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      Evodiamine improves congnitive abilities in SAMP8 and APP swe/PS1 ΔE9 transgenic mouse models of Alzheimer's disease

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          Abstract

          Aim:

          To investigate the effect of evodiamine (a quinolone alkaloid from the fruit of Evodia rutaecarpa) on the progression of Alzheimer's disease in SAMP8 and APP swe/PS1 ΔE9 transgenic mouse models.

          Methods:

          The mice at age of 5 months were randomized into the model group, two evodiamine (50 mg·kg −1·d −1 and 100 mg·kg −1·d −1) groups and an Aricept (2 mg·kg −1·d −1) group. The littermates of no-transgenic mice and senescence accelerated mouse/resistance 1 mice (SAMR1) were used as controls. After 4 weeks of treatment, learning abilities and memory were assessed using Morris water-maze test, and glucose uptake by the brain was detected using positron emission tomography/computed tomography (PET/CT). Expression levels of IL-1β, IL-6, and TNF-α in brain tissues were detected using ELISA. Expression of COX-2 protein was determined using Western blot.

          Results:

          In Morris water-maze test, evodiamine (100 mg·kg −1·d −1) significantly alleviated the impairments of learning ability and memory. Evodiamine (100 mg·kg −1·d −1) also reversed the inhibition of glucose uptake due to development of Alzheimer's disease traits in mice. Furthermore, the dose of evodiamine significantly decreased the expression of IL-1β, IL-6, TNF-α, and COX-2 that were involved in the inflammation due to Alzheimer's disease.

          Conclusion:

          The results indicate that evodiamine (100 mg·kg −1·d −1) improves cognitive abilities in the transgenic models of Alzheimer's disease.

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          Most cited references37

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          Inflammation and Alzheimer's disease.

          Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
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            Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides.

            Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Abeta could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit beta5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease.
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              Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease.

              Resveratrol, a polyphenol found in red wine, peanuts, soy beans, and pomegranates, possesses a wide range of biological effects. Since resveratrol's properties seem ideal for treating neurodegenerative diseases, its ability to diminish amyloid plaques was tested. Mice were fed clinically feasible dosages of resveratrol for forty-five days. Neither resveratrol nor its conjugated metabolites were detectable in brain. Nevertheless, resveratrol diminished plaque formation in a region specific manner. The largest reductions in the percent area occupied by plaques were observed in medial cortex (-48%), striatum (-89%) and hypothalamus (-90%). The changes occurred without detectable activation of SIRT-1 or alterations in APP processing. However, brain glutathione declined 21% and brain cysteine increased 54%. The increased cysteine and decreased glutathione may be linked to the diminished plaque formation. This study supports the concept that onset of neurodegenerative disease may be delayed or mitigated with use of dietary chemo-preventive agents that protect against beta-amyloid plaque formation and oxidative stress.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                March 2011
                31 January 2011
                : 32
                : 3
                : 295-302
                Affiliations
                [1 ]Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College , Beijing 100021, China
                [2 ]Department of Pathology, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College , Beijing 100021, China
                Author notes
                Article
                aps2010230
                10.1038/aps.2010.230
                4002780
                21278785
                089e9119-f6e9-4af2-9595-e6055d7e0cc5
                Copyright © 2011 CPS and SIMM
                History
                : 20 June 2010
                : 22 December 2010
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                evodiamine,alzheimer's disease,imaging,morris water-maze test,samp8,appswe/ps1δe9,inflammation

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