Neuroprotective effect of β-asarone against Alzheimer’s disease: regulation of synaptic plasticity by increased expression of SYP and GluR1
Sijun LiuCong YangYue ZhangRuyu SuJunli ChenMengmeng JiaoHuifang ChenNa ZhengSi LuoYunbo ChenShijian QuanQi Wang
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Aim: β-asarone, an active component of Acori graminei rhizome, has been reported to have neuroprotective effects in Alzheimer's disease. As the underlying mechanism is not known, we investigated the neuroprotective effects of β-asarone in an APP/PS1 double transgenic mouse model and in NG108 cells. Materials and methods: APPswe/PS1dE9 double transgenic male mice were randomly assigned to a model group, β-asarone treatment groups (21.2, 42.4, or 84.8 mg/kg/d), or donepezil treatment group (2 mg/kg/d). Donepezil treatment was a positive control, and background- and age-matched wild-type B6 mice were an external control group. β-asarone (95.6% purity) was dissolved in 0.8% Tween 80 and administered by gavage once daily for 2.5 months. Control and model animals received an equal volume of vehicle. After 2.5 months of treatment, behavior of all animals was evaluated in a Morris water maze. Expression of synaptophysin (SYP) and glutamatergic receptor 1 (G1uR1) in the hippocampus and cortex of the double transgenic mice was assayed by Western blotting. The antagonistic effects of β-asarone against amyloid-β peptide (Aβ) were investigated in vitro in the NG108-15 cell line. After 24 hours of incubation, cells were treated with 10 µm Aβ with or without β-asarone at different concentrations (6.25, 12.5, or 25 µM) for an additional 36 hours. The cytotoxicity of β-asarone was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay of cell viability, and cell morphology was evaluated by bright-field microscopy after 24 hours of treatment. The expression of SYP and GluR1 in cells was detected by Western blot assay in the hippocampus and brain cortex tissues of mice. Results: β-asarone at a high dose reduced escape latency and upregulated SYP and GluR1 expression at both medium and high doses. Cell morphology evaluation showed that β-asarone treatment did not result in obvious cell surface spots and cytoplasmic granularity. β-asarone had a dose-dependent effect on cell proliferation. Conclusion: β-asarone antagonized the Aβ neurotoxicity in vivo, improved the learning and memory ability of APP/PS1 mice, and increased the expression of SYP and GluR1 both in vivo and in vitro. Thus, β-asarone may be a potential drug for the treatment of Alzheimer's disease. Keywords: neuroprotective effect, β-asarone, synaptic plasticity, synaptophysin, glutamatergic receptor 1Keywords:
Viability assay
Amyloid beta
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Amyloid beta
Barnes maze
Elevated plus maze
Spontaneous alternation
Cognitive Decline
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Objective To investigate the effect of donepezil in treating patients with Alzheimer's disease on cognitive disfunction and lacking of capablity of daily living.Methods140 patient's with Alzheimer's disease were randomly divided into treatment group(treated with donepezil)and control group(treated without donepezil).MMSE Scale and ADL Scale of the two groups were assessed before treatment and 1 months、3 months and 6 months af ter treatment.ResultsThe MMSE Scale and ADL Scale of the treatment group were improved more greatly than the control group(P0.05),and the therapeutical effect enhanced as the time of therapy expanded.After treated with donepezil for 1 month、2 months、6 months,the effective percentage of donepezil in treating AD patients with congnitive disfunction are respectively13%、32%、43%hgher than without donepezil,and in treating AD patients lacking of capablity of daily living are respectively 8%、13%、23%hgher than without donepezil.ConclusionDonepezil effectively improves cognition and preserves function in individuals with Alzheimer's disease.
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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 effective in spatial memory than defatted decoction fraction.
Doublecortin
Amyloid beta
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ADAM10
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Cholinesterase
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ABSTRACT Case A 69‐year‐old male presented with a two‐year history of memory decline. Results of his cognitive function tests suggested cognitive impairment and brain magnetic resonance imaging showed cortical atrophy, predominantly in the temporal lobes. Based on these findings, he was diagnosed with Alzheimer's disease. Outcome Although treatment with donepezil was commenced, the patient's cognitive function deteriorated in the year after initiation. However, his cognitive impairment improved in the year after add‐on administration of kamikihito, a traditional Japanese herbal medicine, with donepezil monotherapy. Conclusion Combination therapy with donepezil and kamikihito seems to be beneficial and worth considering for patients who are secondarily non‐responsive to donepezil monotherapy.
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Serotonin 5-HT4 agonism has been proposed as a cognitive enhancing mechanism. It has been shown to enhance release of acetylcholine in frontal cortex and hippocampus and to reverse the cognitive deficits induced by treatment with anticholinergic drugs in non-clinical behavioral models. The loss of cholinergic function believed to be a major cause of the cognitive decline seen in Alzheimer's disease. In addition, compounds that have been shown to increase acetylcholine function, such as the acetylcholinesterase inhibitor donepezil, have demonstrated efficacy in the treatment of cognitive deficits in AD patients while compounds that block ACh activity, such as scopolamine, have been shown to disrupt learning and memory. A 5-HT4 partial agonist, PF-04995274, was tested in a scopolamine disrupted Morris water maze rat model to assess its cognitive enhancing properties. In these experiments it was compared directly to and tested in combination with donepezil. Compounds were administered once daily for 4 days, prior to testing. Rats treated with the 5-HT4 compound showed improved acquisition of the Morris water maze task. Performance was equivalent to the maximum acquisition seen in rats dosed with donepezil alone in the same task. When combined with a sub-active dose of donepezil, a trend suggestive an additive effect on cognitive enhancement was observed. Exposures of PF-4995274 obtained in brain, plasma and CSF were suggestive of ∼40% receptor occupancy of 5-HT4 partial agonist. These findings support the potential use of 5-HT4 agonists in treating Alzheimer's disease-related cognitive deficits. Furthermore, the results of combining the compound with a subactive dose of donepezil demonstrates the therapeutic potential of our current 5-HT4 partial agonist as an add-on therapy without any PK or PD related DDIs. A trend towards an additive effect suggests that combination treatment might yield improved results and/or allow reduction of donepezil dose.
Scopolamine Hydrobromide
Water maze
Acetylcholinesterase inhibitor
Cognitive Decline
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Viability assay
MTT assay
Amyloid beta
Neurotoxicity
Slice preparation
Ex vivo
Amyloid (mycology)
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Abstract Background: Alzheimer’s disease (AD) is a lethal progressive neurodegenerative disorder. Currently, many acetylcholinesterase inhibitors, such as donepezil, is widely used for the treatment of AD. However, the efficacy of long-term donepezil use is limited. SIP3, a mixture of Santalum album , Illicium verum, and Polygala tenuifolia , a new formula derived from traditional Korean herbal medicine. In this study, SIP3 were assessed the survival of Drosophila AD model and synergistic effect of SIP3, donepezil co-treatment of AD using APP/PS1 transgenic mice. Methods: In Drosophila AD models, we analyzed the survival, climbing ability and acridine orange (AO) staining. In APP/PS1 mice, at six months of age were randomized into four groups. Then, these groups were orally administered vehicle (for the control), donepezil, low and high doses SIP3 plus Donepezil respectively for six months. The passive avoidance test (PAT) and the Morris water maze (MWM) were analyzed cognitive behavioral changes. In addition, the forced swimming test (FST) and the tail suspension test (TST) were assessed depression-like behavior. To investigate the molecular and cellular mechanisms underlying positive effects of SIP3 on AD, the cerebral cortex transcriptomes were analyzed by RNA sequencing. Results: Using the passive avoidance test (PAT), we analyzed the combination of SIP3 and donepezil improved the learning capabilities and memory of APP/PS1 mice, compared with the group treated with donepezil only, in late stage of AD. In addition, using the Morris water maze (MWM) test, co-treatment with donepezil and a low concentration of SIP3 significantly ameliorated cognitive impairment. Co-administration of SIP3 and donepezil effectively reduced depression-like behavior in the forced swimming and tail suspension tests. Furthermore, RNA sequencing of cerebral cortex transcriptome revealed that gene expression profiles after low dose of SIP3 co-treatment are slightly similar to those of normal phenotype mice than those obtained after donepezil treatment alone. Gene ontology (GO) along with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway have demonstrated that differentially expressed genes were involved in locomotor behavior and neuroactive ligand-receptor interactions. Collectively : our results suggest that co-treatment of low dose of SIP3 and donepezil improves impaired learning, memory, and depression in late stage of AD in mice.
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