Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease
Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease
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DOI：
10.1016/j.freeradbiomed.2015.02.030
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发表时间：
2015-07-01
影响因子：
7.4
通讯作者：
Chu, Ivan K.
中科院分区：
文献类型：
--
作者：
Zhang, Zaijun;Li, Guohui;Chu, Ivan K.
使用具有不同作用机制的药物组合的基于多药理学的策略作为发现用于神经退行性疾病的潜在创新药物的新方法越来越受到关注。我们用这种方法来检查两个多酚，原儿茶酸（PCA）和白杨素，确定从益智的果实的神经保护作用的组合。我们的研究结果表明，协同神经保护作用，白杨素增强PCA的保护作用，导致更大的细胞活力和6-羟基多巴胺处理的PC 12细胞的乳酸脱氢酶释放减少。它们的组合还显著减弱了斑马鱼和小鼠中化学诱导的多巴胺能神经元损失。我们研究了这些集体的细胞保护作用的分子机制，通过蛋白质组学分析处理的PC 12细胞，导致12个调节蛋白的鉴定。进一步表征了其中两种，从而确定用PCA和白杨素预处理导致（i）增加的核因子-红细胞2相关因子2蛋白表达和转录活性：（ii）用标志性抗氧化酶（包括血红素加氧酶-1、超氧化物歧化酶和过氧化氢酶）的上调表达调节细胞氧化还原状态;和（iii）丙二醛（一种已知的脂质过氧化产物）的水平降低。用PCA和白杨素处理还抑制核因子-κ B的活化和诱导型一氧化氮合酶的表达。我们的研究结果表明，天然产物，当组合使用时，可以是治疗帕金森病等疾病的有效的潜在治疗剂。涉及PCA和白杨素的治疗通过细胞机制的组合表现出其增强的神经保护作用：抗氧化细胞保护和抗炎。(C)2015 Elsevier Inc. All rights reserved.
Polypharmacology-based strategies using drug combinations with different mechanisms of action are gaining increasing attention as a novel methodology to discover potentially innovative medicines for neurodegenerative disorders. We used this approach to examine the combined neuroprotective effects of two polyphenols, protocatechuic acid (PCA) and chrysin, identified from the fruits of Alpinia oxyphylla. Our results demonstrated synergistic neuroprotective effects, with chrysin enhancing the protective effects of PCA, resulting in greater cell viability and decreased lactate dehydrogenase release from 6-hydroxydopamine-treated PC12 cells. Their combination also significantly attenuated chemically induced dopaminergic neuron loss in both zebrafish and mice. We examined the molecular mechanisms underlying these collective cytoprotective effects through proteomic analysis of treated PC12 cells, resulting in the identification of 12 regulated proteins. Two were further characterized, leading to the determination that pretreatment with PCA and chrysin resulted in (i) increased nuclear factor-erythroid 2-related factor 2 protein expression and transcriptional activity: (ii) modulation of cellular redox status with the upregulated expression of hallmark antioxidant enzymes, including heme oxygenase-1, superoxide dismutase, and catalase; and (iii) decreased levels of malondialdehyde, a known lipid peroxidation product. Treatment with PCA and chrysin also inhibited activation of nuclear factor-kappa B and expression of inducible nitric oxide synthase. Our findings suggest that natural products, when used in combination, can be effective potential therapeutic agents for treating diseases such as Parkinson disease. A therapy involving both PCA and chrysin exhibits its enhanced neuroprotective effects through a combination of cellular mechanisms: antioxidant cytoprotection and anti-inflammation. (C) 2015 Elsevier Inc. All rights reserved.