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The Effect of Acori Graminei Rhizoma and Extract Fractions on Spatial Memory and Hippocampal Neurogenesis in Amyloid Beta 1-42 Injected Mice
Abstract
Acori graminei Rhizoma (AGR), the dry rhizoma of Acorus gramineus Soland (Araceae), has been used as an Asian traditional herbal medicine against senile dementia, stroke, and cardiovascular disease. Previous studies have revealed neuroprotective effects of AGR on neuronal damage and learning impairment, while mostly focused on the effect of volatile oil fraction of AGR. This study aimed to investigate the neuroprotective effects of different extract fractions from AGR against Alzheimer disease-like symptoms induced by Amyloid Beta (Aß) 1-42 intra-hippocampal injection. On day 7 after intra-hippocampal injection of saline or Aβ1-42, spatial memory was assessed by the first Morris water maze, followed by 3-week intra-gastric administration of saline or water extract, volatile oil fraction, or defatted decoction fraction of AGR respectively. Mice were subsequently subjected to the second Morris water maze task. Levels of Aβ1-42 and expressions of doublecortin and nestin in the hippocampus were examined using immunohistochemistry. Our results suggested that treatment with these different extract fractions from AGR could ameliorate cognitive impairment and down-regulate expressions of doublecortin and nestin in the hippocampus of Aβ1-42 injected mice, in which water extract and volatile oil fractions were more effectively in spatial memory than defatted decoction fraction.
... and α-asarone (8.8-13.7%) [11], as well as water extract, ethyl ether extract, ethyl acetate extract, N-butanol extract, and the defatted decoction fractions. AGA is often used as a component in some Chinese herbal formulas. ...
... After reading the remaining 285 full-text articles, 228 studies were excluded for at least one of following reasons: (1) not an animal study; (2) the article was not a research about cognitive impairment; (3) the study did not access the effects of AGA or active component on the animal model of cognitive impairment; (4) EAAGA was not used as a monotherapy; and (5) lack of control group. Ultimately, 34 eligible articles [5,6,10,11, were selected ( Figure 1). ...
... Sixteen studies [5,6,10,11,[17][18][19][20][21][22][23][24][25][26][27]37] were published in English, and 18 studies were in Chinese between 1999 and 2019. In total, 34 studies with 1431 animals were included. ...
Extracts or active components from Acorus gramineus Aiton (EAAGA) have been clinically used for cognition impairment more than hundreds of years and are still used in modern times in China and elsewhere worldwide. Previous studies reported that EAAGA improves cognition impairment in animal models. Here, we conducted a preclinical systematic review to assess the current evidence of EAAGA for cognition impairment. We searched 7 databases up until June 2019. Methodological quality for each included studies was accessed according to the CAMARADES 10-item checklist. The primary outcome measures were neurobehavioral function scores evaluated by the Morris water maze test, electrical Y-maze test, step-down test, radial eight-arm maze test, and step-through test. The secondary outcome measures were mechanisms of EAAGA for cognition function. Finally, 34 studies involving 1431 animals were identified. The quality score of studies range from 1 to 6, and the median was 3.32. Compared with controls, the results of the meta-analysis indicated EAAGA exerted a significant effect in decreasing the escape latency and error times and in increasing the length of time spent in the platform quadrant and the number of platform crossings representing learning ability and memory function (all P
... Aβ 1-42 powder was dissolved in sterile saline containing 1% NH 4 OH and aggregated by incubation at 37 C for 7 days to prepare at a concentration of 2.5 μg/μL. A week after the mice were adapted to the new environment, Aβ 1-42 solution was injected into the hippocampal CA1 area (Ma et al., 2015). Mice was injected, a volume of 1.5 μL of Aβ 1-42 using a microsyringe which was inserted perpendicularly through the skull according to the following coordinates from bregma: AP: −2.3 mm, ML: AE1.5 mm, DV: −2.3 mm (Zheng et al., 2013). ...
... Extraction of volatile oil fraction from A. gramineus: 200 g dried powder was soaked in 2 L of distilled water for 1 hr at room temperature then placed in zeolites and boiled until no more volatile oil increase. Quantum libet of volatile oil was diluted with 1% tween-80 to 100 times before animal intragastric administration (Ma et al., 2015). ...
In recent years, the extraction fraction of volatile oil from Acorus gramineus has significant effects on anti‐dementia and improving the learning and memory of animals. To date, limited studies have determined whether volatile oil from A. gramineus has the protective effect on neuronal damage. The aim of this study was to investigate the protective effects of volatile oil from A. gramineus on Alzheimer's disease (AD) mice, by means of behavior test, immunohistochemistry and western blot methods. In this study, mice were injected with Aβ1‐42 in the bilateral hippocampus to establish the AD model. On the seventh day after modeling, the mice with cognitive dysfunction were selected by the novel object recognition task. Subsequently, the volatile oil treatment groups underwent intragastric administration for per 10 g body weight 2.5 or 5 μL volatile oil from A. gramineus for 3 weeks. The control group and the AD group were given the same amount of saline. Our results showed that after treatment of volatile oil from A. gramineus, the number of Doublecortin and Nestin positive cells increased significantly, suggesting that the volatile oil from A. gramineus may induce the regeneration of hippocampal neurons in mice, and promote the growth of hippocampal neurons by upregulation of brain‐derived neurotrophic factor, tyrosine protein kinase B, and neurotrophin‐3 expression. These results might provide more experimental evidences for underlying mechanism about the neuroprotective effects of volatile oil from A. gramineus against AD relevant symptoms. Anat Rec, 302:2261–2270, 2019. © 2019 American Association for Anatomy
... Intra-hippocampal administration of A resulted in cognitive impairment in mice which was remarkably improved by A. gramineus via reducing A expression, doublecortin and nestin in the hippocampus. It has been found that the water extract and volatile oil fractions were more effective in the enhancement of spatial memory than defatted decoction fraction [33]. ...
... Zataria multiflora from the family Labiatae is traditionally known as "S atar" and is used for the treatment of neurodegenerative disorders in traditional Persian medicine. Majlessi et al. reported that essential oil of Z. multiflora could exhibit positive effects in A (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) induced AD in rats. The plant was able to improve cognitive deficit and memory function in Morris water maze behavioral test for AD [85]. ...
Background:
Neurodegenerative diseases are a progressive loss of structure and/or function of neurons. Weak therapeutic response and progressive nature of the diseases, as well as wide range of side effects caused by conventional therapeutic approaches, make patients seek for complementary and alternative medicine.
Objective:
The aim of present paper is to discuss the neuropharmacological basis of medicinal plants and their principle phytochemicals which have been used in traditional Persian medicine for different types of neurodegenerative diseases.
Results:
Medicinal plants introduced in traditional Persian medicine perform beneficial effects in neurodegenerative diseases via various cellular and molecular mechanisms including suppression of apoptosis mediated by the increase in expression of anti-apoptotic agents (e.g. Bcl-2) as well as the decrease in the expression and activity of pro-apoptotic proteins (e.g. Bax, caspase 3 and 9). Alleviating inflammatory responses and suppressing the expression and function of pro-inflammatory cytokines like Tumor necrosis factor α and interleukins, as well as improvement in antioxidative performance mediated by superoxide dismutase and catalase, are among other neuroprotective mechanisms of traditional medicinal plants. Modulation of transcription, transduction, intracellular signaling pathways including ERK, p38, and MAPK, with upstream regulatory activity on inflammatory cascades, apoptosis and oxidative stress associated pathways, play an essential role in preventive and therapeutic potential of the plants in neurodegenerative diseases.
Conclusions:
Medicinal plants used in traditional Persian medicine along with their related phytochemicals by affecting various neuropharmacological pathways can be considered as future drugs or adjuvant therapies with conventional pharmacotherapeutics; though, further clinical studies are necessary for confirmation of their safety and efficacy.
... Four CHMs promoted neurogenesis in AD animal models, and three of them improved the cognition of AD animals, but they had different effects on neurogenesis. Acori graminei rhizoma mainly acted on proliferation and differentiation (Ma et al., 2015), Rosmarinus officinalis mainly acted on differentiation (Mirza et al., 2021), and Cyperus rotundus mainly acted on maturation (Shakerin et al., 2020). In addition, Acori tatarinowii rhizoma (Mao et al., 2015) promoted the proliferation and maturation of neurogenesis in AD animal models, but its effect on cognition has not been shown. ...
Adult neurogenesis plays a crucial role in cognitive function and mood regulation, while aberrant adult neurogenesis contributes to various neurological and psychiatric diseases. With a better understanding of the significance of adult neurogenesis, the demand for improving adult neurogenesis is increasing. More and more research has shown that traditional Chinese medicine (TCM), including TCM prescriptions (TCMPs), Chinese herbal medicine, and bioactive components, has unique advantages in treating neurological and psychiatric diseases by regulating adult neurogenesis at various stages, including proliferation, differentiation, and maturation. In this review, we summarize the progress of TCM in improving adult neurogenesis and the key possible mechanisms by which TCM may benefit it. Finally, we suggest the possible strategies of TCM to improve adult neurogenesis in the treatment of neuropsychiatric disorders.
... One study summarized the drug use pattern of TCM formulas for AD treatment and found that 150 TCMs were used with 132 formulas, among which Acorus calamus var. angustatus Besser (Shichangpu) was the most frequently used TCM (Hu et al., 2012;Ma et al., 2015). ...
Neurodegenerative diseases (NDs) are common chronic disorders associated with progressive nervous system damage, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, among others. Mitochondria are abundant in various nervous system cells and provide a bulk supply of the adenosine triphosphate necessary for brain function, considered the center of the free-radical theory of aging. One common feature of NDs is mitochondrial dysfunction, which is involved in many physiopathological processes, including apoptosis, inflammation, oxidative stress, and calcium homeostasis. Recently, genetic studies revealed extensive links between mitochondrion impairment and dysregulation of non-coding RNAs (ncRNAs) in the pathology of NDs. Traditional Chinese medicines (TCMs) have been used for thousands of years in treating NDs. Numerous modern pharmacological studies have demonstrated the therapeutic effects of prescription, herbal medicine, bioactive ingredients, and monomer compounds of TCMs, which are important for managing the symptoms of NDs. Some highly effective TCMs exert protective effects on various key pathological features regulated by mitochondria and play a pivotal role in recovering disrupted signaling pathways. These disrupted signaling pathways are induced by abnormally-expressed ncRNAs associated with mitochondrial dysfunction, including microRNAs, long ncRNAs, and circular RNAs. In this review, we first explored the underlying ncRNA mechanisms linking mitochondrial dysfunction and neurodegeneration, demonstrating the implication of ncRNA-induced mitochondrial dysfunction in the pathogenesis of NDs. The ncRNA-induced mitochondrial dysfunctions affect mitochondrial biogenesis, dynamics, autophagy, Ca²⁺ homeostasis, oxidative stress, and downstream apoptosis. The review also discussed the targeting of the disease-related mitochondrial proteins in NDs and the protective effects of TCM formulas with definite composition, standardized extracts from individual TCMs, and monomeric compounds isolated from TCM. Additionally, we explored the ncRNA regulation of mitochondrial dysfunction in NDs and the effects and potential mechanisms of representative TCMs in alleviating mitochondrial pathogenesis and conferring anti-inflammatory, antioxidant, and anti-apoptotic pathways against NDs. Therefore, this review presents an overview of the role of mitochondrion-related ncRNAs and the target genes for TCM-based therapeutic interventions in NDs, providing insight into understanding the “multi-level compound-target-pathway regulatory” treatment mechanism of TCMs.
... Treatment with β-asarone was shown to improve cerebral metabolism and blood flow and to downregulate the mRNA expression of endothelin 1 in the hippocampus of AD rats [31]. Treatment with volatile oil fractions or water extracts of AG in Aβ1-42-injected mice was shown to ameliorate cognitive impairment and hippocampal neurogenesis via the upregulation of nestin and doublecortin in the hippocampus [32]. The extracts of AT and its major constituents, namely, α-asarone and β-asarone, have been shown to promote the proliferation of neural progenitor cells with activated extracellular signal-regulated kinase (ERK) in hippocampus-derived progenitor cells [33] and potentiate neuronal differentiation via nerve growth factor (NGF) in PC12 cells [34]. ...
Neurological disorders represent a substantial healthcare burden worldwide due to population aging. Acorus gramineus Solander (AG) and Acorus tatarinowii Schott (AT), whose major component is asarone, have been shown to be effective in neurological disorders. This review summarized current information from preclinical and clinical studies regarding the effects of extracts and active components of AG and AT (e.g., α-asarone and β-asarone) on neurological disorders and biomedical targets, as well as the mechanisms involved. Databases, including PubMed, Embase, and RISS, were searched using the following keywords: asarone, AG, AT, and neurological disorders, including Alzheimer's disease, Parkinson's disease, depression and anxiety, epilepsy, and stroke. Meta-analyses and reviews were excluded. A total of 873 studies were collected. A total of 89 studies were selected after eliminating studies that did not meet the inclusion criteria. Research on neurological disorders widely reported that extracts or active components of AG and AT showed therapeutic efficacy in treating neurological disorders. These components also possessed a wide array of neuroprotective effects, including reduction of pathogenic protein aggregates, antiapoptotic activity, modulation of autophagy, anti-inflammatory and antioxidant activities, regulation of neurotransmitters, activation of neurogenesis, and stimulation of neurotrophic factors. Most of the included studies were preclinical studies that used in vitro and in vivo models, and only a few clinical studies have been performed. Therefore, this review summarizes the current knowledge on AG and AT therapeutic effects as a basis for further clinical studies, and clinical trials are required before these findings can be applied to human neurological disorders.
... Studies have shown that ATT contains volatile oil, flavonoids, alkaloids, organic acids, and other components. The volatile oil is the most important active component and has a good curative effect in treating various diseases (Ma et al., 2015). Modern medicine shows that the volatile oil components of ATT have significant beneficial effects in treating cardiovascular diseases, Alzheimer's disease and depression. ...
Acorus calamus var. angustatus Besser (ATT) is a traditional herb with a long medicinal history. The volatile oil of ATT (VOA) does possess many pharmacological activities. It can restore the vitality of the brain, nervous system and myocardial cells. It is used to treat various central system, cardiovascular and cerebrovascular diseases. It also showed antibacterial and antioxidant activity. Many studies have explored the benefits of VOA scientifically. This paper reviews the extraction methods, chemical components, pharmacological activities and toxicology of VOA. The molecular mechanism of VOA was elucidated. This paper will serve as a comprehensive resource for further carrying the VOA on improving its medicinal value and clinical use.
... Evidence-Based Complementary and Alternative Medicine 7 preventing memory loss in old age [41] and reported to have a potential of neuroprotective effect and improved cognitive function [42,43]. Among the individual herbs for memory impairment, Acori Graminei Rhizoma is known to have a protective effect on cognitive impairment in animal studies [44,45]. In a randomized controlled trial comparing Chinese medicine and placebo for amnestic MCI patients, Polygalae Radix was the representative herb for tonifying the kidney and resolving phlegm and blood stasis formula for treating MCI in a randomized controlled trial [8]. ...
In Korea, patients with mild cognitive impairment can choose to receive treatment of Korean medicine, and Korean medicine hospitals provide specialized medical care for the prevention and management of cognitive disorders. The aim of the study is to explore the role of Korean medicine therapy for patients with mild cognitive impairment in a real clinical setting. Fifteen patients with amnestic mild cognitive impairment were enrolled in this prospective observational study in three Korean medicine hospitals. Korean medicine treatments were delivered by experienced professionals and not restricted to standardized treatment. Outcome measures were prospectively planned to examine the Korean-Montreal Cognitive Assessment (K-MoCA), Korean-Mini Mental State Examination (K-MMSE), and other detailed neuropsychological assessment at the baseline and after 12 and 24 weeks of treatment. Korean medicine treatment for MCI treatment in the real-world clinical setting included herbal medicine and acupuncture. The most frequently used herbs in herbal decoctions were Acori Graminei Rhizoma, Polygalae Radix, and Poria Sclerotium Cum Pini Radix. The herbal medicine formulae used in this study were classified into three categories: tonifying Qi (33.3%), tonifying kidney (46.7%), and calming liver (20%) formulae. In the cognitive ability assessment, the K-MoCA score significantly improved after treatment (mean difference 2.6; 95% CI: 1.3 to 3.9, ). The K-MMSE score slightly increased after treatment; however, the improvement was not statistically significant (mean difference 0.8; 95% CI: −0.5 to 2.0, ). In detailed neuropsychological assessment, the cognitive domains of executive functions and memory after the treatment were distinctively improved. In this prospective observational case series, we could see the real clinical environments of treating patients with mild cognitive impairment in Korean medicine hospitals. Patients treated with Korean medicine showed improved results in the neuropsychological assessment after 12 and 24 weeks.
1. Introduction
Mild cognitive impairment (MCI) is a transitional state between normal aging and early dementia. The diagnostic and statistical manual of mental disorders-5 (DSM-5) distinguishes mild neurocognitive disorder from major neurocognitive disorder. Mild neurocognitive disorder is defined by a noticeable decrement in cognitive functioning that goes beyond normal changes seen in aging but that does not interfere with the independence of the individual in relation to everyday activities [1–3]. MCI is clinically important, in that it elevates the risk of progression for dementia. In the elderly aged 65 or older, 46% of people with mild cognitive impairment develop dementia, while 3% of normal people develop dementia within 3 years [4]. Early detection of mild neurocognitive impairment and prevention of its progression may ease the burden of major neurocognitive disorder.
There is no recommended conventional treatment for MCI with sufficient evidence, and representatively, cholinesterase inhibitors did not show consistent effectiveness for MCI patients in the systematic review [1]. The need for effective therapies treating MCI is increasing, and the potential effectiveness of acupuncture and herbal medicine for MCI is receiving attention. Numerous studies have reported that acupuncture is effective in treating MCI and can be an alternative and adjunctive treatment for MCI patients [5–7]. There have been many randomized controlled trials [8–11] and systematic reviews [12–14] of Chinese herbal medicine for MCI treatment. Although the randomized controlled trial and systematic review are good strategies to provide high quality evidence with low risk of bias, they have some restrictions in reflecting the current healthcare environments. Studies exploring which treatment is applied in the real clinical setting, and which domain is improved after treatment, are also required for the purpose of reflecting reality.
In the South Korean healthcare system, patients with mild cognitive impairment can choose to receive the medical care of Korean traditional medicine for the prevention and management of cognitive disorders in the dual medical system of Western medicine and Korean medicine (KM) [15]. Most KM hospitals run dementia clinics by certified neuropsychiatrists of KM [16]. The integrative treatments used in the dementia clinic in KM hospitals include acupuncture, herbal medicine, and cupping therapy. Some public health centers in South Korea have an MCI management program using herbal medicines that showed successfully improved MCI symptoms [17].
To observe the variation in treatment options and patient-specific treatments, observational studies or pragmatic trials with no restriction on the treatment are needed. For this purpose, we designed a prospective, observational, case series to explore the effectiveness and real-world usage of KM for MCI patients.
2. Materials and Methods
2.1. Study Design
This study is a multicenter prospective observational case series conducted by three university KM hospitals. The names of the three hospitals are labelled in this report as A, B, and C hospitals, respectively. This study was conducted in accordance with the study protocol approved by the institutional review boards of Kyung Hee University Korean Medicine Hospital (KOMCIRB-150901-HR-036), Wonkwang University Sanbon Hospital (WMCSB 2016-51-1635), and Dunsan Korean Medicine Hospital of Daejeon University (DJDSKH-16-BM-13). Written informed consent was obtained from all participants before the procedures. The protocol was retrospectively registered with the clinical research information service (KCT0002322).
2.2. Participants
Eligible patients were recruited in three KM university hospitals in the outpatient setting from December 07, 2016, to March 29, 2017. The inclusion criteria included that patients met the Petersen diagnostic criteria of MCI [18], were aged from equal to or more than 45 years of age, and agreed to participate with written informed consent. The following patients were excluded: (1) history of cognitive impairment due to any other causes (for example, head trauma or brain injury); (2) brain disorders including Parkinson’s disease, Huntington’s Disease, normal pressure hydrocephalus, or brain tumor; (3) cardiovascular disease, endocrinopathy, or gastrointestinal tract disorders not controlled by diet therapy and drug treatment; (4) diabetic not controlled by hypoglycemic agents or insulin; (5) seriously unstable medical condition; (6) severe kidney disease or liver disease; (7) anemia, hypothyroidism, vitamin deficiencies, or malignancy; (8) any history of drug or alcohol dependence during the past 6 months; (9) history of major psychiatric disorders, such as schizophrenia, delusional disorder, depression, bipolar disorder alcohol, or substance abuse disorders; (10) involved in other clinical trials within 4 weeks; (11) pregnant, breastfeeding, or inadequate contraception; (12) mental retardation, emotional, or intellectual problems and difficulty in understanding the research; (13) blindness, hypacusis, or dysphonia; (14) not eligible for the clinical research in accordance with the researcher’s judgement.
2.3. Procedures
All patients received KM treatment by experienced professionals in three university hospitals. Because the aim of the study was to observe the real clinical setting in a KM hospital, interventions were not restricted to a fixed protocol, and the clinicians in the three university hospitals were free to choose treatment options for patients with MCI. The applied treatment details, including the composition of the prescribed herbal formula and the acupuncture points, were recorded in detail at every visit. To determine the effectiveness of the KM treatment, an evaluation method was prospectively planned. Patients received fixed neuropsychological assessment battery at the baseline and at the 12th and 24th week of treatment.
2.4. Outcome Measurement
The Korean-Montreal Cognitive Assessment (K-MoCA) [19, 20] and Korean-Mini Mental State Examination (K-MMSE) [21, 22] were examined at the baseline and after the 12 and 24 weeks of treatment. For the detailed neuropsychological assessment, Seoul neuropsychological screening battery (SNSB) was also done on the same day. SNSB is composed of five domains: attention, language and related functions, visuospatial functions, memory, and frontal/executive functions [23, 24]. Digit span test (DST) for the attention domain [25], Korean-Boston Naming Test (K-BNT) for the language domain [26], Rey Complex Figure Test (RCFT) [27], and Seoul Verbal Learning Test (SVLT) [28] for the visuospatial domain and the memory domain, respectively, Contrasting Program and Go-No-Go Test for the frontal function, and Korean-Color Word Stroop Test (K-CWST) [29] and Controlled Oral Word Association Test (K-COWAT) [30] for the executive function domain are included in the battery.
2.5. Safety Assessment
For safety assessment, every adverse event was carefully documented during the study, and the laboratory parameters related to liver function (aspartate aminotransferase, alanine aminotransferase, and total bilirubin), kidney function (blood urea nitrogen and creatinine), and thyroid function (thyroid stimulating hormone and free thyroxine) were analyzed by the blood test at the baseline and at the 12th and 24th week of treatment.
2.6. Statistical Analysis
Data are shown in mean ± standard deviation. Depending on the normality of the data, a paired t-test or Wilcoxon signed rank test was used to evaluate the efficacy of the KM treatment for patients with MCI. The Shapiro–Wilk normality test was done to test the normality of the data. A -value of less than 0.05 was considered to represent statistical significance. The software used for all the statistical analyses was R version 3.6.0. Network analysis and visualization of the frequently used herbs in decoctions were also done using the software R version 3.6.0. Association rule mining was used to score the support between herbs with the arules, the R extension package [31]. Then, network visualization was done with the igraph, another extension package of R, with nodes for each herb and edges for the associations between herbs. We also conducted community detection, which can distinguish groups according to the density of connection, by the Newman–Girvan algorithm [32, 33].
3. Results
3.1. Baseline Characteristics
Twenty-two participants were screened for eligibility, and fifteen patients diagnosed with MCI were included from the three KM universities. The patients visited hospital every two weeks, to be prescribed herbal medicine. Some patients had additional visits for acupuncture treatment. Among the total of 15 patients, 80% were women and 20% were men. The mean age and education level were 64.5 ± 10.0 and 8.3 ± 3.2 years, respectively. The type of MCI was amnestic MCI in all participants based on Peterson’s criteria [34] of having a memory complaint and objective memory impairment for the patient’s age. The average K-MoCA score was 19.7 ± 3.6, and the K-MMSE score was 25.9 ± 2.4. In a previous study of MCI patients conducted in Korea [35], the average K-MoCA score was 18.5 ± 3.7 and the average K-MMSE score was 24.0 ± 2.9, which were similar to the results of our study. The demographical distribution and baseline neuropsychological assessment score of patients were similar among the three hospitals (Table 1). Five patients terminated their treatment between 12 and 24 weeks of treatment for personal reasons. Figure 1 shows the flow chart outlining the study design.
A hospital (n = 8)
B hospital (n = 2)
C hospital (n = 5)
Total (n = 15)
value
Age
65.6 ± 6.3
49.0 ± 0.0
68.8 ± 11.5
64.5 ± 10.0
0.738
Female, % (n)
87.5 (7)
50 (1)
80 (4)
80.0 (12)
0.495
Education level
8.5 ± 1.9
10.5 ± 1.4
7.2 ± 3.4
8.3 ± 3.2
0.324
K-MoCA
18.6 ± 2.3
23.5 ± 0.7
20.0 ± 5.1
19.7 ± 3.6
0.441
K-MMSE
24.9 ± 2.3
28.0 ± 1.4
26.6 ± 2.3
25.9 ± 2.4
0.176
SGDS
6.4 ± 4.3
4.0 ± 0.0
4.2 ± 3.3
5.3 ± 3.7
0.296
B-ADL
19.9 ± 0.4
20 ± 0.0
19.8 ± 0.4
19.9 ± 0.4
0.777
K-IADL
2.2 ± 1.5
2.0 ± 1.4
2.4 ± 3.7
2.3 ± 2.3
0.925
Values are expressed as mean ± standard deviation. K-MoCA, Korean-Montreal Cognitive Assessment; K-MMSE, Korean-Mini Mental State Examination; SGDS, Short version of the Geriatric Depression Scale; B-ADL, Barthel-Activities of Daily Living; K-IADL, Korean-Instrumental Activities of Daily Living.
... Moreover, treatment with essential oil derived from Acori Graminei Rhizoma improved learning and memory in aged rats and mice [3]. In traditional Chinese and Korean medicine, Acori Graminei Rhizoma is used as a therapeutic agent for dementia, stroke, eczema, and indigestion [4]. Previous studies of Acori Graminei rhizome reported some phenolic compound including -asarone and -asarone, which were closely associated with antiinflammatory effect [5][6][7]. ...
The dry rhizome of Acorus gramineus Solander, known as Acori Graminei Rhizoma, is used to treat dementia, stroke, eczema, and indigestion in traditional Chinese medicine, traditional Korean medicine, and traditional Japanese Kampo medicine. Previous studies have reported that Acori Graminei Rhizoma extract ameliorated cognitive impairment in A β 1-42 injected mice. However, the effect of Acori Graminei Rhizoma on type II collagen induced arthritis (CIA) has not been elucidated. Thus, we evaluated the water extract of Acori Graminei Rhizoma (WAG) in CIA mice models. Male DBA/1 mice were separated into five groups (NOR; n=10, CON; n=10, CIA + methotrexate (MTX); n=10, CIA + 100 mg/kg WAG; n=10, CIA + 500 mg/kg WAG; n=10). CIA was induced by injecting the mice with bovine type II collagen, after which the mice were treated with WAG and/or MTX. Hematological parameters and liver and kidney serum toxicity markers were analyzed. Further, serum levels of interleukin (IL)-6, TNF- α , and type II collagen IgG were analyzed via enzyme-linked immunosorbent assay (ELISA). Treatment with 500 mg/kg WAG decreased serum levels of IL-6, TNF- α , and collagen IgG in a CIA model. Moreover, WAG treatment decreased CIA-induced swelling of mouse hind legs, infiltration of inflammatory cells into the synovial membrane, and blood neutrophil levels. WAG administration did not influence hematological parameters or kidneys and liver toxicity markers. WAG may be used to treat arthritis by reducing the inflammation indicators. However, further experiments are required to determine how WAG affects inflammation mechanisms in vitro and in vivo .
... [11][12][13][14]. 더욱이 asarone은 혈관-뇌 장벽 (blood-brain barrier)을 통과할 수 있으며 [15], 특히 α-asarone은 해마와 관자엽 피질에서 과산화질소 과다생성을 억제하여 β-am-yloid에 의한 신경독성 및 공간기억장애에 보호 효과를 보 인다 [12]. ...
... The roots of AGR were purchased from Haozhou Yucheng market of traditional Chinese herbal medicines Co. Ltd., (Anhui, China). The water extract of AGR acquired according to the method of Ma et al. [24]. Briefly, the 200 g dried roots of AGR were grinded into powder and dissolved into 2 L of sterile distilled water for 1 h, then refluxed for another 1 h. ...
Alzheimer’s disease (AD) severely threatens human health in their old age, however the potential etiology underlying it is still unclear. Both Ginsenoside Rg1 (GRg1) and Acori graminei Rhizoma (AGR) are the traditional Chinese herbal drug, while their potential role in AD remains need further identification. Both SAMP1 and SAMP8 mice were employed as the control and AD mice. Morris water maze method was used to detect the cognitive function of the mice, TUNEL assay was performed to determine cell apoptosis. Real-time PCR and western blot were carried out to measure gene expression. The relationship between miR-873-5p and HMOX1 was determined using luciferase reporter assay. Comparing with SAMP1, the cognitive function was impaired and cell apoptosis was increased in SAMP8 mice. GRg1 + AGR treatment significantly attenuated the symptom of AD. The expression of miR-873-5p was decreased, while HMOX1 was increased in SAMP8 mice. GRg1 + AGR treatment significantly promoted the expression of miR-873-5p, but decreased HMOX1. MiR-873-5p targets HMOX1 to regulate its expression. Aβ1–42 stimulation decreased the expression of miR-873-5p, but increased HMOX1 in PC12 cells. GRg1 + AGR treatment reversed the effect of Aβ1–42, while miR-873-5p inhibitor abolished the effect of GRg1 + AGR. In vivo experiments confirmed the protect role of GRg1 + AGR in AD. GRg1 + AGR suppressed neuron cell apoptosis by regulating the expression of miR-873-5p in AD.
... Nerve injury and neurotoxicity prevent DCX expression (Ko et al., 1999). However, nerve injury can cause increased DCX expression (Ma et al., 2015). Therefore, it is likely that different protection mechanisms deal with distinct types of damage. ...
Previous studies have demonstrated a neuroprotective effect of extract of Ginkgo biloba against neuronal damage, but have mainly focused on antioxidation of extract of Ginkgo biloba. To date, limited studies have determined whether extrasct of Ginkgo biloba has a protective effect on neuronal damage. In the present study, acrylamide and 30, 60, and 120 mg/kg extract of Ginkgo biloba were administered for 4 weeks by gavage to establish mouse models. Our results showed that 30, 60, and 120 mg/kg extract of Ginkgo biloba effectively alleviated the abnormal gait of poisoned mice, and up-regulated protein expression levels of doublecortin (DCX), brain-derived neurotrophic factor, and growth associated protein-43 (GAP-43) in the hippocampus. Simultaneously, DCX- and GAP-43-immunoreactive cells increased. These findings suggest that extract of Ginkgo biloba can mitigate neurotoxicity induced by acrylamide, and thereby promote neuronal regeneration in the hippocampus of acrylamide-treated mice.
... ATR, AGR, and ACR are well-known traditional medicines for treating CNS-related disorders. All these herbs are reported to be responsible for various CNS pharmacological disorders, such as epilepsy, cerebrovascular diseases, and Alzheimer's disease (Zhang et al., 2007;Liu et al., 2010;Han et al., 2013;Ma et al., 2015). The previously mentioned three Acorus species were easily being confused in the herbal market due to similar morphologies. ...
Acori Tatarinowii Rhizoma (ATR), the rhizome of Acorus tatarinowii Schott, is a common traditional Chinese medicine being used clinically for mental disorder. However, other Acorus species herbs are all having the same Chinese name 'Chang Pu', making the confusion in herbal market. Acori Graminei Rhizoma (AGR) and Acori Calami Rhizoma (ACR) are common adulterants of ATR. Here, we aim to provide a comparative analysis between ATR, AGR, and ACR in potentiating neuronal differentiation. Volatile oil, derived from Acorus species, was applied onto cultured PC12 cells, and various parameters were determined: (i) transcriptional activation of neurofilament promoters was determined by the promoter-driven luciferase activity assay; (ii) the neurite outgrowth of PC12 cells was captured and measured; and (iii) the neurofilament expression and its underlying mechanism were analyzed by western blotting. The co-treatment of ATR, AGR, or ACR volatile oil with low concentration of nerve growth factor (NGF) could potentiate the NGF-induced neuronal differentiation in cultured PC12 cells. In addition, application of protein kinase A inhibitor H89 in cultures blocked the induction of neurofilament. Among these three Acorus species, ATR volatile oil showed the highest NGF-induced induction in neurite outgrowth and neurofilament expression, as compared with that of AGR and ACR. Copyright © 2017 John Wiley & Sons, Ltd.
... Acori graminei rhizoma commontly known as dwarf sedge, is one of the best-known Asian traditional herbal medicine frequently used against stroke, cardiovascular diseases and senile dementia [319,320]. For this plant, there are limited information regarding its chemical constituents. ...
Brain ischemia-reperfusion injury is a complex pathological condition that involves a cascade of events like excitotoxicity, peri-infarct depolarization, oxidative/nitrosative stress, inflammation, apoptosis, necrosis and autophagic degeneration. Since the past decades, researchers have provided significant information about the therapeutic potential and possible mechanism of action of plant extracts and derived chemicals to target multiple pathways of the ischemic cascade. Here, we summarized experimental, clinical and epidemiological therapeutic interventions of plants extracts and phytochemicals against brain ischemia-reperfusion injury. Whether oxidative stress is the cause or consequence of brain ischemia is open for debate but details about oxidative burden and inflammation following brain ischemia are also described. Furthermore, the antioxidant mechanism of these extracts/phytochemicals was reviewed. Although these plant extracts and phytochemicals showed the ability to act on the multiple steps of the ischemic cascade in in vitro and in vivo models of brain ischemia, further investigations are needed for their validation and for the development of new drugs.
... In our continuous drug discovery for a potent natural agent that can mitigate neuroinflammation, we found a-asarone (trans-1-propenyl-2,4,5-trimethoxy-benzene), a chemical constituent found in roots, rhizomes and the bark of diverse plants such as Araceae and Annonaceae species. It is an active constituent of Acorus gramineus Solander rhizome (AGR) used to treat senile dementia (Lin et al., 2012;Ma et al., 2015) and was claimed traditionally in East Asian countries to possess sedative, digestive, analgesic, diuretic and antifungal activities. Apart from its traditional claims, scientific reports showed that AGR can be used as neuroprotective (Jiang et al., 2012;Limon et al., 2009;Manikandan and Devi, 2005), antiamnesic , anticonvulsant (Pages et al., 2010) and hyperlipidemic agent (Garduno et al., 1997). ...
Several plants are recognized as asarone rich plants. As a bioactive compound, asarone has benefits is to treat infectious diseases. The aims of this review are to compile information from previous articles on the antifungal and antibacterial activities of asarone rich herbal materials. Several plants are good source for asarone, namely Acorus calamus, Acorus gramineus, Eusideroxylon zwageri, Perilla frutescens, Piper cubeba, Pycnocycla spinose and Sphallerocarpus gracilis. Ethyl acetate extracts/fractions have good antifungal activity followed by essential oil. Candida albicans and many filamentous fungi can be inhibited by ethyl aceate extract and essential oils from asarone rich herbal materials. Only essential oils, not ethyl acetate extract, are good in inhibition either Gram negative or Gram positive bacteria. Isolated asarone also shows antimicrobial activity. The asarone content in the extract depends on the polarity of the solvent. The nonpolar extract trends to have higher asarone than the polar. It can be concluded that the essential oils from asarone rich herbal material have good inhibitory activity against pathogenic yeast/fungal and bacteria. The ethyl acetate extract is only effective in inhibition of pathogenic yeast or filamentous fungi.
Quercetin is one of the most abundant dietary flavonoid compounds, and its mechanism for combating age-related neurodegenerative diseases is unclear. In this study, quercetin (35 and 70 mg kg⁻¹, orally administered for 4 weeks) was administered to 7-month-old aging mice (senescence-accelerated mouse prone 8 mice). As a result, it was found that quercetin could improve spatial learning and memory impairment displayed by aging mice in the Morris water maze. The results of immunoblotting reflected the protein expressions of the longevity factor (sirtuin1), inflammasomes (NLRP3 and ASC), synaptic marker (PSD95) and neurotrophic factors (BDNF and NGF) in the hippocampus of the brain. It indicated that the intervention of quercetin could increase the expression of sirtuin1 and prevent neuroinflammation, which was evident from the decrease in the protein levels of the astrocyte marker (GFAP) and inflammatory factors (cleaved-caspase 1, IL-1β and IL-18). In addition, quercetin could reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in the hippocampus of aging mice. Current data indicated that quercetin might improve neuroinflammation in aging mice by regulating the Sirtuin1/NLRP3 pathway.
Ethnopharmacological relevance
Cognitive symptom is a “core” symptom of major depressive disorder (MDD) patients with clear deficit in memory, social and occupational function, and may persist during the remitting phase. Therefore, the remission of cognitive symptom has been considered as one of the main objectives in the treatment of MDD. Herbal antidepressants have been used to treat MDD, and there has been great advances in the understanding of the ability of these herbs to improve cognitive deficit linked to brain injury and various diseases including depression, Alzheimer disease, diabetes and age-related disorders. This systematic review summarizes the evidence from preclinical studies and clinical trials of herbal antidepressants with positive effects on cognitive deficit. The potential mechanisms by which herbal antidepressants prevent cognitive deficit are also reviewed. This review will facilitate further research and applications.
Materials and methods
We conducted an open-ended, English restricted search of MEDLINE (PubMed), Web of Science and Scopus for all available articles published or online before 31 December 2019, using terms pertaining to medical herb/phytomedicine/phytochemical/Chinese medicine and depression/major depressive disorder/antidepressant and/or cognitive impairment/cognitive deficit/cognitive dysfunction.
Results
7 prescriptions, more than 30 individual herbs and 50 phytochemicals from China, Japan, Korea and India with positive effects on the depressive state and cognitive deficit are reviewed herein. The evidence from preclinical studies and clinical trials proves that these herbal antidepressants exhibit positive effects on one or more aspects of cognitive defect including spatial, episodic, aversive, and short- and long-term memory. The action mode of the improvement of cognitive deficit by these herbal antidepressants is mediated mainly through two pathways. One pathway is to promote hippocampal neurogenesis through activating brain derived neurotrophic factor-tropomyosin-related kinase B signaling. The other pathway is to prevent neuronal apoptosis through the inhibition of neuro-inflammation and neuro-oxidation.
Conclusion
These herbal antidepressants, having potential therapy for cognitive deficit, may prevent pathological processes of neurodegenerative diseases. Furthermore, these herbal medicines should provide a treasure trove, which will accelerate the development of new antidepressants that can effectively improve cognitive symptom in MDD. Studies on their molecular mechanisms may provide more potential targets and therapeutic approaches for new drug discovery.
In recent years, as the infertility rate in China has been increasing year by year and semen quality decreasing, male reproductive toxicity of drugs attracts more and more attention. There are many factors that cause male reproductive toxicity, among which Chinese materia medica is an important aspect. This article will introduce the male reproductive toxicity of Chinese materia medicas grouped by different effectivenesses such as immunosuppressant, evacuant, diuretic, cardiotonic, anti-infective drug and analgesic.
Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and subsequently deposition of amyloid beta (Aβ) within the brain. The immune cells of brain migrate to and invest their processes within Aβ plaques and clear plaques from the brain. Previous studies have shown that treatment of myeloid cell with nuclear factor inhibitor increases expression of phagocytesis-related genes, such as triggering receptor expressed on myeloid cells 2 (TREM2). In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation as well as inflammatory response in vitro. The purpose of this study was to further investigate microglial proliferation, phagocytosis and the expression of brain derived neurotrophic factor (BDNF) induced by up-regulation of TREM2 in Aβ1–42 injected mice. We first singly injected Aβ1–42 into the hippocampus of mice to build the model of AD-like symptoms. Subsequently, ammonium pyrrolidinedithiocarbamate (PDTC) was injected into the lateral ventricle of mice. Various immunohistochemical techniques and Western blot analyses were applied to examine expressions of TREM2, microglia, Aβ, Neuronal migration protein doublecortin (DCX) and BDNF in the hippocampus of mice. In the present study, we found the plaques-associated microglia lowly expressed TREM2 and BDNF in Aβ1–42 intra-hippocampal injected mice. Treatment of the models with a nuclear factor inhibitor, PDTC, further induced the expression of TREM2 and enhanced microglial phagocytosis, coincident with the rapid reduction in plaque burden. The expression of BDNF was up-regulated and the expression of DCX was partly restored. This means that up-regulation of TREM2 might induce the microglia to express the BDNF. These findings further indicate that the level of TREM2 may affect the microglia response to pathological process induced by Aβ.
Background:
Fangjiang decoction is a Traditional Chinese Medicine that exhibits anticonvulsive effects in treating febrile seizures (FS). Its action mechanism and the regulation on AKT/mTOR pathway were revealed in this study.
Methods:
FS model was established in SD rats with or without Fangjing Decoction treatment. On day 5 following initiation of drug treatment, seizures were monitored. Hippocampal neuron apoptosis was assessed using terminal dUTP nick end-labeling (TUNEL) method. The levels of Bax, Akt, p-Akt, m-TOR and p-mTOR protein were analyzed using Western blotting. The content of hippocampal γ-aminobutyric acid (GABA) was measured by using ELISA assay.
Results:
Compared with the control group (n=8), Fangjing Decoction effectively shortened escape latency and duration of FS and decreased the frequency of FS in rats (n=8). Concomitantly, the apoptosis of hippocampal neurons, as well as Bax protein levels were also decreased in FS rats which were treated with Fangjing Decoction. In addition, the Akt/mTOR signaling was found to be activated in rat hippocampus following FS, as evidenced by increased p-Akt and p-mTOR, while Fangjing Decoction could inhibit the activation of Akt/mTOR signaling. Furthermore, the low GABA content in rat hippocampu following FS was significantly elevated by Fangjing Decoction treatment. More importantly, SC79, a specific activator for Akt, apparently attenuated the protective effects of Fangjing Decoction on FS rats.
Conclusion:
These results suggest that Fangjing Decoction protects the hippocampal neurons from apoptosis by inactivating AKT/mTOR pathway, which may contribute to mitigating FS-induced brain injury.
Cognitive deficits and behavioral and psychological symptoms of dementia (BPSD) are typical features of patients with dementia such as Alzheimer's disease (AD), vascular dementia (VD), and other forms of senile dementia. Clinical evidence has demonstrated the potential usefulness of chotosan (CTS) and yokukansan (YKS), traditional herbal formulations called Kampo medicines, in the treatment of cognitive disturbance and BPSD in dementia patients, although the indications targeted by CTS and YKS in Kampo medicine differ. The availability of CTS and YKS for treating dementia patients is supported by preclinical studies using animal models of dementia that include cognitive/emotional deficits caused by aging and diabetes, dementia risk factors. These studies have led not only to the concept of a neuronal basis for the CTS- and YKS-induced amelioration of cognitive function and emotional/psychiatric symptom-related behavior in animal models, but also to a proposal that ingredient(s) of Uncariae Uncis cum Ramulus, a medicinal herb included in CTS and YKS, may play an important role in the actions of these formulae in dementia patients. Further studies are needed to clarify the active ingredients of these formulae and their target endogenous molecules implicated in the anti-dementia drug-like actions.
Background
Egyptians recognized the healing power of herbs and used them in their medicinal formulations. Nowadays, “Attarin” drug shops and the public use mainly the Unani medicinal system for treatment of their health problems including improvement of memory and old age related diseases. Numerous medicinal plants have been described in old literature of Arabic traditional medicine for treatment of Alzheimer’s disease (AD) (or to strengthen memory).
Methods
In this study, some of these plants were evaluated against three different preliminary bioassays related to AD to explore the possible way of their bio-interaction. Twenty three selected plants were extracted with methanol and screened in vitro against acetylcholinesterase (AChE) and cycloxygenase-1 (COX-1) enzymes. In addition, anti-oxidant activity using DPPH was determined.
Results
Of the tested plant extracts; Adhatoda vasica and Peganum harmala showed inhibitory effect on AChE at IC50 294 μg/ml and 68 μg/ml respectively. Moreover, A. vasica interacted reversibly with the enzyme while P. harmala showed irreversible inhibition. Ferula assafoetida (IC50 3.2 μg/ml), Syzygium aromaticum (34.9 μg/ml) and Zingiber officinalis (33.6 μg/ml) showed activity against COX-1 enzyme. Potent radical scavenging activity was demonstrated by three plant extracts Terminalia chebula (EC50 2.2 μg/ml), T. arjuna (3.1 μg/ml) and Emblica officinalis (6.3 μg/ml).
Conclusion
Interestingly, differential results have been obtained which indicate the variability of the mode of actions for the selected plants. Additionally, the reversible interaction of A. vasica against AChE and the potent activity of F. assafoetida against COX-1 make them effective, new and promising agents for treatment of AD in the future, either as total extracts or their single bioactive constituents.
To investigate the effect of Bushenyisui Formula on cell apoptosis and positive B cell lymphoma (Bcl-2) in the Brain of rat models of Alzheimer's disease (AD) induced by beta-amyloid protein (Abeta) and the mechanism underlying the effect.
Total of 40 SD rats, 20 females and 20 males, were randomly assigned to 4 groups, controlled group (A), model group (B), conventional treatment group (C) and Bushenyisui Formula treatment (BYFT) group (D), 10 rats in each group. Abeta 1-42 was injected into the bilateral hippocampus of the rats in group B, C and D to create the models of AD. Sham operation was performed on the rats of group A in the same way by injecting equal volume of 0.9% sodium chloride solution into their bilateral hippocampus. 5 days after operation, Bushenyisui Formula was intraperitoneally administered at a dose of 450 mg/kg to the rats of group D (QD) for 20 days. Equal volume of 0.9% sodium chloride solution was intraperitoneally injected into the rats of group B with the same procedure. C suspension (20 mg/mL) was intraperitoneally injected into the rats of group B with the same procedure. The number of apoptotic cells in Brain and the positive Bcl-2 were counted. The changes of learning and memory abilities were evaluated using Y-maze.
Right after the establishment of the models, group B, C and D compared to group A respectively, the outcomes of Y-maze were significantly different from that of group A, which suggested obvious learning and memory disorder in those groups (P < 0.01). After treatment, the times of electronic shocks of group C and D were significantly less than that of group B (P < 0.05), and the numbers of apoptotic cells and positive Bcl-2 were significantly different from those of group B, apoptotic sells' number of group C and D smaller than that of group B and the number of positive Bcl-2 greater than that of group B.
Bushenyisui Formula could increase the number of Bcl-2 in brain, which improved the function of nervous system pertaining to learning and memory abilities.
Background:
This multicentre open-label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies.
Methods:
Sixty-three dementia with Lewy bodies patients with probable BPSD (M:W, 30:33; mean age, 78.2±5.8 years) were enrolled and treated with YKS for 4 weeks.
Results:
Significant improvements in Neuropsychiatric Inventory scores (mean decrease, 12.5 points; P<0.001) and Zarit Burden Interview-Japanese edition tests (mean decrease, 3.6 points; P=0.024) were observed. In patients who consented to an assessment after 2 weeks of treatment, a time-dependent significant improvement was observed in the Neuropsychiatric Inventory score (n=23; mean decrease, 14.4; P<0.001), each subscale, including delusions and hallucinations, the Zarit Burden Interview-Japanese edition (n=22; mean decrease, 8.2; P<0.01) and the behavioural pathology in Alzheimer's disease insomnia subscale. The Mini-Mental State Examination and the Disability Assessment for Dementia (DAD) showed no significant change. Adverse events were observed in 11 (18%) patients. Three patients (5%) discontinued YKS due to adverse reactions, namely, spasticity and exacerbation of BPSD, edema, and nausea. Hypokalaemia (<3.5 mEq/L) was present in four patients (6%) at the study endpoint. Worsening of extrapyramidal symptoms was not observed.
Conclusion:
YKS improved BPSD in dementia with Lewy bodies patients and caregiver burden scores without deterioration in cognitive function. YKS is useful for the treatment of delusions and hallucinations in BPSD.
Glial fibrillary acidic protein (GFAP) is the main astrocytic intermediate filament (IF). GFAP splice isoforms show differential expression patterns in the human brain. GFAPδ is preferentially expressed by neurogenic astrocytes in the subventricular zone (SVZ), whereas GFAP(+1) is found in a subset of astrocytes throughout the brain. In addition, the expression of these isoforms in human brain material of epilepsy, Alzheimer and glioma patients has been reported. Here, for the first time, we present a comprehensive study of GFAP isoform expression in both wild-type and Alzheimer Disease (AD) mouse models. In cortex, cerebellum, and striatum of wild-type mice, transcripts for Gfap-α, Gfap-β, Gfap-γ, Gfap-δ, Gfap-κ, and a newly identified isoform Gfap-ζ, were detected. Their relative expression levels were similar in all regions studied. GFAPα showed a widespread expression whilst GFAPδ distribution was prominent in the SVZ, rostral migratory stream (RMS), neurogenic astrocytes of the subgranular zone (SGZ), and subpial astrocytes. In contrast to the human SVZ, we could not establish an unambiguous GFAPδ localization in proliferating cells of the mouse SVZ. In APPswePS1dE9 and 3xTgAD mice, plaque-associated reactive astrocytes had increased transcript levels of all detectable GFAP isoforms and low levels of a new GFAP isoform, Gfap-ΔEx7. Reactive astrocytes in AD mice showed enhanced GFAPα and GFAPδ immunolabeling, less frequently increased vimentin and nestin, but no GFAPκ or GFAP(+1) staining. In conclusion, GFAPδ protein is present in SVZ, RMS, and neurogenic astrocytes of the SGZ, but also outside neurogenic niches. Furthermore, differential GFAP isoform expression is not linked with aging or reactive gliosis. This evidence points to the conclusion that differential regulation of GFAP isoforms is not involved in the reorganization of the IF network in reactive gliosis or in neurogenesis in the mouse brain.
After peripheral nerve injury, the number of sensory neurons in the adult dorsal root ganglia (DRG) is initially reduced but recovers to a normal level several months later. The mechanisms underlying the neuronal recovery after injury are not clear. Here, we showed that in the DRG explant culture, a subpopulation of cells that emigrated out from adult rat DRG expressed nestin and p75 neurotrophin receptor and formed clusters and spheres. They differentiated into neurons, glia, and smooth muscle cells in the presence or absence of serum and formed secondary and tertiary neurospheres in cloning assays. Molecular expression analysis demonstrated the characteristics of neural crest progenitors and their potential for neuronal differentiation by expressing a set of well-defined genes related to adult stem cells niches and neuronal fate decision. Under the influence of neurotrophic factors, some of these progenitors gave rise to neuropeptide-expressing cells and protein zero-expressing Schwann cells. In a 5-bromo-2′-deoxyuridine chasing study, we showed that these progenitors likely originate from satellite glial cells. Our study suggests that a subpopulation of glia in adult DRG is likely to be progenitors for neurons and glia and may play a role in neurogenesis after nerve injury.
Disclosure of potential conflicts of interest is found at the end of this article.
The aim of this review is to summarize current knowledge on nestin expression in human tumors and corresponding tumor cell lines. Nestin belongs to class VI of the intermediate filaments and it is expressed primarily in mammalian nervous tissue during embryonic development. In adults, nestin occurs only in a small subset of cells and tissues. This protein has been observed in the subventricular zone of the adult mammalian brain, where neurogenesis is localized. Nestin expression has also been detected in various types of human solid tumors, as well as in the corresponding established cell lines. This article provides an up-to-date overview of tumors in which nestin has been found. Another aim of this review is to summarize recent findings on the intracellular localization of nestin in human tumor cells, especially with regard to the possible correlation between nestin expression and the malignant phenotype of transformed cells. Nestin expression in vascular endothelial cells during angiogenesis is also reviewed. Special attention is paid to the detection of nestin in cancer stem cells because this protein, together with the CD133 surface molecule, is considered to be a possible marker of cancer stem cells, especially in tumors of neuroectodermal origin.
Synapse loss is an early and invariant feature of Alzheimer's disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid beta-protein (Abeta) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Abeta are mediators of synaptic compromise. We also discuss the possible mechanisms of Abeta synaptotoxicity and potential targets for therapeutic intervention.
Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme for the biosynthesis of catecholamines that are considered to be involved in a variety of neuropsychiatric functions. Here, we report behavioral and neuropsychological deficits in mice carrying a single mutated allele of the TH gene in which TH activity in tissues is reduced to approximately 40% of the wild-type activity. In the mice heterozygous for the TH mutation, noradrenaline accumulation in brain regions was moderately decreased to 73-80% of the wild-type value. Measurement of extracellular noradrenaline level in the frontal cortex by the microdialysis technique showed a reduction in high K(+)-evoked noradrenaline release in the mutants. The mutant mice displayed impairment in the water-finding task associated with latent learning performance. They also exhibited mild impairment in long-term memory formation in three distinct forms of associative learning, including active avoidance, cued fear conditioning, and conditioned taste aversion. These deficits were restored by the drug-induced stimulation of noradrenergic activity. In contrast, the spatial learning and hippocampal long-term potentiation were normal in the mutants. These results provide genetic evidence that the central noradrenaline system plays an important role in memory formation, particularly in the long-term memory of conditioned learning.
We injected a combination of the beta-amyloids (Abetas) Abeta40 and Abeta43 to "seed" formation of amyloid deposits in the dorsal dentate gyrus of rats in vivo, on the basis of a theory of Jarrett and Landsbury (1993). Rats were tested on several different learning tasks, and synaptic transmission and plasticity were assessed in vivo. Between 7 and 16 weeks after injection, we found aggregated amyloid material, reactive astrocytosis, microgliosis, and cell loss around the sites of injection. Rats were impaired specifically in working memory type tasks in accordance with the type of memory deficit observed in the early stages of Alzheimer's disease. Synaptic transmission and long-term potentiation, a candidate cellular mechanism for memory, were severely impaired in vivo. Injections of the same dose of fragments individually did not induce these effects. These findings suggest that aggregated amyloid material induces cognitive deficits similar to those observed in the early phases of Alzheimer's disease via an alteration in neuronal transmission and plasticity.
Acori graminei Rhizoma is one of the best-known traditional herbal medicines frequently used for the treatment of cardiovascular symptoms in Asian countries. The anti-ischemic effect of Acori graminei Rhizoma on ischemia-induced isolated rat heart was investigated through analysis of changes in perfusion pressure, aortic flow, coronary flow, and cardiac output. The subjects in this study were divided into two groups, an ischemia-induced group without any treatment (I), and an ischemia-induced group with Acori graminei Rhizoma treatment (I+AGR). There were no significant differences in perfusion pressure, aortic flow, coronary flow, or cardiac output between the two groups before ischemia was induced. The supply of oxygen and buffer was stopped for 10 min to induce ischemia in isolated rat hearts, and Acori graminei Rhizoma was administered while inducing ischemia. The data showed that Acori graminei Rhizoma treatment significantly prevented decreases in perfusion pressure, aortic flow, coronary flow, and cardiac output under an ischemic condition. In addition, hemodynamics (except heart rate) of the AGR-treated group was significantly recovered 60 min after reperfusion compared to the control group, (systolic aortic pressure: 85.5% vs. 62.5%, aortic flow volume: 68.1% vs. 49.4%, coronary flow volume: 86.8% vs. 60.1%, and cardiac output: 73.1% vs. 54.1%, p<0.01). These results suggest that Acori graminei Rhizoma has distinct anti-ischemic effects.
The present study was designed to evaluate central inhibitory effects of the essential oil from Acori graminei Rhizoma (AGR), the dry rhizomes of Acorus gramineus SOLANDER (Araceae) upon fragrance inhalation (aroma therapy). Preinhalation of the oil markedly delayed the appearance of pentylenetetrazole-induced convulsion. Furthermore, inhalation impressively inhibited the activity of gamma-aminobutyric acid (GABA) transaminase, a degrading enzyme for GABA as the inhalation period was lengthened. The GABA level was significantly increased and glutamate content was significantly decreased in mouse brain by preinhalation of the essential oil. The above results suggest that the anticonvulsive effect of this AGR oil is originated by the enhancement of GABA level in the mouse brain, because convulsion depends partially on GABA concentration which can be properly preserved by inhibiting GABA transaminase. Moreover, fragrance inhalation progressively prolonged the pentobarbital-induced sleeping time as inhalation time was lengthened. Ten hour inhalation corresponded almost to the effect (145% increase) of oral administration (60 mg/kg). This sedative effect after inhalation or oral administration of AGR essential oil suggests that this oil may act on the CNS via the GABAergic system. The inhibitory activity of preinhalation of the essential oil on lipid peroxidation, to which the anticonvulsive action is attributed, also supported the above results, confirming and amplifying our previous reports on the CNS inhibitory effects of AGR.
This review describes the most recent data on an intermediate filament protein nestin, which is regarded by most of the authors as a possible neural stem/progenitor cells marker. Several structure-functional characteristics of nestin, its occurrence in different cell types at various stages of ontogenesis in physiological and pathological conditions are reviewed.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by accumulation of amyloid plaques and neurofibrillary tangles. Amyloid-beta (A beta) is widely recognized as a key factor in the pathogenesis of AD. A beta(1-42), a major component of amyloid plaques, has shown synaptotoxicity associated with impaired long-term potentiation and cognitive deficits. Alteration of neurogenesis in AD patients has been reported, while little is known about how A beta(1-42) affects hippocampal neurogenesis in the adult brain. In this study, we injected human A beta(1-42) peptide into hippocampal CA1 area of adult mouse brain bilaterally and evaluated histological change and neurogenesis in the hippocampus. Hematoxylin and eosin (HE) stain showed that A beta(1-42)-injection resulted in an extensive neurodegeneration in the A beta-accumulated area and CA3 in hippocampus. Immunostaining showed that intrahippocampal A beta(1-42)-injection dramatically decreased the number of bromodeoxyuridine (BrdU)-positive cells in the dentate gyrus (DG) compared to the vehicle injection. Moreover, a significant decrease in the number of BrdU/double-cortin double-positive cells in A beta(1-42)-injected hippocampus was observed, suggesting that A beta(1-42)-injection inhibited progenitor cell proliferation and neurogenesis in subgranular zone of the DG in the adult brain. We also found that the A beta(1-42)-mediated decline of neurogenesis was associated with decreased protein levels of cytokines interferon-gamma (IFN-gamma) and transcription factor nuclear factor-kappa B (NF-kappa B) in the hippocampus. These results suggest that A beta(1-42) inhibits hippocampal neurogenesis in the adult brain possibly through down-regulation of INF-gamma and NF-kappa B signaling pathway. This study provides a new insight into A beta(1-42)-mediated decrease in hippocampal neurogenesis in the adult central nervous system.
The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knockout mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.
Doublecortin (DCX), a microtubule-associated phosphoprotein, has been recently utilized as a marker of newly born neurons in the adult dentate gyrus (DG). Nonetheless, it is unknown whether DCX exclusively labels newly formed neurons, as certain granule cells with the phenotype of differentiated neurons express DCX. We addressed the authenticity of DCX as a marker of new neurons in the adult DG by quantifying cells that are positive for 5′-bromodeoxyuridine (BrdU), DCX and both BrdU and DCX in hippocampal tissues of adult rats treated with daily injections of BrdU for 12 consecutive days. We provide new evidence that neurons visualized with DCX immunostaining in the adult rat DG are new neurons that are predominantly born during the 12 days before euthanasia. This is confirmed by the robust expression of BrdU in 90% of DCX-positive neurons in the DG of animals injected with BrdU for 12 days. Furthermore, DCX expression is specific to newly generated healthy neurons, as virtually all DCX-positive cells express early neuronal antigens but lack antigens specific to glia, undifferentiated cells or apoptotic cells. As DCX expression is also robust in the dendrites, DCX immunocytochemistry of thicker sections facilitates quantification of the dendritic growth in newly born neurons. Thus, both absolute number and dendritic growth of new neurons that are generated in the adult DG over a 12-day period can be quantified reliably with DCX immunostaining. This could be particularly useful for analysing changes in dentate neurogenesis in human hippocampal tissues as a function of ageing or neurodegenerative diseases.
Effects of hindlimb suspension (HS) and ambulation recovery on hippocampal neurogenesis of newly weaned rats were studied by using immunohistochemical techniques. The number of proliferating cell nuclear antigen-positive (PCNA(+)) cells in the subgranular zone (SGZ) markedly decreased during normal growth. However, neither HS nor subsequent recovery caused additional changes in the number of PCNA(+) cells. The number of doublecortin-positive (DCX(+)) neurons decreased gradually during normal growth. HS resulted in a further decrease in these neurons. However, DCX(+) cell numbers became identical to the levels in age-matched controls after 14 days of recovery. PCNA and DCX-double positive cells in the SGZ were also observed, and their cell numbers were not affected by HS and 14-day ambulation. Thus, HS suppressed the generation of DCX(+) neurons without affecting PCNA(+) cells in the SGZ of weaned rats. Taken together, hippocampal neurogenesis in weaned rats was not severely affected by HS while it decreased significantly as they had grown.
Suyu-Jiaonang (SYJN) is a Chinese herbal formula that contains four herbs: Bupleurum chinense DC, Curcuma aromatica Salisb., Perilla frutescens (Linn.) Britt., and Acorus tatarinowii Schott. Previous studies conducted in our laboratory have revealed an antidepressant-like effect of the formula in various mouse models of behavioral despair. The present study aimed to investigate whether SYJN could produce antidepressant-like effects in chronic unpredictable stress (CUS)-induced depression model in rats and its possible mechanism(s).
Rats were subjected to an experimental setting of CUS. The effect of SYJN treatment on CUS-induced depression was examined using behavioral tests including the sucrose consumption and open field tests. The mechanism underlying the antidepressant-like action of SYJN was examined by measuring brain-derived neurotrophic factor (BDNF) protein and mRNA expression in brain tissues of CUS-exposed rats.
Exposure to CUS for 4 weeks caused depression-like behavior in rats, as indicated by significant decreases in sucrose consumption and locomotor activity (assessed in the open field test). In addition, it was found that BDNF protein and mRNA levels in the hippocampus and frontal cortex were lower in CUS-treated rats, as compared to controls. Daily intragastric administration of SYJN (1300 or 2600 mg/kg) during the 4-week period of CUS significantly suppressed behavioral changes and attenuated the CUS-induced decrease in BDNF protein and mRNA levels in the hippocampus and frontal cortex.
The results suggest that SYJN alleviates depression induced by CUS. The antidepressant-like activity of SYJN is likely mediated by the increase in BDNF expression in brain tissues.
Valid animal models for a specific human disease are indispensable for development of new therapeutic agents. The conclusions drawn from animal models largely depend on the validity of the model. Several studies have shown that administration of Abeta into the brain causes some of the pathological events observed in Alzheimer disease (AD). However, the validity of these models has not fully been examined. In this present study, we further characterized and validated Abeta1-40 injected mice as an animal model for AD, based on three major criteria: face, construct and predictive validity. Intracerebroventricular (i.c.v.) injection of Abeta1-40 into mice significantly impaired memory acquisition, but not memory retrieval, which implies similarity to the episodic anterograde memory deficit observed in the early stage of AD. Electrophysiological assessment showed that i.c.v. administration of Abeta1-40 significantly attenuated hippocampal long-term potentiation. Treatment with galantamine, a drug currently in clinical use for AD, significantly improved cognitive dysfunction in this model. These results demonstrate that i.c.v. injection of Abeta1-40 caused specific dysfunction of memory processes, which at least partly fulfills three validity criteria for AD. Symptomatic and pathophysiological similarities of this model to AD are quite important in considering the usefulness of this animal model. This validated animal model could be useful to develop and evaluate potential new drugs for AD.
The chemical alpha-asarone is an important active substance of the Acori graminei rhizome (AGR). It has pharmacological effects that include antihyperlipidemic, antiinflammatory, and antioxidant activity. Our aim was to study the effects alpha-asarone on nitric oxide (NO) levels in the hippocampus and temporal cortex of the rat after injection of the fraction 25-35 from amyloid-beta (Abeta((25-35))). In addition we examined the working spatial memory in an eight-arm radial maze. Our results showed a significant increase of nitrites in the hippocampus and temporal cortex of Abeta((25-35))-treated rats. Other evidence of neuronal damage was the expression of a glial-fibrillar-acid protein and a silver staining. There were impairments in the spatial memory evaluated in the eight-arm radial maze. We wanted to determine whether alpha-asarone improves the memory correlated with NO overproduction and neuronal damage caused by the injection of Abeta((25-35)) into rats. Then animals received a 16-day treatment of alpha-asarone before the Abeta((25-35)) injection. Our results show a significant decrease of nitrite levels in the hippocampus and temporal cortex, without astrocytosis and silver-staining cells, which correlates with memory improvement in the alpha-asarone-treated group. Our results suggest that alpha-asarone may protect neurons against Abeta((25-35))-caused neurotoxicity by inhibiting the effects of NO overproduction in the hippocampus and temporal cortex.
We have previously reported that dietary docosahexaenoic acid (DHA) improves and/or protects against impairment of cognition ability in amyloid beta(1-40) (Abeta(1-40))-infused Alzheimer's disease (AD)-model rats. Here, after the administration of DHA to AD model rats for 12 weeks, the levels of Abeta(1-40), cholesterol and the composition of fatty acids were investigated in the Triton X100-insoluble membrane fractions of their cerebral cortex. The effects of DHA on the in vitro formation and kinetics of fibrillation of Abeta(1-40) were also investigated by thioflavin T fluorescence spectroscopy, transmission electron microscopy and fluorescence microscopy. Dietary DHA significantly decreased the levels of Abeta(1-40), cholesterol and saturated fatty acids in the detergent insoluble membrane fractions of AD rats. The formation of Abeta fibrils was also attenuated by their incubation with DHA, as demonstrated by the decreased intensity of thioflavin T-derived fluorescence and by electron micrography. DHA treatment also decreased the intensity of thioflavin fluorescence in preformed-fibril Abeta peptides, demonstrating the anti-amyloidogenic effects of DHA. We then investigated the effects of DHA on the levels of oligomeric amyloid that is generated during its in vitro transformation from monomers to fibrils, by an anti-oligomer-specific antibody and non-reducing Tris-Glycine gradient (4-20%) gel electrophoresis. DHA concentration-dependently reduced the levels of oligomeric amyloid species, suggesting that dietary DHA-induced suppression of in vivo Abeta(1-40) aggregation occurs through the inhibitory effect of DHA on oligomeric amyloid species.
Nestin is an intermediate filament which was first identified in neuroepithelial stem cells. This expression has also been reported in restricted locations in adults. Previous studies have suggested that the periodontal Ruffini endings remain immature in nature even in adulthood. The present study reports on a characteristic expression of immunoreaction for nestin in the periodontal Ruffini endings during postnatal development. RT-PCR analysis detected nestin mRNA in a reverse transcripted cDNA sample from both the rat trigeminal ganglion and periodontal ligament. The nestin immunoreaction existed in the periodontal ligament at postnatal day 3 (PO 3 days), when many spindle-shaped Schwann cells were positive for nestin immunoreaction. At PO 1 week, when periodontal nerve fibers displayed a dendritic fashion, the round cells came to show the nestin immunoreaction. These immunopositive cells were also reactive for S-100 protein and non-specific cholinesterase, indicating that these cells could be categorized as terminal Schwann cells associated with the periodontal Ruffini endings. Some ordinary Schwann cells also exhibited nestin immunoreaction. From PO 2 to 3 weeks, nestin positive terminal Schwann cells increased in number in accordance with the postnatal development of the periodontal Ruffini endings, while this immuno-expression pattern remained unchanged. Nestin immunoreaction was also recognizable in the satellite cells - but never in the neurons - in the trigeminal ganglion throughout this observation period. This immuno-expression pattern suggests that nestin serves as an intermediate filament for mechanical stability in the periodontal Ruffini endings against external stimuli.
Pharmacological antagonism of the ionotropic purinergic P2X7R has been studied for effects on inflammatory reactivity and neuronal viability in amyloid-beta1-42-injected rat hippocampus. Amyloid-beta1-42-injected brains (7-day postinjection) demonstrated marked increases in P2X7R expression, gliosis, leakiness of blood-brain barrier and loss of hippocampal neurons. The P2X7R antagonist, brilliant blue G reduced levels of purinergic receptor expression, attenuated gliosis, diminished leakiness of blood-brain barrier and was neuroprotective in peptide-injected brain. Brilliant blue G also demonstrated neuroprotection and antagonism against inflammatory responses induced by the P2X7R agonist, 2',3'-(benzoyl-4-benzoyl)-ATP. The findings constitute the first report that pharmacological inhibition of P2X7R, possibly by acting to inhibit inflammatory reactivity, confers neuroprotection in an animal model of Alzheimer's disease brain.
This study analyzed hypersensitization in sensory systems after mechanical irritation of the dorsal root ganglion.
To develop a reliable and reproducible animal model of hyperalgesia arising from the dorsal root ganglion and to understand the unique contributions of the dorsal root ganglion to clinical manifestations of sciatica.
The dorsal root ganglion likely plays an important role in disorders of sciatica. However, no previous study has analyzed sciatica after irritation of the dorsal root ganglion. Thermal hyperalgesia indicates a decrease in thermal nociceptive threshold and hypersensitization in sensory systems.
The left L4 and L5 dorsal root ganglia in rats (n = 22) were exposed circumferentially. Other rats (n = 22) also had the left L4 and L5 dorsal root ganglia ligated loosely with two 4-0 chromic gut sutures. Changes in thermal withdrawal latency were examined in the hindpaws across time. Substance P and vasoactive intestinal polypeptide contents were quantified in the dorsal root ganglion and spinal cord. Substance P, calcitonin gene-related peptide, and c-fos expression also were examined in the spinal cord by immunohistochemistry. In addition, histologic changes in myelinated nerve content were examined in the dorsal root ganglion.
Thermal hyperalgesia occurred in rats with exposure of the dorsal root ganglion and in rats with loose ligation of the dorsal root ganglion, and was accompanied by an increase in c-fos expression and spontaneous pain-related behaviors.
This experimental model reliably produced a disorder resembling an acute phase sciatica and should help further advance the understanding of pathomechanisms of spinal pain after irritation of the dorsal root ganglion in humans.
The intermediate filament nestin is highly expressed in multipotential stem cells of the developing central nervous system (CNS). During neuro- and gliogenesis, nestin is replaced by cell type-specific intermediate filaments, e.g. neurofilaments and glial fibrillary acidic protein (GFAP). In this study, we demonstrate that nestin expression is re-induced in reactive astrocytes in the lesioned adult brain. Following ischaemic and mechanical lesioning, a strong and sustained expression of nestin was noted in GFAP-positive cells surrounding the lesion site. Lesion experiments in transgenic mice carrying the lacZ gene under control of regulatory sequences from the nestin gene suggested that the upregulation of nestin in reactive astrocytes is mediated via the same sequences that control nestin expression during CNS development. These observations and recent data on the co-expression of glial and neuronal marker antigens in reactive astrocytes point to a close relationship between proliferating astrocytes and neuroepithelial precursor cells.
Previous reports have shown that the methanol extract and the essential oil from Acori graminei Rhizoma (AGR) inhibited excitotoxic neuronal cell death in primary cultured rat cortical cells. In the present study, an active principle was isolated from the methanol extract by biological activity-guided fractionations and identified as asarone. We evaluated neuroprotective actions and action mechanisms of the isolated asarone as well as the alpha- and the beta-asarone obtained commercially. The isolated asarone inhibited the excitotoxicity induced by the exposure of cortical cultures for 15 min to 300 microM NMDA in a concentration-dependent manner, with the IC50 of 56.1 microg/ml. The commercially obtained alpha- and beta-asarone exhibited more potent inhibitions of the NMDA-induced excitotoxicity than the isolated asarone. Their respective IC50 values were 18.2 and 26.5 microg/ml. The excitotoxicity induced by glutamate (Glu) was also inhibited, but with much less potency than the toxicity induced by NMDA. The IC50 values for the alpha-, beta-, and the isolated asarone were 89.7, 121.7, and 279.5 microg/ml, respectively. Based on the receptor-ligand binding studies using a use-dependent NMDA receptor-channel blocker [3H]MK-801, asarone inhibited the specific bindings in a concentration-dependent fashion. These results indicate that asarone, the major essential oil component in AGR, exhibits neuroprotective action against the NMDA- or Glu-induced excitotoxicity through the blockade of NMDA receptor function. The alpha-asarone was found to exhibit more potent inhibition of [3H]MK-801 bindings, which is consistent with its more potent neuroprotective action than the beta- or the isolated asarone.
The effects of water extracts of six medicinal herbs (Radix polygalae tenuifoliae, Radix salviae miltiorrhizae, Rhizoma acori graminei, Rhizoma pinelliae ternatae, Tuber curcumae and Scletrotium poriae cocos) on the cytotoxic action of Abeta(1-40) were tested with PC-12 cells. Only the extract of R. acori graminei (RAG) significantly decreased Abeta(1-40)-induced cell death. Further, eugenol and beta-asarone were isolated and identified as the major active principles. Both purified eugenol and beta-asarone protected PC-12 cells from the toxic effect of Abeta(1-40). Eugenol was active between 1 and 100 microM, and 10 microM eugenol gave approximately a 50% response. beta-Asarone was less potent and exhibited little, if any, activity at this concentration. Both eugenol and beta-asarone inhibited Ca(2+) intake by PC-12 cells: beta-asarone mainly inhibited basal Ca(2+) intake, whereas eugenol inhibited Abeta-induced Ca(2+) intake preferentially. These results suggest that eugenol may act by blocking Abeta-induced-Ca(2+) intake and provide a strong case for further pursuit of the therapeutic and prophylactic potentials of RAG and its active principles for the management of Alzheimer's disease.
The present study was designed to evaluate central inhibitory effects of the essential oil from Acori graminei Rhizoma (AGR), the dry rhizomes of Acorus gramineus SOLANDER (Araceae) upon fragrance inhalation (aroma therapy). Preinhalation of the oil markedly delayed the appearance of pentylenetetrazole-induced convulsion. Furthermore, inhalation impressively inhibited the activity of gamma-aminobutyric acid (GABA) transaminase, a degrading enzyme for GABA as the inhalation period was lengthened. The GABA level was significantly increased and glutamate content was significantly decreased in mouse brain by preinhalation of the essential oil. The above results suggest that the anticonvulsive effect of this AGR oil is originated by the enhancement of GABA level in the mouse brain, because convulsion depends partially on GABA concentration which can be properly preserved by inhibiting GABA transaminase. Moreover, fragrance inhalation progressively prolonged the pentobarbital-induced sleeping time as inhalation time was lengthened. Ten hour inhalation corresponded almost to the effect (145% increase) of oral administration (60 mg/kg). This sedative effect after inhalation or oral administration of AGR essential oil suggests that this oil may act on the CNS via the GABAergic system. The inhibitory activity of preinhalation of the essential oil on lipid peroxidation, to which the anticonvulsive action is attributed, also supported the above results, confirming and amplifying our previous reports on the CNS inhibitory effects of AGR.
Acori graminei rhizoma (AGR) and Uncariae Ramulus et Uncus (URE) have been widely used as herbal medicine against ischemia. In order to investigate whether AGR and URE influenced cerebral ischemia-induced neuronal and cognitive impairments, we examined the effect of AGR and URE on ischemia-induced cell death in the striatum, cortex and hippocampus, and on the impaired learning and memory in the Morris water maze and radial eight-arm maze in rats. After middle cerebral artery occlusion (MCAO) for 2 h, rats were administered saline, AGR or URE (100 mg/kg, p.o.) daily for three weeks, followed by their training to the tasks. In the water maze test, the animals were trained to find a platform in a fixed position during 6 days and then received a 60-s probe trial in which the platform was removed from the pool on the 7th day. In the radial eight-arm maze, animals were tested six times per week for 1 week. Rats with ischemic insults showed impaired learning and memory on the tasks. Pretreatment with AGR and URE produced a significant improvement in escape latency to find the platform in the Morris water maze and in the number of choice errors in the radial arm maze test. Consistent with behavioral data, pretreatments with AGR and URE significantly reduced ischemia-induced cell death in the hippocampal CA1 area. These results demonstrated that AGR and URE have a protective effect against ischemia-induced neuronal loss and learning and memory damage. Our studies suggest that AGR and URE may be useful in the treatment of vascular dementia.
Neurogenesis, which persists in the adult mammalian brain, may provide a basis for neuronal replacement therapy in neurodegenerative diseases like Alzheimer's disease (AD). Neurogenesis is increased in certain acute neurological disorders, such as ischemia and epilepsy, but the effect of more chronic neurodegenerations is uncertain, and some animal models of AD show impaired neurogenesis. To determine how neurogenesis is affected in the brains of patients with AD, we investigated the expression of immature neuronal marker proteins that signal the birth of new neurons in the hippocampus of AD patients. Compared to controls, Alzheimer's brains showed increased expression of doublecortin, polysialylated nerve cell adhesion molecule, neurogenic differentiation factor and TUC-4. Expression of doublecortin and TUC-4 was associated with neurons in the neuroproliferative (subgranular) zone of the dentate gyrus, the physiological destination of these neurons (granule cell layer), and the CA1 region of Ammon's horn, which is the principal site of hippocampal pathology in AD. These findings suggest that neurogenesis is increased in AD hippocampus, where it may give rise to cells that replace neurons lost in the disease, and that stimulating hippocampal neurogenesis might provide a new treatment strategy.
100 years after the first description, Alzheimer's disease is one of the most disabling and burdensome health conditions worldwide. We used the Delphi consensus method to determine dementia prevalence for each world region.
12 international experts were provided with a systematic review of published studies on dementia and were asked to provide prevalence estimates for every WHO world region, for men and women combined, in 5-year age bands from 60 to 84 years, and for those aged 85 years and older. UN population estimates and projections were used to estimate numbers of people with dementia in 2001, 2020, and 2040. We estimated incidence rates from prevalence, remission, and mortality.
Evidence from well-planned, representative epidemiological surveys is scarce in many regions. We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81.1 million by 2040. Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040). Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours.
We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.
Kami-shoyo-san (KSS), a traditional Chinese medicine, has been used to treat patients with neuropsychiatric disorders. The aim of the present paper was to investigate whether KSS has antidepressant-like effects, and to assess its mechanism of action, using male Sprague-Dawley rats given 10-fold (KSS 10X) or 20-fold (KSS 20X) the typical human daily dosage. Immobility time was measured by the forced swimming test, and hippocampal neurogenesis was quantified under immobilization stress. Rats given KSS 20X, but not those given KSS 10X, had a significantly lower immobility time and improved neurogenesis in the hippocampus. These results suggest that KSS possesses an antidepressant-like effect at a behavioral and molecular level.
Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signs of Alzheimer's disease (AD) that have been widely associated to inflammatory response. We have recently shown that a single i.c.v. injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400 pmol/mouse) results in marked deficits of learning and memory in mice which are related to oxidative stress and synaptic dysfunction. In the present study, we investigated by means of genetic or pharmacological approaches the role of kinin system in the Abeta(1-40) cognitive effects on the water maze paradigm. Spatial learning and memory deficits observed at 7 days following Abeta(1-40) treatment were significantly reduced by the i.c.v. administration of the selective kinin B(2) receptor antagonist d-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-BK (Hoe 140). A similar effect was found in mice lacking kinin B(2) receptor. On the other hand, genetic deletion of the inducible kinin B(1) receptor or its blockage by i.c.v. injection of des-Arg(9)-[Leu(8)]-BK antagonist attenuated only the long-term (30 days after treatment) cognitive deficits induced by Abeta(1-40). Moreover, treatment with Abeta(1-40) resulted in a sustained increase in the expression of the kinin B(1) receptor in the hippocampus and prefrontal cortex of mice, while it did not alter the expression of the kinin B(2) receptor in these brain areas. These findings provide convincing evidence that kinins acting via activation of B(1) and B(2) receptors in the CNS exert a critical role in the spatial learning and memory deficits induced by Abeta peptide in mice. Therefore, selective kinin receptor antagonists, especially the new orally active non-peptide antagonists, might represent drugs of potential interest for the treatment of AD.
This literature review reflects current knowledge on the intermediate filament protein nestin, which most authors regard as a marker of "neural stem/progenitor cells." The structural-functional characteristics of nestin and its presence in various central nervous system cells at different stages of ontogenesis in normal and pathological conditions are discussed.
Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by amyloid beta (Abeta)-containing plaques and neurofibrillary tangles, and synaptic and neuronal loss, along with progressive cognitive impairment. Although growing evidence suggests the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) on AD, this notion is still controversial. To evaluate the efficacy of statins for Abeta-induced cognitive impairment, we employed an Abeta injection model. Using this model, the present study demonstrated that pretreatment with fluvastatin, but not post-treatment just after Abeta exposure, prevented Abeta-induced memory impairment. We also observed that fluvastatin significantly decreased Abeta accumulation and oxidative stress after Abeta injection. Mice treated with simvastatin, but not fluvastatin, did not demonstrate the prevention of Abeta-induced memory impairment, and showed no significant decrease in oxidative stress. More importantly, fluvastatin significantly prevented the loss of neurons in the basal forebrain induced by Abeta. Overall, the present study demonstrated that fluvastatin significantly prevented memory impairment induced by Abeta. The beneficial effects of fluvastatin might be explained by the preservation of neurons through a significant decrease in Abeta accumulation and oxidative stress. In clinical practice, the timing of the start of fluvastatin treatment might be critical in achieving a beneficial effect on cognitive function.
Effects of Rhizoma Acori Tatarinowii on
- H M Tang
- P Xi
- M Wu
- Q Cai
Tang HM, Xi P, Wu M, Cai Q. Effects of Rhizoma Acori
Tatarinowii on Amino Acids Neurotransmitter in Mice Brain 2004;
15: 310-11.