alpha-asarone and Disease-Models--Animal

Multiple sclerosis (MS), an autoimmune disease, has been considered an inflammatory disorder of the central nervous system (CNS) with demyelination and axonal damage. Although there are certain first-line therapies to treat MS, their unsatisfactory efficacy is partly due to the limited CNS access after systemic administration. Besides, there is an urgent need to treat MS by enhancing remyelination or neuroprotection, or dampen the activity of microglia. Astragaloside IV (ASI) bears anti-inflammatory, antioxidant, remyelination and neuroprotective activity. While its poor permeability, relatively high molecular weight and low lipophilicity restrict it to reach the brain. Therefore, β-asarone modified ASI loaded chitosan nanoparticles (ASI-βCS-NP) were prepared to enhance the nose-to-brain delivery and therapeutic effects of ASI on EAE mice. The prepared ASI-βCS-NP showed mean size of about 120 nm, and zeta potential from +19 to +25 mV. DiR-βCS-NP was confirmed with good nose-to-brain targeting ability. After intranasal administration, the ASI-βCS-NP significantly reduced behavioral scores, decreased weight loss, suppressed inflammatory infiltration and astrocyte/microglial activation, reduced demyelination and increased remyelination on a mice EAE model. Our findings indicate that ASI-βCS-NP may be a potent treatment for MS after nose-to-brain drug delivery.

Topics: Animals; Brain; Chitosan; Disease Models, Animal; Mice; Multiple Sclerosis

Secondary brain injury (SBI) has been confirmed as a leading cause for the poor prognosis of patients suffering from intracerebral hemorrhage (ICH). SBI co-exists in ischemia and hemorrhagic stroke. Neuro-excitotoxicity is considered the initiating factor of ICH-induced SBI. Our previous research has revealed alpha-asarone (ASA)'s efficacy against cerebral ischemia-reperfusion stroke by mitigating neuro-excitotoxicity. It is not yet known if ASA exhibit neuroprotection against ICH.. This work aimed to investigate ASA's therapeutic effects and potential mechanisms of action against ICH in a classic rat model induced by collagenase Ⅶ injection.. An in vivo ICH model of Sprague-Dawley rats was established by collagenase Ⅶ injection. We administrated different ASA doses (10, 20, or 40 mg/kg, i.p.) at 2 h post-ICH. Then, rats' short- and long-term neurobehavioral function, bodyweight change, and learning and memory ability were blindly evaluated. Histological, Nissl, and flow cytometry were applied to assess the neuronal damage post-ICH. The wet/dry method and Evans blue extravasation estimated brain edema and blood-brain barrier function. Pathway-related proteins were investigated by immunofluorescence staining, enzyme-linked immunosorbent assay, and Western-blot analysis.. The results demonstrated that ASA ameliorated neurological deterioration, bodyweight loss, and learning and memory ability of ICH rats. Histological, Nissl, and flow cytometry analyses showed that ASA reduced neuronal damage and apoptosis post-ICH. Besides, ASA probably mitigated brain edema and blood-brain barrier dysfunction via inhibiting astrocyte activation and consequent pro-inflammatory response. The mechanism investigation attributed ASA's efficacy to the following aspects: 1) promoting sodium ion excretion, thus blocking excitatory signal transduction along the axon; 2) preventing glutamate-involved pathways, i.e., decrease of N-methyl-d-aspartic acid receptor subunit 2B, increase of glutamate transporter-1, and alleviation of calcium-related cascades, mitochondrion-associated apoptosis, and neuronal autophagy; 3) enhancing the expression of GABA. Our study first confirmed the effect of ASA on ameliorating the neurobehavioral deterioration of ICH rats, possibly via alleviation of glutamate-involved neuro-excitotoxicity, i.e., calcium cascades, mitochondrion-involved apoptosis, neuronal autophagy, and astrocyte-related inflammation. These findings not only provided a promising drug candidate for clinical treatment of ICH but also shed light on the future drug discovery against ICH.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Apoptosis; Brain Edema; Brain Injuries; Calcium; Cerebral Hemorrhage; Disease Models, Animal; Glutamates; Rats; Rats, Sprague-Dawley

Topics: Allylbenzene Derivatives; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anisoles; Cognition; Disease Models, Animal; Hippocampus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative Diseases; Neurons; Presenilin-1; Rats

In the present study, we compared the antiepileptic effects of α-asarone derivatives to explore their structure-activity relationships using the PTZ-induced seizure model. Our research revealed that electron-donating methoxy groups in the 3,4,5-position on phenyl ring increased antiepileptic potency but the placement of other groups at different positions decreased activity. Besides, in allyl moiety, the optimal activity was reached with either an allyl or a 1-butenyl group in conjugation with the benzene ring. The compounds 5 and 19 exerted better neuroprotective effects against epilepsy in vitro (cell) and in vivo (mouse) models. This study provides valuable data for further exploration and application of these compounds as potential anti-seizure medicines.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Anticonvulsants; Cells, Cultured; Disease Models, Animal; Epilepsy; Male; Mice; Neuroprotective Agents; Rats, Sprague-Dawley; Structure-Activity Relationship

Alpha-asarone has been found to possess many pharmacological activities, which can improve cognitive function and exert anti-oxidant, anxiolytic, anti-epileptic and protective effects against endothelial cell injury. The anti-inflammatory activity of α-asarone was evaluated using lipopolysaccharide (LPS)-induced paw oedema. Moreover, leukocyte migration, inducible nitric oxide synthase (iNOS) expression and tumour necrosis factor-alpha (TNF-α) levels were quantified in footpads. Formalin and LPS-induced thermal hyperalgesia models were generated using adenosinergic, opioidergic, serotonergic and muscarinic receptor antagonists. The effects on motor coordination were evaluated by means of the rota-rod test. Oral treatment (p.o.) with α-asarone (3 mg/kg) significantly inhibited paw oedema by 62.12 and 72.22%, 2 and 4 h post LPS injection, respectively. Alpha-asarone (3 mg/kg, p.o.) attenuated the inflammatory infiltrate 1, 3 and 6 h after LPS injection. Furthermore, α-asarone (3 mg/kg, p.o.) suppressed iNOS expression and TNF-α production, 6 and 1 h after inflammatory stimulus, respectively. Alpha-asarone (3, 10 and 30 mg/kg, p.o.) inhibited both phases of formalin-induced licking. In the hot-plate test, α-asarone (10 and 30 mg/kg, p.o.) increased the latency to response 3 and 5 h post LPS stimulus. Caffeine and naloxone abolished the central anti-nociceptive effect of α-asarone (neurogenic phase of formalin and hot plate tests), suggesting the participation of the adenosinergic and opioidergic systems. Furthermore, naloxone reversed the peripheral activity of α-asarone (inflammatory phase of formalin test), indicating the possible involvement of the opioidergic pathway. In the rota-rod test, α-asarone did not change motor coordination. These findings suggest that α-asarone has anti-inflammatory, peripheral and central anti-nociceptive effects and could represent a promising agent for future research.

Topics: Allylbenzene Derivatives; Analgesics; Animals; Anisoles; Anti-Inflammatory Agents; Disease Models, Animal; Edema; Hyperalgesia; Inflammation; Leukocytes; Male; Mice; Nitric Oxide Synthase Type II; Pain; Pain Measurement; Plant Extracts; Tumor Necrosis Factor-alpha

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly population. Autophagy is a well‑known regulator of neurodegenerative diseases and β‑asarone has been discovered to have certain neuropharmacological effects. Thus, the present study aimed to analyze the potential effects of β‑asarone in AD and its possible mechanism of action in relation to autophagy. The present study investigated the effects of β‑asarone on the number of senile plaques and amyloid β(Aβ)40, Aβ42, amyloid precursor protein (APP) and Beclin‑1 mRNA levels in the hippocampus of APP/presenilin‑1 (PS1) transgenic mice. The possible mechanism of β‑asarone on autophagy‑related proteins, including Beclin‑1, light chain (LC)3A, LC3B and p62 levels, and the number of autophagosomes was also investigated. Mice were divided into a normal control group, a model group, a β‑asarone‑treated group, a 3‑MA‑treated group and a rapamycin‑treated group. Treatments were continuously administered to all mice for 30 days by intragastric administration. The mice, including those in the normal and model control groups, were given equal volumes of saline. It was demonstrated that β‑asarone treatment reduced the number of senile plaques and autophagosomes, and decreased Aβ40, Aβ42, APP and Beclin‑1 expression in the hippocampus of model mice compared with untreated model mice. β‑asarone also inhibited LC3A/B expression levels, but increased p62 expression. It was deduced that the neuroprotective effects of β‑asarone in APP/PS1 transgenic mice resulted from its inhibition of autophagy. In conclusion, the data suggested that β‑asarone should be explored further as a potential therapeutic agent in AD.

Topics: Allylbenzene Derivatives; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anisoles; Autophagy; Autophagy-Related Proteins; Beclin-1; Brain; Disease Models, Animal; Female; Hippocampus; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Neurodegenerative Diseases; Peptide Fragments; Plaque, Amyloid; Presenilin-1

Alzheimer's disease (AD) is a chronic neurodegenerative disease that is characterized by the extracellular accumulation of β-amyloid (Aβ). Many studies have shown a close relationship between autophagy and the formation of Aβ. As AD develops and progresses, mitophagy diminishes insoluble Aβ, and mitochondrial dysfunction seems to be a determining factor in the pathogenesis of AD. In our previous study, we showed that β-asarone pharmacological effects in APP/PS1 transgenic mice, reducing Aβ expression. However, the specific mechanism of this effect remains unclear. In this study, AD model rats induced by intracerebroventricular injection of Aβ

Topics: Allylbenzene Derivatives; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anisoles; Disease Models, Animal; Female; Hippocampus; Learning; Male; Maze Learning; Memory; Mitophagy; Neurons; Peptide Fragments; Protein Kinases; Rats; Rats, Wistar; Ubiquitin-Protein Ligases

Learning and memory impairment is a common symptom in the early stages of various types of dementia. It is likely to reduce the incidence of dementia with correct intervention. α-Asarone is the main bioactive substance isolated from Acorus tatarinowii Schott and has been proven to improve memory dysfunction; however, at present, the specific underlying mechanism is poorly understood. The aim of the present study was to investigate the effect of α-asarone on ethanol-impaired cognitive ability and explore the underlying mechanism in mice.. A mouse model of impaired learning and memory was created by ethanol (2.0 g/kg, i.g.). α-Asarone (7.5, 15 or 30 mg/kg, i.p.) was delivered 10 min prior to ethanol administration. The behavioral effect of α-asarone was evaluated using the novel object recognition test. Glutamate (Glu) and γ-aminobutyric acid (GABA) levels in the hippocampus were determined by ELISA, and the protein expression levels of hippocampal GluR2, NMDAR2B, SYNΙ, GLT-1 and CaMKⅡ were detected by western blotting.. Pretreatment with α-asarone significantly improved the behavioral performance, regulated the imbalance of Glu and GABA in the hippocampus and the abnormal expression of related proteins. A possible underlying mechanism is regulation of the calcium signaling cascade to correct functioning of related proteins, and thus, maintain the level of Glu.. Our results show that the improvement in learning and memory elicited by α-asarone may providing a possible novel candidate for the prevention of learning and memory impairment in the early stages of dementia.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Central Nervous System Depressants; Disease Models, Animal; Ethanol; Fibrinolytic Agents; Glutamic Acid; Hippocampus; Learning; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Neurotransmitter Agents

β-Asarone (1,2,4-trimethoxy-5-[(Z)-prop-1-enyl]benzene) is an essential component of Acorus tatarinowii Schott volatile oil. Previous research has observed that β-asarone effectively attenuated symptoms in parkinsonian rats and improved their performance, but the mechanism of this effect remains unclear. Other research has shown that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of Parkinson's disease (PD). The protein kinase RNA-like endoplasmic reticulum kinase (PERK) was observed in the nigrostriatal dopaminergic neurons of patients with PD. However, our group observed that ER stress and autophagy occurred in 6-hydroxy dopamine (6-OHDA)-induced parkinsonian rats, and ER stress might induce autophagy. We assume that the protective role of β-asarone in parkinsonian rats is mediated via the ER stress-autophagy pathway. To support this hypothesis, we investigated the expressions of glucose regulated protein 78 (GRP78), PERK phosphorylation (p-PERK), C/EBP homologous binding protein (CHOP), Bcl-2 and Beclin-1 in 6-OHDA-induced parkinsonian rats after β-asarone treatment. The results showed that the β-asarone group and PERK inhibitor group had lower levels of GRP78, p-PERK, CHOP and Beclin-1 while having higher levels of Bcl-2. We deduced that β-asarone might regulate the ER stress-autophagy via inhibition of the PERK/CHOP/Bcl-2/Beclin-1 pathway in 6-OHDA-induced parkinsonian rats.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; bcl-X Protein; Beclin-1; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Oxidopamine; Protein Serine-Threonine Kinases; Rats, Sprague-Dawley; Signal Transduction

The evidence suggests that the hyperglycemia and hyperinsulinemia of diabetes mellitus (DM) are risk factors for the development of hepatocellular carcinoma (HCC). The aim of the present study was to examine the effect of streptozotocin (STZ)-induced DM on promoting diethylnitrosamine (DEN) induced HCC in male wistar rats. Further, we investigated the administration of (α)-and (β)-asarone and metformin HCl on experimentally induced diabetic-hepatocellular carcinoma.. Diabetes was induced by single dose of STZ (55 mg/2 ml/kg b.w. i.p.) and HCC by single dose of DEN (200 mg/ml/kg b.w. i.p.). Another group received the STZ followed by DEN two weeks later to mimic diabetic-HCC. The combined dose of (α)-and (β)-asarone (50 μg/1.5 ml/kg b.w. p.o. in the ratio of 1:1) and metformin HCl (250 mg/1.5 ml/kg b.w. p.o.) treatment was compared with the STZ + DEN group. The blood and liver samples were collected at the end of 12 and 18-weeks to study biochemical and histopathological changes in liver.. The STZ induced diabetes promoted the tumor progression due to administration of DEN. The treatment of asarones and metformin significantly reduced the levels of glucose, glycosylated hemoglobin, liver dysfunction markers and tumor biomarkers along with an increase in level of insulin when compared to diabetic-HCC group. Histopathological examination indicated that asarones and metformin attenuate the inflammation, fibrosis, cirrhosis and development of spontaneous HCC.. The STZ can be used to promote the DEN induced HCC. Treatment with (α)-and (β)-asarone attenuates the effect of STZ + DEN induced HCC akin to metformin.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Carcinoma, Hepatocellular; Diabetes Mellitus, Experimental; Diethylnitrosamine; Disease Models, Animal; Hyperglycemia; Hypoglycemic Agents; Insulin; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Metformin; Rats; Rats, Wistar

Topics: Allylbenzene Derivatives; Animals; Anisoles; Apoptosis; Brain Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Glioma; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Humans; Mice; Mitochondria; Proto-Oncogene Proteins c-bcl-2; RNA Splicing; Signal Transduction; Xenograft Model Antitumor Assays

Some traditional Oriental herbal medicines, such as Acorus tatarinowii and Acorus gramineus, produce beneficial effects for cognition enhancement. An active compound in rhizomes and the bark of these plants is α-asarone.. This study investigated the effects of α-asarone on the proliferation and differentiation of neural progenitor cells (NPCs) in a primary culture and a murine model of ischemic stroke.. NPCs were isolated from mouse fetal cerebral cortices on embryonic day 15, and all experiments were performed using passage 3 NPCs. We utilized a cell counting kit-8 assay, flow cytometry, western blot, and immunohistochemical analysis to assess proliferation and differentiation of NPCs and employed α-asarone in NPC transplanted ischemic stroke mice to evaluate stroke-related functional recovery using behavioral and immunohistochemical analysis.. Treatment with 1 µM, 3 µM, or 10 μM α-asarone induced significant NPC proliferation compared to vehicle treatment. Induced NPCs expressed the neuronal marker neuronal nuclei (NeuN) or the astrocyte marker S100 calcium-binding protein B (S100β). Both immunohistochemistry and flow cytometry revealed that treatment with α-asarone increased the number of NeuN-immunoreactive cells and decreased the number of S100β-immunoreactive cells. Treatment with α-asarone also increased the expression of β-catenin, cyclin D1, and phosphorylated extracellular signal-regulated kinase (ERK) compared to vehicle treatment. In a murine model of ischemic stroke, treatment with α-asarone and transplanted NPCs alleviated stroke-related functional impairments. The corner and rotarod test results revealed that treatment with α-asarone in the NPC transplanted group had greater-than-additive effects on sensorimotor function and motor balance. Moreover, α-asarone treatment promoted the differentiation of transplanted NPCs into NeuN-, glial fibrillary acidic protein (GFAP)-, platelet-derived growth factor-α (PDGFR-α)-, and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)-immunoreactive cells.. α-asarone may promote NPC proliferation and differentiation into neuron-lineage cells by activating β-catenin, cyclin D1, and ERK. Moreover, α-asarone treatment facilitated neurofunctional recovery after NPC transplantation in a murine model of ischemic stroke. Therefore, α-asarone is a potential adjunct treatment to NPC therapy for functional restoration after brain injuries such as ischemic stroke.

Topics: Acorus; Allylbenzene Derivatives; Animals; Anisoles; Astrocytes; beta Catenin; Brain Ischemia; Cell Differentiation; Cyclin D1; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Female; Mice; Mice, Inbred C57BL; Neural Stem Cells; Neurons; Stroke

Topics: Allylbenzene Derivatives; Animals; Anisoles; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Chronic Pain; Disease Models, Animal; Hyperalgesia; Male; Mice; Pain Threshold; Treatment Outcome

This study was aimed to investigate the protective effect and mechanism of β-asarone on the animal model of Alzheimer's disease(AD) which was induced by intracerebroventricular injection of Aβ₁₋₄₂ combined cerebral ischemia. One hundred and five rats were randomly divided into seven groups including sham-operated group, AD model group, β-asarone 10 mg•kg⁻¹ group, β-asarone 20 mg•kg⁻¹ group, β-asarone 30 mg•kg⁻¹ group, donepezil group(0.75 mg•kg⁻¹) and Ginkgo biloba extract group(24 mg•kg⁻¹). Rats' learning and memory abilities, cerebric regional blood flow, pathological changes in hippocampal CA1 region, the expression level of HIF-1α and serum CAT, SOD and MDA level were detected 4 weeks later. The results showed that the application of intracerebroventricular injection of Aβ₁₋₄₂ joint 2-VO could lead to rats' dysfunction of learning and memory, decrease in regional cerebral blood flow. Neurons in CA1 region were arranged in disorder, and amyloid deposition was increased. The number of cerebral cortical cells expressing HIF-1α was increased as well. The level of serum CAT and SOD decreased, while level of serum MDA increased. However these symptoms were improved by 20 mg•kg⁻¹ and 30 mg•kg⁻¹ β-asarone. The results indicated that β-asarone could effectively relieve the symptoms of the AD model induced by intracerebroventricular injection of Aβ₁₋₄₂ combined cerebral ischemia, and the potential mechanism might be that it could attenuate damage of MDA to the body by improving the level of CAT and SOD, meanwhile the level of HIF-1α decreased as the decline of hyperoxide which might attenuate its damage to neuron, so it finally achieved alleviating Alzheimer's disease.

Topics: Allylbenzene Derivatives; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anisoles; Catalase; Disease Models, Animal; Malondialdehyde; Oxidative Stress; Peptide Fragments; Rats; Superoxide Dismutase

Elevated β-amyloid (Aβ) is a hallmark of Alzheimer's disease (AD). Recent evidence has suggested that the receptor of advanced glycation end products (RAGE) is a key target for Aβ-induced perturbation in AD, and blockade of RAGE significantly alleviates synaptic injury. Our previous study has suggested that β-asarone could reduce neuronal apoptosis and improve memory deficits in β-amyloid precursor protein and presenilin-1 (APP/PS1) double transgenic AD-model mice. In the present study, we evaluated the effects of β-asarone on amyloidosis in APP/PS1 mice. We found that the survival of neurons of APP/PS1 mice was improved by β-asarone, meanwhile, β-asarone decreased Aβ deposition and down-regulated Aβ1-42 levels in cortex and hippocampus of APP/PS1 mice brain. Interestingly, the level of RAGE was also significantly down-regulated by β-asarone. Our findings suggest that β-asarone might be effective for the treatment of AD, and the decreasing effects of β-asarone on Aβ might associate with its down-regulation of RAGE.

Topics: Allylbenzene Derivatives; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Anisoles; Cell Survival; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Hippocampus; Mice, Transgenic; Neurons; Plaque, Amyloid; Presenilin-1; Receptor for Advanced Glycation End Products

Numerous long non-coding RNAs (lncRNA) have been identified in neurodegenerative disorders including Parkinson's disease (PD). Emerging evidence demonstrates that β-asarone functions as neuroprotective effects in both in vitro and in vivo models. However, the role of β-asarone and its potential mechanism in PD remain not completely clear.. MPTP-induced PD mouse model and SH-SY5Y cells subjected to MPP+ as its in vitro model were used to evaluate the effects of β-asarone on PD. LncRNA MALAT1 and α-synuclein expression were determined by real-time PCR and western blot methods.. β-Asarone significantly increased the TH+ cells number and decreased the expression levels of MALAT1 and α-synuclein in midbrain tissue of PD mice. RNA pull-down and immunoprecipitation assays confirmed that MALAT1 associated with α-synuclein, leading to the increased stability of α-synuclein and its expression in SH-SY5Y cells. β-asarone elevated the viability of cells exposed to MPP+. Either overexpressed MALAT1 or α-synuclein could canceled the protective effect of β-asarone on cell viability. In PD mice, pcDNA-MALAT1 also decreased the TH+ cells number and increased the α-synuclein expression in PD mice with treatment of β-asarone.. β-Asarone functions as a neuroprotective effect in both in vivo and in vitro models of PD via regulating MALAT1 and α-synuclein expression.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Allylbenzene Derivatives; alpha-Synuclein; Animals; Anisoles; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Humans; Male; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Parkinson Disease; RNA, Long Noncoding; Tyrosine 3-Monooxygenase

The commercially available alpha-asarone injections (CA-ARE) were frequently found to cause severe anaphylactic reactions by the solubilizer contained in the formulation such as polysorbate 80 and propylene glycol. This study aimed to develop a new ARE injection using Kolliphor HS 15 as solubilizing agent (HS 15-ARE) by the dissolution method to resolve its poor solubility problem and reduce the anaphylaxis of CA-AREs caused by Polysorbate 80. The HS 15-ARE micelle showed a homogeneous round shape with the mean particle size of around 13.73 ± 0.02 nm, polydisperse index (PDI) of 0.19 ± 0.01 and solubilizing efficiency of 95.7% ± 2.4%. In vitro and in vivo studies showed that HS 15-ARE is a stable injection presenting the same pharmacokinetic profile with CA-ARE. Moreover, improved therapeutic effect was observed for HS 15-ARE in treating asthma compared to CA-ARE (p < 0.05) with no anaphylactic reactions observed. These results demonstrate that the new formulation of ARE (HS 15-ARE) has a great potential for replacing CA-AREs injections.

Topics: Allylbenzene Derivatives; Anaphylaxis; Animals; Anisoles; Anti-Asthmatic Agents; Asthma; Biological Availability; Cells, Cultured; Chemistry, Pharmaceutical; Disease Models, Animal; Drug Stability; Erythrocytes; Guinea Pigs; Hemolysis; Histamine; Injections, Intravenous; Male; Molecular Structure; Particle Size; Polyethylene Glycols; Rats, Wistar; Sheep; Solvents; Stearates; Surface Properties; Tissue Distribution

Aberrant neural progenitor cell (NPC) proliferation and self-renewal have been linked to age-related neurodegeneration and neurodegenerative disorders including Alzheimer's disease (AD). Rhizoma Acori tatarinowii is a traditional Chinese herbal medicine against cognitive decline. In this study, we found that the extract of Rhizoma Acori tatarinowii (AT) and its active constituents, asarones, promote NPC proliferation. Oral administration of AT enhanced NPC proliferation and neurogenesis in the hippocampi of adult and aged mice as well as that of transgenic AD model mice. AT and its fractions also enhanced the proliferation of NPCs cultured in vitro. Further analysis identified α-asarone and β-asarone as the two active constituents of AT in promoting neurogenesis. Our mechanistic study revealed that AT and asarones activated extracellular signal-regulated kinase (ERK) but not Akt, two critical kinase cascades for neurogenesis. Consistently, the inhibition of ERK activities effectively blocked the enhancement of NPC proliferation by AT or asarones. Our findings suggest that AT and asarones, which can be orally administrated, could serve as preventive and regenerative therapeutic agents to promote neurogenesis against age-related neurodegeneration and neurodegenerative disorders.

Topics: Acorus; Age Factors; Allylbenzene Derivatives; Alzheimer Disease; Animals; Anisoles; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Drugs, Chinese Herbal; Extracellular Signal-Regulated MAP Kinases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Stem Cells; Neurogenesis

In this study, we investigated the influence of β-asarone, the major ingredient of Acorus tatarinowii Schott, on depressive-like behavior induced by the chronic unpredictable mild stresses (CUMS) paradigm and to clarify the underlying mechanisms. The results show that β-asarone treatment partially reversed the CUMS-induced depression-like behaviors in both the forced swim and sucrose preference tests. The behavioral effects were associated with increased hippocampal neurogenesis indicated by bromodeoxyuridine (BrdU) immunoreactivity. β-Asarone treatment significantly increased the expression of brain-derived neurotrophic factor (BDNF) at levels of transcription and translation. Moreover, CUMS caused significant reduction in ERK1/2 and CREB phosphorylation, both of which were partially attenuated by β-asarone administration. It is important to note that β-asarone treatment had no effect on total levels or phosphorylation state of any of the proteins examined in ERK1/2-CREB pathway in no stress rats, suggesting that β-asarone acts in a stress-dependent manner to block ERK1/2-CREB signaling. We did not observe a complete reversal of depression-like behaviors to control levels by β-asarone. To our knowledge, the present study is the first to demonstrate that adult neurogenesis is involved in the antidepressant-like behavioral effects of β-asarone, suggesting that β-asarone is a promising candidate for the treatment of depression.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Hippocampus; Humans; Neurogenesis; Rats; Swimming

Stress is a condition or stimulus that threatens an organism's survival. Noise is an environmental stressor. It is well known that long term as well as acute exposure to noise led to oxidative stress. In the present study, it was investigated that the persistence of noise stress (100 dBA/4 h/d for 30 days) could cause memory impairment in rats and whether ethylacetate extract of AC EAAC (50 mg kg(-1) b.wt.) and alpha-Asarone (9 mg kg(-1) b.wt.). treatment can prevent or not. In order to understand the possible mechanism behind it, antioxidant status and acetylcholinesterase (AChE) activity in hippocampus was evaluated after rats were tested in Radial Eight-arm Maze (RAM). Heat shock protein 70 (hsp 70) expression in hippocampus was also evaluated to understand the intensity of stress level. Results showed that after noise stress exposure, time taken to visit all the baited arms, working and reference memory errors were increased in RAM. The superoxide dismutase, lipid peroxidation, AChE activity, hsp 70 were significantly increased with concomitant decrease in catalase, glutathione peroxidase activity and G6PD activity of non-enzymatic levels was observed in the 30 days noise stress exposed group. When rats were co-administrated with EAAC and alpha-Asarone prevents the noise stress induced alterations significantly. In Conclusion, noise stress induced oxidative stress, increased AChE activity, and over expression of hsp 70 in hippocampus region might have led to the impairment of spatial memory. EAAC and alpha-Asarone prevents this noise stress induced memory impairment.

Topics: Acetylcholinesterase; Acorus; Allylbenzene Derivatives; Animals; Anisoles; Disease Models, Animal; GPI-Linked Proteins; Hippocampus; HSP72 Heat-Shock Proteins; Lipid Peroxidation; Memory; Memory Disorders; Motor Activity; Noise; Nootropic Agents; Oxidative Stress; Phytotherapy; Plant Extracts; Plants, Medicinal; Rats; Rats, Wistar; Stress, Psychological; Superoxide Dismutase; Time Factors

For centuries, extracts of Acorus gramineus have been used extensively in traditional Chinese medicine for the treatment, management, and/or control of human ailments, including central nervous system disorders such as convulsions and epilepsy. In the present study, we investigated the anticonvulsant activity of chronic treatment with the plant's major essential oil component (a-asarone, 50-200 mg/kg, per os (p.o.)) against maximal electroshock seizure (MES), pentylenetetrazole (PTZ)-induced seizures in mice, lithium-pilocarpine (LI-PILO)-induced status epilepticus (SE), and spontaneous recurrent seizures (SRSs) in rats and determined whether a single acute administration of a-asarone at various doses could produce anticonvulsant activity. As the standard antiepileptic drugs used, chronically administered a-asarone (50-200 mg/kg, p.o.) significantly delayed (p<0.05) the onset of, and antagonized maximal electroshock seizure and PTZ-induced seizures. Chronically administered a-asarone (50-200 mg/kg) also profoundly antagonized LI-PILO-induced seizures. The SE incidence, SE latency and seizure severity as well as mortality were significantly reduced after treatment with a-asarone at different doses. Higher doses of a-asarone (100-200 mg/kg) significantly reduced spontaneous recurrent seizure incidence, severity, and seizure frequency during treatment in LI-PILO-induced SRSs rats. On the other hand, a single acute administration of a-asarone (50-200 mg/kg) produced weak anticonvulsant activity in MES and PTZ-induced seizures. The results of this laboratory animal study indicate that chronically administered a-asarone possesses anticonvulsant activity in the mammalian experimental model used, and thus suggest that a-asarone may be used as a natural supplementary remedy in the management of convulsions and epilepsy.

Topics: Acorus; Allylbenzene Derivatives; Animals; Anisoles; Anticonvulsants; Disease Models, Animal; Lethal Dose 50; Mice; Phytotherapy; Rats; Rats, Wistar; Seizures

Colorectal cancer is a leading cause of cancer mortality with a complex carcinogenesis that includes reduced cellular senescence. Lamin proteins are decreased in senescing cells, and frequently decreased in malignancies. This study identified a new drug candidate for colorectal cancer that appears to target cell senescence via a lamin protein. β-Asarone (1-propenyl-2,4,5-methoxybenzol) is a compound from the traditional medical herb Acorus calamus Linn. This study tested the in vitro and in vivo effects of β-asarone on colorectal cancer cells by testing cell viability using human colorectal cell lines HT29 and SW480 in MTT assays; tumorigenesis using xenografts in nude mice and a mouse model of colorectal cancer; cell senescence using senescence-associated β-galactosidase activity; and expression of cancer and senescence-related proteins, specifically lamins, Oct-1, p53, p21, and p15, by Western blot. β-Asarone appeared to increase expression of lamin B1, p53, p21, but not lamin A/C. β-Asarone regulates p15 expression by regulation of Oct-1 binding. Collectively, the results suggested that β-asarone inhibits colon cancer formation in vivo and in vitro by inducing senescence. Since β-asarone induced lamin B1 expression, a model is proposed in which β-asarone inhibits colorectal cancer by inducing senescence through lamin B1.

Topics: Acorus; Allylbenzene Derivatives; Animals; Anisoles; Antineoplastic Agents, Phytogenic; beta-Galactosidase; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cellular Senescence; Colorectal Neoplasms; Disease Models, Animal; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Lamin Type B; Lamins; Male; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Phytotherapy; Plant Extracts; Transplantation, Heterologous

Depression is one of the most common psychiatric diseases. Acorus tatarinowii Schott (Araceae) has shown many bioactivities in treatment of senile dementia and epilepsy. However, there is no report on antidepressant-like effects of the essential oil (EO) and its major components on animals under standardized experimental procedures.. This study was designed to investigate the antidepressant properties of EO and asarones from the rhizomes of A. tatarinowii.. Gas chromatography-mass spectrometry (GC/MS) was used to determine the composition of EO. The forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) were used to evaluate the antidepressant-like effects of EO and asarones. EO [30, 60, 120 or 240 mg/kg, per os (p.o.)], asarones (α-asarone and β-asarone) [5, 10 and 20 mg/kg, intraperitoneal (i.p.)] and imipramine (15 mg/kg, i.p.) were administered at 1 h, 30 min and 30 min before the test, respectively.. From the results of GC/MS, it was found that the main components of the EO were α-asarone (9.18%) and β-asarone (68.9%). From the results of FST and TST, the immobility time can be reduced to 166 ± 17 s (p < 0.01) and 146 ± 15 s (p < 0.05) by EO at the dose of 120 mg/kg. Moreover, significant antidepressant-like effects were shown by α-asarone with the immobility time of 178 ± 15 s (p < 0.05) and 159 ± 17 s (p < 0.01) in FST, or 147 ± 12 (p < 0.05) and 134 ± 12 s (p < 0.01) in TST at the dose of 10 and 20 mg/kg. β-Asarone also displayed antidepressant-like effects with an immobility time of 179 ± 18 s (p < 0.05) in FST or 142 ± 14 (p < 0.05) in TST at 20 mg/kg. However, no change in ambulation was observed in the OFT.. The results obtained indicate that the EO and asarones from the rhizomes of A. tatarinowii can be considered as a new therapeutic agent for curing depression.

Topics: Acorus; Allylbenzene Derivatives; Animals; Anisoles; Antidepressive Agents; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Gas Chromatography-Mass Spectrometry; Hindlimb Suspension; Imipramine; Male; Mice; Mice, Inbred ICR; Oils, Volatile; Rhizome; Swimming; Time Factors

A series of alpha-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of alpha-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Binding Sites; Computer Simulation; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Design; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, Inbred ICR; Schizosaccharomyces

Anticonvulsant properties of α-asarone were studied in mice at three doses with different toxicity. The 100mg/kg dose decreased both treadmill performance and locomotor activity, caused hypothermia, and potentiated pentobarbital-induced sleep. The last two effects and no toxicity were observed at 60 and 22mg/kg, respectively. In chemical (pentylenetetrazole, picrotoxin, N-methyl-D-aspartate, pilocarpine) and electrical (maximal electroshock) seizure tests, neither seizures nor death were prevented by 60 mg/kg α-asarone which, however, exhibited protective-like effects (delay in the onset of clonic and/or tonic seizures and/or in the death of mice). Magnesium deficiency-dependent audiogenic seizures responded to non-toxic doses of α-asarone (60 mg/kg and less): 22 mg/kg protecting 50% of tested animals. Because these seizures respond to both anti-seizure and antioxidant compounds, antioxidant properties of α-asarone were studied, indicating 5 Units of superoxide dismutase-like activity per mg α-asarone. Treatment of mice by α-asarone (daily dose of 100mg/kg during 7 days) induced brain antioxidant enzymes (superoxide dismutase, glutathione peroxidase and reductase) in striatum and hippocampus and to a lesser extent in cortex. In view of recent findings about deleterious roles of chronic inflammatory/oxidant stresses in human epilepsy outcome, antioxidant and inductive properties of α-asarone are proposed to be coherent bases for traditional clinical efficacy.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Anticonvulsants; Antioxidants; Brain; Disease Models, Animal; Female; Glutathione Peroxidase; Glutathione Reductase; Mice; Motor Activity; Seizures; Superoxide Dismutase

Topics: Administration, Oral; Allylbenzene Derivatives; Animals; Anisoles; Cholesterol, HDL; Cholesterol, LDL; Disease Models, Animal; Hypercholesterolemia; Male; Mice; Plants, Medicinal; Polysorbates; Triglycerides