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  • Since the aggregation of neurotoxic forms

    2019-11-08

    Since the aggregation of neurotoxic forms of Aβ plays a pivotal role in AD pathogenesis, an approach that using small molecules to bind Aβ monomers and prevent their assembly into cytotoxic oligomers attracts great interest for the development of AD drugs. Therefore, the potential inhibitory activity of compounds , , , and towards Aβ self-aggregation was determined using thioflavin T fluorescence method in the present study. As shown in , SAR131675 showed the highest inhibitory activity against Aβ aggregation in a dose-dependent manner (53.74% at 20 μM, 65.70% at 40 μM, and 73.35% at 80 μM), which was only slightly lower than that of the positive control (curcumin). By contrast, two isoflavones ( and ) were inactive, indicating isoflavones might not be responsible for anti-Aβ aggregation in this plant. In addition, dihydroflavone demonstrated slightly lower inhibitory effect (50.93%, 63.48%, and 73.47% at 20, 40, and 80 μM, respectively) than . In the search for novel and effective leads for AD treatment from natural resources, many flavonoids have been reported to be cholinesterase inhibitors, β-secretase (BACE)-1 inhibitors, and agents promoting anti-aggregation and clearance of Aβ peptides. Selective BChE inhibitors attract increasing attention for the development of AD drugs due to the compensatory role of BChE for acetyl choline hydrolysis in the late stage of AD. In addition, given the multifactorial pathogenesis of AD, multifunctional inhibitors targeting cholinesterase as well as Aβ aggregation may provide more effective drug candidates for AD treatment. In the present study, it should be noted that two flavonoids and with prominent anticholinesterase activities also exhibited significant anti-Aβ aggregation effects. Additionally, the significant inhibitory activity of on BACE-1 (IC = 9.8 μM) has been reported previously, suggesting that could be a potential multi-target lead compound worthy of further investigation. Meanwhile, the weak activities on Aβ aggregation of isoflavones and suggested they could serve as specific BChE inhibitors for AD therapy. In summary, the current study firstly reported the inhibitory effects of extracts and its chemical constituents on cholinesterases and Aβ aggregation. One novel rotenoid () and nine known flavonoids (–) were obtained from the active EtOAc part of this species. The biological assays results indicated that compounds , , and should be further investigated as multifunctional or specific agents for AD therapy. These findings revealed the potential medicinal and economic values of in AD prevention/treatment. Acknowledgments Financial support from the Science and Technology Project of Sichuan Province in China (No. 2016JY0062, 2019ZDYF1197) is gratefully acknowledged.
    Introduction Rosemary (Rosmarinus officinalis) is a plant of the Labiatae family. It contains active substances that have desirable properties for industrial and herbal medicine applications, e.g. essential oils (1.5–2.5%), tannins, flavonoids, triterpenes, bitters, saponins, resins, phytosterols, rosmarinic acid and many others. Essential oil in rosemary emits strong camphor aroma. It is composed of camphor (14.5%), cineol (12%), borneol (10.5%), pinene (8.5%) and camphene (7%) [1]. Reference publications list a wide range of properties of rosemary resulting from its content of active compounds, with most reports on its antioxidative properties. Researchers prove that the antioxidative effect of rosemary extract could successfully substitute butylhydroxytoluene (BHT) in dehydrated chicken eggs and fish, and rosemary extract could replace it in sausages, pasta, peanut butter and oil [1], [2], [3]. Scientific reports also provide information about antioxidative and health-promoting properties of compounds contained in rosemary leaves, which inhibit neurodegenerative processes. There were also reports on the influence of rosemary on better results in cognitive tests [4]. Another study confirmed the positive effect of rosemary extract on short-term memory [5]. Rosemary extract exhibited high activity against acetylcholinesterase and butyrylcholinesterase in an experimental combination with cholinesterases [6].