are the only approved medications and moreover western medicine is concentrating in isolation of moieties from the extracts that are responsible for therapeutic action. Even though several herbals have shown neuroprotective actions, we have mentioned about the phytoconstituents that have been tested experimentally against different Alzheimer's pathology models.
This review is devoted to adaptogens, plant products capable of producing nonspecific responses in the human body, resulting in increasing the resistance against multiple stressors (physical, chemical or biological) and capable of having a normalizing effect to the human body. Adaptogens must be non-toxic, harmless, capable of not influencing normal body functions more than required, and capable of treating depression, a common neuropsychiatric illness, the importance of which is increasing by number of new patients every year. Number of plants are able to produce natural compounds, which meet the criteria of becoming adaptogens. The most known of them are used in traditional medicine for centuries. This review summarizes data from several most important plant sources of adaptogens, however, it does not cover the field of adaptogens in all its variability. Based on the literature search covering the two past decades, it is focused at several most important plant species and their products, and at their proven or potential pharmacological effects in treating several important diseases.
In this study, we investigated the potential effect of onjisaponin B (OB) on aging rats induced by D-gal (D-galactose). Sub-acute aging model was established in rats by the subcutaneous injection of D-gal (120 mg/kg) for 42 days, accompanied with OB (10, 20 mg/kg, p.o.) or normal saline intervention for 28 days since the 14th day after the beginning of D-gal stimulation. Morris water maze test and step-down passive avoidance test were conducted to evaluate the cognitive function of the rats. The superoxidase dismutase (SOD), malondialdehyde (MDA), glutathione (GSH) and glutathione peroxidase (GSH-px) contents in hippocampus were measured by according kits, respectively. And the hippocampus levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were assayed by enzyme-linked immunosorbent assay (ELISA). Furthermore, the expressions of SOD1, MDA5, GSH, GSH-px, NF-кB pathway were present by western blot. It revealed that administration of OB was able to significantly attenuate the D-gal-induced changes in the hippocampus, ranging from cognitive capacity, oxidative stress to inflammation response. In a nutshell, our data provided evidence that OB could contribute to the restoration of cognitive ability by improving the antioxidant and anti-inflammatory capacity in D-gal induced aging rats.
Tenuigenin (TEN), a major active component of polygala tenuifolia root, has been reported to have a number of biological properties, such as anti-oxidative and anti-inflammatory activities. However, the protective effect of TEN on acute liver injury has not yet been reported. This research aims to detect the protective effect of TEN on lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced acute liver injury in mice and to investigate the molecular mechanisms. TEN was administered intraperitoneally 1 h before LPS/D-GalN treatment. The levels of TNF-α, IL-1β, ALT, and AST were measured. The expression of NF-κB, ASK1, MAPKs, Nrf2, and HO-1 were detected by western blot analysis. The results showed that TEN significantly inhibited LPS/D-GalN-induced serum ALT and AST levels. TEN also inhibited LPS/D-GalN-induced TNF-α and IL-1β production. Furthermore, LPS/D-GalN-induced hepatic MDA and MPO activities were also inhibited by TEN. In addition, TEN was found to inhibit LPS/D-GalN-induced ASK1 expression, NF-κB and MAPKs activation and up-regulate the expression of Nrf2 and HO-1. In conclusion, TEN protected against LPS/GalN-induced acute liver injury by suppressing inflammatory and oxidative responses.
Acute kidney injury (AKI) is a severe complication of sepsis, which largely contributes to the associated high mortality rate. Tenuigenin (TNG) is a natural product isolated from Polygala tenuifolia root, which possesses anti-inflammatory and anti-oxidant properties. The present study investigated the effects of TNG on sepsis-associated AKI in mice subjected to cecal ligation and puncture (CLP). TNG was demonstrated to alleviate sepsis-induced AKI by reducing pathological changes and significantly decreasing the levels of blood urea nitrogen, serum creatinine and kidney coefficient. The production of inflammatory cytokines, including tumor necrosis factor α and interleukin-6, was markedly inhibited by TNG. Hematoxylin-eosin staining revealed that the morphological changes of kidney tissues in CLP mice were reversed following TNG treatment. Furthermore, treatment with TNG inhibited the production of nitric oxide and prostaglandin E2. Finally, TNG inhibited the activation of the nuclear factor-κB (NF-κB) signaling pathway. The present study suggested that TNG alleviates sepsis-induced AKI by inhibiting the NF-κB signaling pathway, which provides a novel approach for treating sepsis-induced AKI.
A method of ultra-fast liquid chromatography with tandem mass spectrometry was developed and validated for the simultaneous quantitation of eight bioactive components, including polygalaxanthone III, sibiricaxanthone B, tenuifolin, sibiricose A5, sibiricose A6, tenuifoliside A, ginsenoside Re and ginsenoside Rb1 in rat plasma after oral administration of Kai-Xin-San. The plasma samples were extracted by liquid-liquid extraction using digoxin as internal standard. Chromatographic separation was performed on a Venusil MP C18 column (100 mm × 2.1 mm, 3 μm) with methanol and 0.05% acetic acid in water as mobile phase. The tandem mass spectrometric detection was performed in the multiple reaction monitoring with turbo ion spray source in the negative ionization. Validation parameters were within acceptable ranges. The established method has been successfully applied to comparing the pharmacokinetic profiles of the analytes between normal and Alzheimer's disease rats. The results indicated that there were significant differences in pharmacokinetic parameters of some components between two groups, which may be due to the mechanisms of Alzheimer's disease and pharmacological effects of the analytes. The pharmacokinetic research in the pathological state might provide more useful information to guide the clinical usage of the herb medicine. This article is protected by copyright. All rights reserved
OBJECTIVE To systematically review the clinical efficacy and safety on TCHMs that are used for vascular dementia(VaD).METHODS To identify studies for systematical review,electronic searches were performed through several databases-ALOIS,CNKI,CBM,Weipu,Wanfang,etc.Only randomized control trials(RCTs)or controlled clinical trials(CCTs)were included.Patients were diagnosed with VaD by diagnostic criteria(DSM,NINDS-AIREN,ICD or HIS)as well as imaging technique(CT,MRI or functional imaging,etc).Eligible TCHMs must be recognized in the Chinese Pharmacopeia or the National Essential Drug List of the People′s Republic of China.Included studies were appraised using the Cochrane Collaboration risk-of-bias criteria.Efficacy and safety outcomes were evaluated by meta-analysis.Efficacy outcomes include cognition,daily function,global performance and behaviour;safety was assessed by the number of adverse events and number of subjects experiencing adverse events.Assessment of heterogeneity,subgroup analysis and sensitivity analysis were also performed.RESULTS A total of 46 trials on 29TCHMs(3522patients)were included.45 studies were RCTs and 1was CCT.In these 45 RCTs,only 2were appraised as adequately randomised.5of 46 trials were appraised as having low risk of bias in blinding.Sample sizes were generally small ranging from 26 to 216with a median of 68.All trials were conducted in China from 1997 to 2013.All 46 studies assessed cognition using one or a combination of the following scales:MMSE(n=40 studies;3096 patients),HDS(n=22;1664 patients),ADAS-Cog(n=4;241 patients),CDT(n=1;60patients)and CCSE(n=1;26patients).Half of the studies assessed daily function using either the ADL(n=22;1743 patients)or IADL(n=2;203patients).Only 6studies measured behaviour using the FAQ(n=3;226 subjects),BBS(n=1;48patients),NPI(n=1;100subjects)or Neurological Deficits Function Scale(n=1;91patients).30 studies measured global performance.31 of 46 studies made conclusions regarding the safety of the TCHMs.Despite the problems of methodology and re
Senegenin, an effective component of Polygala tenuifolia root extract, promotes proliferation and differentiation of neural progenitor cells in the hippocampus. However, the effects of senegenin on mesencephalon-derived neural progenitor cells remain poorly understood. Cells from a ventral mesencephalon neural progenitor cell line (ReNcell VM) were utilized as models for pharmaceutical screening. The effects of various senegenin concentrations on cell proliferation were analyzed, demonstrating that high senegenin concentrations (5, 10, 50, and 100 μmo/L), particularly 50 μmol/L, significantly promoted proliferation of ReNcell VM cells. In the mitogen-activated protein kinase signal transduction pathway, senegenin significantly increased phosphorylation levels of extracellular signal-regulated kinases. Moreover, cell proliferation was suppressed by extracellular signal-regulated kinase inhibitors. Results suggested that senegenin contributed to in vitro proliferation of human neural progenitor cells by upregulating phosphorylation of extracellular signal-regulated kinase.
With its traditional use in relieving insomnia and anxiety, our previous study has identified onjisaponin B from Radix Polygalae (RP), as a novel autophagic enhancer with potential neuroprotective effects. In current study, we have further identified a novel active fraction from RP, contains 17 major triterpenoid saponins including the onjisaponin B, by the combinational use of cell membrane chromatography (CMC) and ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry {UHPLC-(Q)TOF-MS}. By exhibiting more potent autophagic effect in cells, the active fraction enhances the clearance of mutant huntingtin, and reduces protein level and aggregation of α-synuclein in a higher extent when compared with onjisaponin B. Here, we have reported for the first time the new application of cell-based CMC and UHPLC-(Q)TOF-MS analysis in identifying new autophagy inducers with neuroprotective effects from Chinese medicinal herb. This result has provided novel insights into the possible pharmacological actions of the active components present in the newly identified active fraction of RP, which may help to improve the efficacy of the traditional way of prescribing RP, and also provide new standard for the quality control of decoction of RP or its medicinal products in the future.
In vivo brain microdialysis was used to monitor changes in dopamine (DA) release in the nucleus accumbens (NAc) during anticipatory and consummatory components of feeding behavior. During 10 daily training sessions, rats were first confined to one compartment of a testing chamber for 10 minutes. During this period (anticipatory phase) they were prevented from gaining access to a highly palatable liquid meal by a wire mesh screen. The screen was then removed and the animals were permitted to consume the meal for 20 min (consummatory phase). On removal of the screen, the latency to begin drinking decreased and the amount consumed increased as a function of days of training, both measures reaching asymptotic levels by day 7. Trained animals were implanted with dialysis probes in the NAc on day 10, and on day 12 DA release was monitored during the feeding session. Compared to controls, trained animals failed to show significantly greater increases in accumbal DA release during the anticipatory phase, all groups showing small (approximately 10%) increases on being placed in the test chamber. In contrast, compared to controls, DA release increased significantly in the NAc during consumption of the palatable meal. The magnitude of this increase was significantly enhanced (30% vs 71% peak increase) in animals that were 20 hr food deprived at the time of testing. The latter animals also showed a statistically significant increase (24%) in DA release during the anticipatory phase. A subsequent experiment in which consumption of the palatable liquid was limited to 5 ml in deprived and nondeprived animals indicated that only part of the deprivation-induced potentiation of accumbal DA release could be attributed to the larger volume consumed by the deprived animals. That is, the same volume and rate of consumption of a small amount of the liquid diet produced a significantly greater increase in accumbal DA release in deprived than in nondeprived animals (42% vs 23% peak increase). Feeding-induced increases in accumbal DA release were not due to postingestional factors as direct injections of the liquid diet into the stomach by gavage failed to produce this effect. The results of these experiments indicate (1) that consummatory rather than anticipatory aspects of feeding are robustly associated with increases in DA release in the NAc, and (2) that motivational state can influence the magnitude of the neurochemical events that are associated with goal-directed behaviors.
Memory is often considered to be a process that has several stages, including acquisition, consolidation and retrieval. Memory can be modified further through reconsolidation and performance can change during extinction trials while the original memory remains intact. Recent studies of the molecular basis of these processes have found that many signaling molecules are involved in several stages of memory but, in some cases, molecular pathways may be selectively recruited only during certain stages of memory.
Although there are normal cognitive changes that take place as a person becomes older, ageing in humans is generally associated with a deterioration of cognitive performance, in particular of learning and memory. There are a number of herbal medicines that are reported to improve brain function and intelligence. In the present study, the ameliorating effects of an essential oil extracted from Acori graminei rhizoma on learning and memory in aged, dysmnesia rats and mice were determined using the step-down passive avoidance test and Y maze. Oral administration of the essential oil (0.02, 0.04 and 0.08 g kg(-1)) to rats for 30 days and to mice for 15 days improved the latency and number of errors in aged, dysmnesia rats and mice. The cerebral neurotransmitters in aged rats given the essential oil (0.02, 0.04, 0.08 g kg(-1)) for 30 days were also investigated, and increased levels of norepinephrine, dopamine and serotonin, and decreased levels of acetylcholinesterase activity were found. The results suggest that the essential oil improves cognitive function in aged animals possibly by increasing norepinephrine, dopamine and serotonin relative levels, and by decreasing the activity of acetylcholinesterase in the cerebra.
AIM To observe the effect of tenuigenin (TEN), an active component isolated from Yuanzhi, on cholinergic function in rats with β-amyloid peptide and ibotenic acid injection into right nucleus basalis magnocellularis (NBM). METHODS: A combined injection of β-AP1-40 and ibotenic acid into the right NBM was used as a dementialike rat model. The ability of learning and memory was detected by the step-through test. The activity of choline acetyltransferase (ChAT) and the muscarinic receptor density were determined by 3H-acetylcoenzyme and [3H]-quinuclidinyl benzilate (3H-QNB) binding tests, respectively. The activity of acetylcholinesterase (AChE) was determined by improved Ellman's method. RESULTS: The model animals were treated with daily oral administration of TEN for 60 d. The learning and memory ability were obviously improved. i.e., in the step-through test, the number of error was obviously decreased and the latency was obviously prolonged. The muscarinic receptor density and the activity of ChAT within rats brain were markedly enhanced, whereas the activity of AChE in rat brain was significantly inhibited. CONCLUSION: These results suggest that TEN probably have certain improving and treating action for the reductions in cholinergic function in Alzheimer's disease.
A method is presented for the fluorometric analysis of serotonin, norepinephrine, and dopamine. The method is relatively easy, relatively fast, and uses manageable sample volumes. The method has the additional advantage of saving 1/3 the time, compared to the time involved to accomplish a similar analysis that was reported previously.
Unlabelled:
We investigated whether an aqueous extract of Polygala tenuifolia Willd (PTW) could improve the rats' memory and behavioral disorders produced by lesioning nucleus basalis magnocellularis (NBM) in rats. The animals were divided into four groups for surgery, and following that they were orally administered PTW extract for 7 and 21 days. Each group consisted of eight male Sprague-Dawley rats and were treated as follows:
Control:
no surgery (n = 8), PBS: 1M (mol/L) phosphate buffered saline (n = 8), IBO: 0.12 M (n = 8), QUIS: 0.12 M (n = 8). Two 0.5 microL injections were made in the vicinity of the bilateral side of the nucleus basalis magnocellularis (NBM). All rats were tested in the neurological tests and the step-through passive avoidance memory test during pre-surgery, surgery and post-surgery drug treatment. The results suggest that PTW extract has some repairing effects on the memory and behavioral disorders produced by lesioning of the NBM in rats.
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
1. Cholinergic enzymes (ChAT, AChE) in different areas of the brain and cortical electroencephalography (EEG) activity were investigated in young and old rats. 2. In old rats, ChAT activity was low in the striatum, but high in the amygdala. Compared to young rats, ChAT activity in old rats was unchanged in the frontal, parietal/occipital and entorhinal cortex as well as in the hypothalamus, midbrain, hippocampus and brain stem. 3. AChE activity in old rats was lower than in young animals in the parietal/occipital cortex, hippocampus, striatum and brainstem. In other areas of the brain AChE activity was unchanged. 4. In old rats the peak frequency (Fp) of cortical EEG activity (mobility-related) was significantly lower than in young animals, both frontally and occipitally. The power of 5-10 Hz frequency band was markedly lower than in young rats. During immobility, the power of the 1.5-3 Hz and 3-5 Hz bands was lower in the frontal cortex of old rats. The power of 3-5 Hz, 5-10 Hz and 10-20 Hz bands was lower in the occipital cortex of old rats. In all of the old rats, but not in any of the young ones, symmetric high voltage activity was observed in the frontal pole of the cortex. 5. These results suggest that the age-related decrease of higher frequencies of cortical EEG activity may be related to the decrease of AChE activity in the parietal/occipital cortex. This decrease in AChE may reflect degeneration of the cholinergic synapses.
1. The choline acetyltransferase and acetylcholinesterase activities in the cerebral cortex and hippocampus and muscarinic binding in the cerebral cortex did not differ significantly between male and female Wistar rats. 2. Choline acetyltransferase activities in the cerebral cortex and hippocampus of rats were not altered during ageing. 3. Acetylcholinesterase activities in these same brain areas were markedly decreased during ageing, possibly reflecting a loss of postsynaptic enzyme activity. 4. When measured using 3H-pirenzepine, binding to the postsynaptic muscarinic receptors was slightly higher in 26-month-old rats than in 12-month-old rats; total muscarinic binding measured using 3H-quinuclidinyl benzilate did not alter during ageing. 5. The present study does not support the hypothesis that in the rat brain the number of postsynaptic muscarinic binding sites decreases during ageing.
The time-course of effects of a single dose of p-chlorophenylanine on rat brain amines shows a significant lowering of serotonin (5HT) and 5-hydroxyindole-3-acetic acid (5HIAA) beginning on day 1 and lasting for about 8 days. In most brain areas, levels of norepinephrine (NE) are also lowered significantly on days 1 through 5. In contrast, both p-chloroamphetamine and p-chloro-N-methylamphetamine decrease brain 5HT and 5HIAA, beginning at 2–4 hr after dosage and continuing for > 4 days, with no depleting effect on brain NE.
MOST theories of learning assume some change in the synaptic conductivity of cortical pathways1,2. Facilitation by use alone, however, will not account for the most characteristic feature of learning-that what is learned are those motor responses which lead to a satisfactory or adaptive state of affairs for the organism3-5.
Aged Long-Evans rats (24-25 months old) were classified into cognitively impaired or unimpaired subgroups based on their performances in the Morris Swim Maze task compared to young controls. Using quantitative in vitro receptor autoradiography, we investigated the status of various cholinergic markers in these two groups and in young adults (six months) animals. The apparent density of [3H]pirenzepine (muscarinic M1) sites was similar in the three groups of rats in various cortical areas, subfields of the hippocampus, medial septum and striatum. Similarly, choline acetyltransferase activity and the density of [3H]hemicholinium-3 (high-affinity choline uptake) and [3H]cytisine (nicotinic) binding sites were also unchanged in the brain regions studied between the aged cognitively impaired, unimpaired and young adult rats. In contrast, significant increases in [3H]AF-DX 384 (muscarinic M2) binding density were observed in various cortical areas and in the molecular layer of the dentate gyrus of aged cognitively impaired versus unimpaired rats and in few cortical regions of old as compared to young animals. Therefore, a selective alteration in the regulation of putative M2 receptor sites is apparent, particularly in the aged cognitively impaired rats. Increases in M2 binding sites could lead to a decrease in the capacity to release acetylcholine, as some of the M2 receptors are believed to act as negative autoreceptors. This could influence cognitive functions as selective M2 blockers have recently been reported to facilitate spatial memory in aged impaired rats [Doods et al. (1993) Life Sci. 52, 497-503: Quirion et al. (1995) J. Neurosci. 15, 1455-1462.
Rats were tested with a one-trial inhibitory avoidance paradigm in which the latency to enter the shock compartment served as a measure of memory retention. Pretraining administration of the non competitive NMDA receptor antagonist MK-801 (0.3 mg/kg i.p.) significantly reduced the response latency during the retention test given 24 h after rats received a step-through inhibitory avoidance training. MK-801 at 0.1 mg/kg did not affect the retention latency. The muscarinic receptor antagonist scopolamine (1.0 mg/kg i.p.) also interfered with the inhibitory avoidance response in the retention test when administered before the training trial. The lower dose of 0.3 mg/kg scopolamine, which by itself was ineffective, significantly impaired inhibitory avoidance learning when administered simultaneously with the behaviorally subthreshold dose of 0.1 mg/kg MK-801 before the training trial. These results suggest that interactive mechanisms regulated by concurrent activation of NMDA and muscarinic receptors are involved in learning processes of inhibitory avoidance performance in rats.
The effect of age on the monoamines 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA), their metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3,4-dihydroxphenylacetic acid (DOPAC), and the 5-HT precursor 5-hydroxy-L-tryptophan (5-HTP), together with the peptides neuropeptide Y (NPY), somatostatin (SOM), and corticotropin-releasing factor (CRF), was studied in frontal cortex, gyrus cinguli and hypothalamus from 23 healthy control subjects, aged 16-75 years. After correcting for postmortem interval, significant decreases in gyrus cinguli NA, NPY and CRF, and hypothalamic DA, HVA, and 5-HIAA concentrations were obtained with advancing age. The involvement of the monoaminergic system in several functional abnormalities appearing in senescence is suggested. Furthermore, evidence is given of the participation of the peptidergic systems in the aging process.
Individual differences in spatial memory among young and aged rats were assessed using memory tasks related to integrity of the hippocampus and the neostriatum. Relationships were then examined between measures of spatial memory and regional choline acetyltransferase (ChAT) activity, a marker for cholinergic integrity. Twenty-four-month-old Long-Evans rats were impaired in comparisons with 6-month-old rats on measures of place learning, working memory, reference memory, and perseveration in water-maze tasks. Aged rats that were impaired on one measure of memory, however, were not necessarily impaired on other measures. ChAT activity in the ventromedial and dorsolateral neostriatum of aged rats was significantly reduced in comparisons with young rats whereas no difference was found in the hippocampus. Aged rats with the most ChAT activity in the anterior ventromedial neostriatum performed best on the place-learning and reference memory tasks but also made the most perseverative errors on the working memory task. In addition, young and aged rats with the most ChAT activity in the anterior dorsolateral neostriatum were those with the least accurate working memory. No relationships were found between ChAT activity in the hippocampus and spatial memory. Thus age-related memory impairment has components that can be segregated by measuring relationships between cholinergic integrity in subregions of the anterior neostriatum and memory tasks with different strategic requirements.
In an attempt to clarify the role of the brain serotonergic system in the psychopathology of anxiety, we examined the effect of a psychological stress, conditioned fear stress, on extracellular serotonin (5-hydroxytryptamine, 5-HT) concentrations in the rat medial prefrontal cortex using the method of in vivo microdialysis, while simultaneously observing conditioned fear stress-induced freezing behavior, an index of anxiety. Conditioned fear stress increased extracellular 5-HT levels in the medial prefrontal cortex, and this 5-HT level increase was followed by a resolution of the freezing behavior. A dose of 10 mg/kg of a selective 5-HT reuptake inhibitor, citalopram, administered 60 min before exposure to conditioned fear stress increased extracellular 5-HT concentrations immediately and potently, reducing freezing behavior. These findings strongly suggest that facilitation of brain 5-HT neurotransmission decreases anxiety, which is in agreement with the clinical reports that selective 5-HT reuptake inhibitors are effective in the treatment of anxiety disorders.
Acetylcholine (ACh) efflux in the frontoparietal cortex was studied with in vivo microdialysis while rats performed in an operant task designed to assess sustained attention. Transferring animals from the baseline environment into the operant chambers elicited a robust increase in cortical ACh efflux that persisted throughout the 18-min pre-task period. Subsequent performance in the 36-min sustained attention task was associated with further significant increases in frontoparietal ACh efflux, while the termination of the task resulted in a delayed decline in ACh levels. Upon the 12-min presentation of a visual distracter (flashing houselight, 0.5 Hz) during task performance, animals initially developed a significant response bias to the left lever in the first 6-min distracter block, reflecting a reduction of attentional effort. Under continued conditions of increased attentional demand, performance recovered during the second 6-min distracter block. This return to attentional processing was accompanied by an increase in cortical ACh efflux, suggesting that the augmentation of attentional demand produced by the distracter elicited further increases in ACh release. The enhancement of cortical ACh efflux observed prior to task performance implies the presence of complex relationships between cortical ACh release and anticipatory and/or contextual factors related to operant performance and attentional processing. This finding, along with the further increases in cortical ACh efflux associated with task performance, extends hypotheses regarding the crucial role of cortical cholinergic transmission for attentional functions. Furthermore, the effects of the distracter stimulus provide evidence for a direct relationship between attentional effort and cortical ACh release.
As a result of its presence in various structures of the central nervous system serotonin (5-HT) plays a role in a great variety of behaviours such as food intake, activity rythms, sexual behaviour and emotional states. Despite this lack of functional specialization, the serotonergic system plays a significant role in learning and memory, in particular by interacting with the cholinergic, glutamatergic, dopaminergic or GABAergic systems. Its action is mediated via specific receptors located in crucial brain structures involved in these functions, primarily the septo-hippocampal complex and the nucleus basalis magnocellularis (NBM)-frontal cortex. Converging evidence suggests that the administration of 5-HT2A/2C or 5-HT4 receptor agonists or 5-HT1A or 5-HT3 and 5-HT1B receptor antagonists prevents memory impairment and facilitates learning in situations involving a high cognitive demand. In contrast, antagonists for 5-HT2A/2C and 5-HT4, or agonists for 5-HT1A or 5-HT3 and 5-HT1B generally have opposite effects. A better understanding of the role played by these and other serotonin receptor subtypes in learning and memory is likely to result from the recent availability of highly specific ligands, such as 5-HT1A, 5-HT1B, 5-HT2A receptor antagonists, and new molecular tools, such as gene knock-out mice, especially inducible mice in which a specific genetic alteration can be restricted both temporally and anatomically.
The present work was designed to study the effect of aging on some parameters of the glutamatergic, aminergic and cholinergic neurotransmission, in the main brain areas of mice of the long-surviving BALB/c-nu strain. We have assayed: (1) the density of three ionotropic receptors for excitatory aminoacids (EAA) which selectively bind kainic acid (KA), N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA); (2) the content of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) and the levels of the DA metabolite dihydrophenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA); (3) the level of the choline acetyltransferase (ChAT), the enzyme catalyzing the synthesis of acetylcholine. The parameters were measured in animals at the age of 6, 12, 18 and 24 months; the brain zones under test were the frontal cortex (FC), the corpus striatum (STR), the hippocampus (HIP), the medio-dorsal cortex (DC) and the cerebellum (CER). Significant age-related variations for the density of KA-type and NMDA-type receptors were found in STR and a decrease of the NMDA parameter was found in DC. Neither the monoamine and metabolite contents nor the ChAT levels showed any significant variation in all the tested areas. These findings suggest that an unbalance among different neurotransmission activities could take place with normal aging in rodents: it could be involved in the onset of the motor deficit which occurs in the elderly of these and other mammals.
We carried out this study to search a new active constituent that had cognitive enhancing activity and low side effects from natural source. We found that the extract of dried root of Polygala tenuifolia Willdenow (BT-11, 10 mg/kg, i.p.) could significantly reverse scopolamine-induced cognitive impairments in rat, using a passive avoidance and a water maze test. We also investigated the effects of BT-11 on neurotoxicity induced by glutamate (Glu) and toxic metabolites of amyloid precursor protein (APP) such as amyloid beta protein (A beta) and C-terminal fragment of APP (CT) in primary cultured neurons of rat. The pretreatment of BT-11 (0.5, 3, and 5 micro g/ml) significantly reduced cell death induced by Glu (1 mM), A beta (10 micro M) and CT105 (10 micro M) in a dose-dependent manner. In addition, BT-11 inhibited acetylcholinesterase (AChE) activity in a dose-dependent and non-competitive manner (IC(50) value; 263.7 micro g/ml). Our novel findings suggest the possibility that this extract may have some protective effects against neuronal death and cognitive impairments in Alzheimer's disease (AD), or other neurodegenerative diseases related to excitotoxicity and central cholinergic dysfunction.
We have previously shown that differences in life span among members of Swiss mouse populations appear to be related to their exploration of a T-maze, with a slow exploration ("slow mice") being linked to increased levels of emotionality/anxiety, an impaired immune function and a shorter life span. Thus, we proposed the slow mice as prematurely ageing mice (PAM). We have now compared the monoaminergic systems of the PAM and of the non-prematurely ageing mice (NPAM), in discrete brain regions. PAM had decreased noradrenaline (NA) levels in all the brain regions analysed, whereas the 3-methoxy-4-hydroxyphenyl glycol (MHPG)/NA ratios were not significantly modified. PAM also showed decreased serotonine (5-HT) levels in hypothalamus, striatum and midbrain, as well as increased 5-hydroxyindol-3-acetic acid (5-HIAA)/5-HT ratios in hypothalamus and hippocampus. The dopamine (DA) content was lower in PAM in most regions, whereas the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA and homovanillic acid (HVA)/DA ratios were either increased or unchanged depending on the region analysed. In most cases, the differences between PAM and NPAM involved both sexes. One exception was the hypothalamus where the differences only affected the male mice. The neurochemical alterations found in PAM resemble some changes reported for aged animals and are related with their behavioural features.
From previous literature, it appears that most classical neurotransmitter systems can in some way influence learning and memory in the rat. A matter of crucial interest is, however, whether the chemical systems contribute in a similar manner or whether they have different abilities to support cognitive processes. The purpose of the present study was to investigate this issue. The investigation was carried out by reviewing relevant studies of neurochemistry and cognition. Inclusion criteria were set for selection of behavioral tasks to be elucidated and for studies employing acceptable tasks. Morris water maze, radial maze, passive avoidance, and spontaneous alternation met the criteria for inclusion, and a table for each of these tests summarizes the neurochemical results of the studies accepted for inclusion. In this way, a reliable comparability of results from relevant studies was obtained. The comparisons revealed that for both systemic and targeted infusions of agents the neurochemical systems possess different abilities to influence learning and memory. Calculation of impact factors (percentage of significant effects of chemical agents like agonists, antagonists, neurotoxins) showed that glutamate was ranking highest (93), followed by GABA (81), dopamine (81), acetylcholine (81), serotonin (55), and norepinephrine (48). No task specific roles were observed for the transmitter systems. The highest sensitivity (percentage of significant effects) to interference with neurochemical systems was found for the spontaneous alternation task (86), followed by water maze (76), passive avoidance (72), and radial maze (58). The multiple memory systems in the rat brain can hardly be related to specific transmitter systems, because of the great extent of interactions between the systems.
Aged (25-27 months) Long-Evans female rats were distinguished according to whether they showed no significant impairment (AU), moderate impairment (AMI), or severe impairment (ASI) in a spatial reference-memory task. Young (3-5 months) rats served as controls. Electrically evoked overflow of tritium was assessed in hippocampal slices preloaded with [3H]choline or [3H]serotonin (5-HT). Nicotine-evoked overflow of tritium was measured after preloading with [3H]noradrenaline (NA). Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, and concentration of monoamines were assessed in homogenates. Aged rats exhibited reduced accumulation of [3H]choline and [3H]5-HT, increased accumulation of [3H]NA, and weaker electrically evoked overflow of [3H]acetylcholine ([3H]ACh) and [3H]5-HT. The overflow of [3H]NA was not altered consistently by aging. Roughly, drugs acting presynaptically had comparable effects in aged rats: oxotremorine and CP 93,129 inhibited the overflow of [3H]ACh, CP 93,129 and UK 14,304 reduced that of [3H]5-HT. ChAT or AChE activity, and 5-HT concentration were not changed by age; NA concentration was reduced. When significant, changes were comparable in AU, AMI, and ASI rats. Data show that aging alters cholinergic and serotonergic hippocampal innervations, release of ACh and 5-HT, but not presynaptic release-modulating mechanisms. These alterations do not account for variability in water-maze performance of aged rats.
Amyloid beta-protein (A beta) is a pivotal pathological factor in Alzheimer's disease (AD). Tenuigenin, extracted from the Chinese herb Polygala tenuifolia, seems to ameliorate the reduction in cholinergic function on rat models induced by A beta. To examine this therapeutic effect, we tested whether Tenuigenin could inhibit secretion of A beta in neuroblastoma cells stably transfected with two amyloid precursor protein (APP) constructs: the APP695 cDNA (SH-SY5Y APP695) and the C-terminal 99 amino acid residues of APP plus the signal peptide (SH-SY5Y SPA4CT). Tenuigenin inhibited the secretion of A beta and the C-terminal 99 amino acids of APP (C99) in SH-SY5Y APP695 cells, but did not change the A beta and C99 levels in SH-SY5Y SPA4CT cells. Fluorescence Resonance Energy Transfer (FRET) assays showed that Tenuigenin inhibited the proteolytic activities of BACE1 (beta-secretase) on its substrate in vitro. In addition, Tenuigenin did not demonstrate any cytotoxic effects, nor did it affect APP mRNA expression, holoAPP synthesis or sAPP alpha secretion. Our data suggest that Tenuigenin can inhibit the secretion of A beta in SH-SY5Y APP 695 cells via BACE1 inhibition. Taken together, these results suggest that Tenuigenin may be worthy of future study as an anti-AD drug.
Disciplinarian investigation of Chinese complex prescription with promoting intelligence in past dynasties
- Liu
Liu, W.B., Liu, W.Z., 2005. Disciplinarian investigation of Chinese complex prescription with promoting intelligence in past dynasties. Jiangxi J. Traditional Chin. Med. 36, 62–63.
Improvement of Ellman assay of AchE in brain
- Ni
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