期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 84, 期 -, 页码 331-343出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.02.030
关键词
Neuroprotection; Anti-inflammation; Proteomics; NRF2; NF-kappa B; Parkinson disease; Free radicals
资金
- Hong Kong Research Grans Council [HKU 701611P, 701613P]
- University of Hong Kong
- Science and Technology Development Fund of Macao SAR [045/2007/A3, 058/2009/A2, 078/2011/A3]
- Research Committee, University of Macau [UL017/09-Y1]
- National Natural Science Foundation of China [NSFC 81303251]
- Science and Technology Program of Guangzhou [2014J4100097]
- China Postdoctoral Science Foundation [2012T50748, 2013M531911]
- Fundamental Research Funds for the Central Universities [21613331]
- 111 Project [B13038]
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.
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