Maiti Panchanan, Manna Jayeeta, Thammathong Joshua, Evans Bobbi, Dubey Kshatresh Dutta, Banerjee Souvik, Dunbar Gary L
Field Neurosciences Institute, Ascension St. Mary's Hospital, Saginaw, MI 48604, USA.
Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mt. Pleasant, MI 48859, USA.
Antioxidants (Basel). 2021 Oct 11;10(10):1592. doi: 10.3390/antiox10101592.
Despite its potent anti-amyloid properties, the utility of curcumin (Cur) for the treatment of Alzheimer's disease (AD) is limited due to its low bioavailability. Tetrahydrocurcumin (THC), a more stable metabolite has been found in Cur-treated tissues. We compared the anti-amyloid and neuroprotective properties of curcumin, bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC) and THC using molecular docking/dynamics, in-silico and in vitro studies. We measured the binding affinity, H-bonding capabilities of these compounds with amyloid beta protein (Aβ). Dot blot assays, photo-induced cross linking of unmodified protein (PICUP) and transmission electron microscopy (TEM) were performed to monitor the Aβ aggregation inhibition using these compounds. Neuroprotective effects of these derivatives were evaluated in N2a, CHO and SH-SY5Y cells using Aβ42 (10 µM) as a toxin. Finally, Aβ-binding capabilities were compared in the brain tissue derived from the 5× FAD mouse model of AD. We observed that THC had similar binding capability and Aβ aggregation inhibition such as keto/enol Cur and it was greater than BDMC and DMC. All these derivatives showed a similar degree of neuroprotection in vitro and labeled Aβ-plaques ex vivo. Overall, ECur and THC showed greater anti-amyloid properties than other derivatives. Therefore, THC, a more stable and bioavailable metabolite may provide greater therapeutic efficacy in AD than other turmeric derivatives.
尽管姜黄素（Cur）具有强大的抗淀粉样蛋白特性，但其治疗阿尔茨海默病（AD）的效用因生物利用度低而受到限制。在经姜黄素处理的组织中发现了一种更稳定的代谢产物四氢姜黄素（THC）。我们通过分子对接/动力学、计算机模拟和体外研究，比较了姜黄素、双去甲氧基姜黄素（BDMC）、去甲氧基姜黄素（DMC）和四氢姜黄素的抗淀粉样蛋白和神经保护特性。我们测量了这些化合物与淀粉样β蛋白（Aβ）的结合亲和力和氢键结合能力。进行斑点印迹分析、未修饰蛋白质的光诱导交联（PICUP）和透射电子显微镜（TEM），以监测使用这些化合物对Aβ聚集的抑制作用。使用Aβ42（10 µM）作为毒素，在N2a、CHO和SH-SY5Y细胞中评估这些衍生物的神经保护作用。最后，在源自AD的5×FAD小鼠模型的脑组织中比较Aβ结合能力。我们观察到，四氢姜黄素具有与酮/烯醇姜黄素相似的结合能力和Aβ聚集抑制作用，且大于双去甲氧基姜黄素和去甲氧基姜黄素。所有这些衍生物在体外均表现出相似程度的神经保护作用，在体内外均标记了Aβ斑块。总体而言，姜黄素和四氢姜黄素比其他衍生物表现出更强的抗淀粉样蛋白特性。因此，四氢姜黄素这种更稳定且生物利用度更高的代谢产物，在AD治疗中可能比其他姜黄衍生物具有更高的治疗效果。
