ABSTRACT
The present study investigated the therapeutic effects of the curcumin derivative 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy)phenyl]ethenyl]-1H-pyrazole (GT863) in amyotrophic lateral sclerosis (ALS). The inhibitory effect of GT863 on superoxide dismutase 1 (SOD1) aggregation was evaluated in cell-free assays. GT863 interfered with the conformational changes of the SOD1 protein and later, oligomeric aggregation. Furthermore, its antioxidant, anti-inflammatory, and neuroprotective effects were evaluated in cell-free and cultured cell assays. GT863 inhibited H2O2- and glutamate-induced cytotoxicity and activated an antioxidant responsive element pathway. Additionally, in vivo effects of GT863 in the ALS mice model were evaluated by its oral administration to H46R mutant SOD1 transgenic mice. Rotarod test showed that GT863 administration significantly slowed the progression of motor dysfunction in the mice. In addition, GT863 substantially reduced highly-aggregated SOD1, further preserving large neurons in the spinal cord of GT863-treated mice. Collectively, these results indicated that GT863 could be a viable therapeutic agent with multiple vital actions for the treatment of ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Curcumin , Mice , Animals , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Curcumin/pharmacology , Curcumin/therapeutic use , Antioxidants/therapeutic use , Hydrogen Peroxide/metabolism , Hydrogen Peroxide/therapeutic use , Mice, Transgenic , Superoxide Dismutase/genetics , Disease Models, Animal , Spinal Cord/metabolismABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disease and is known to be the most common cause of dementia. We previously described the benefits of aromatherapy on the cognitive function of patients with AD utilizing various aromatic essential oils; however, its mechanism of action remains poorly understood. Consequently, in the present study, this mechanism was thoroughly evaluated employing a dementia mice model, specifically the senescence-accelerated mouse prone 8. The mice were exposed to a mixture of lemon and rosemary oil at nighttime as well as to a mixture of lavender and orange oil in the daytime for 2 months. The cognitive function of the mice was assessed before and after treatment with the aromatic essential oils using the Y-maze test. Moreover, the brain levels of amyloid beta (Aß), abnormally phosphorylated tau, and brain-derived neurotrophic factor (BDNF) were measured following treatment. The benefits of aromatherapy on the cognitive function in mice were confirmed. It was also established that the brain levels of Aß and abnormally phosphorylated tau were considerably lower in the aromatherapy group, while the levels of BDNF were marginally higher. These results suggest that aromatherapy employing these aromatic essential oils is beneficial for the prevention and treatment of AD.
Subject(s)
Alzheimer Disease/psychology , Amyloid beta-Peptides/metabolism , Aromatherapy/methods , Cognitive Dysfunction/therapy , Oils, Volatile/administration & dosage , tau Proteins/metabolism , Alzheimer Disease/therapy , Animals , Brain/drug effects , Brain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Citrus/chemistry , Disease Models, Animal , Down-Regulation , Humans , Male , Maze Learning , Mice , Oils, Volatile/pharmacology , Phosphorylation , Plant Oils/administration & dosage , Plant Oils/pharmacology , Treatment OutcomeABSTRACT
Alzheimer's disease (AD) is the most common form of dementia and its prevention and treatment is a worldwide issue. Many natural components considered to be effective against AD have been identified. However, almost all clinical trials of these components for AD reported inconclusive results. We thought that multiple factors such as amyloid ß (Aß) and tau progressed the pathology of AD and that a therapeutic effect would be obtained by using multiple active ingredients with different effects. Thus, in this study, we treated ferulic acid (FA), phosphatidylserine (PS) and curcumin (Cur) in combination or alone to APPswe/PS1dE9 transgenic mice and evaluated cognitive function by Y-maze test. Consequently, only the three-ingredient group exhibited a significant improvement in cognitive function compared to the control group. In addition, we determined the amounts of Aß, brain-derived neurotrophic factor (BDNF), interleukin (IL)-1ß, acetylcholine and phosphorylated tau in the mouse brains after the treatment. In the two-ingredient (FA and PS) group, a significant decrease in IL-1ß and an increasing trend in acetylcholine were observed. In the Cur group, significant decreases in Aß and phosphorylated tau and an increasing trend in BDNF were observed. In the three-ingredient group, all of them were observed. These results indicate that the intake of multiple active ingredients with different mechanisms of action for the prevention and treatment of AD.
Subject(s)
Alzheimer Disease/drug therapy , Coumaric Acids/therapeutic use , Curcumin/therapeutic use , Neuroprotective Agents/therapeutic use , Phosphatidylserines/therapeutic use , Acetylcholine/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Brain/drug effects , Brain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Cognition/drug effects , Coumaric Acids/pharmacology , Curcumin/pharmacology , Drug Therapy, Combination , Interleukin-1beta/metabolism , Mice, Transgenic , Neuroprotective Agents/pharmacology , Phosphatidylserines/pharmacology , Presenilin-1/genetics , tau Proteins/metabolismABSTRACT
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia and the number of AD patients continues to increase worldwide. Components of the germ layer and bran of Brown rice (BR) help maintain good health and prevent AD. Because the germ layer and bran absorb little water and are very hard and difficult to cook, they are often removed during processing. To solve these problems, in this study, we tried to use a high-pressure (HP) technique. METHODS: We produced the highly water pressurized brown rice (HPBR) by pressurizing BR at 600 MPa, and then we fed it to an AD mouse model, senescence-accelerated mouse prone 8, to investigate the therapeutic effects of HPBR on cognitive dysfunction by Y-maze spatial memory test. RESULTS: HP treatment increased the water absorbency of BR without nutrient loss. HPBR ameliorated cognitive dysfunction and reduced the levels of amyloid-ß, which is a major protein responsible for AD, in the brain. CONCLUSIONS: These results suggest that HPBR is effective for preventing AD.
Subject(s)
Amyloid beta-Peptides/analysis , Behavior, Animal/drug effects , Brain Chemistry/drug effects , Cooking/methods , Dietary Fiber/pharmacology , Oryza , Alzheimer Disease , Animals , Body Weight/drug effects , Diet , Locomotion/drug effects , Male , Maze Learning/drug effects , Mice , Mice, Transgenic , Pressure , WaterABSTRACT
Aggregation of amyloid-ß (Aß) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of Aß and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aß and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aß aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aß and tau aggregation in vivo. PE859 inhibited Aß aggregation in vitro and protected cultured cells from Aß-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aß and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.