Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease

• Published in: Free radical biology & medicine Vol. 84; pp. 331 - 343
• Main Authors: Zhang, Zaijun, Li, Guohui, Szeto, Samuel S.W., Chong, Cheong Meng, Quan, Quan, Huang, Chen, Cui, Wei, Guo, Baojian, Wang, Yuqiang, Han, Yifan, Michael Siu, K.W., Yuen Lee, Simon Ming, Chu, Ivan K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2015
• Subjects: Animals; Anti-inflammation; Antiparkinson Agents - pharmacology; Antiparkinson Agents - therapeutic use; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - physiology; Drug Evaluation, Preclinical; Flavonoids - pharmacology; Flavonoids - therapeutic use; Free radicals; Heme Oxygenase-1 - metabolism; Hydroxybenzoates - pharmacology; Hydroxybenzoates - therapeutic use; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; NF-E2-Related Factor 2 - metabolism; NF-κB; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; NRF2; Oxidative Stress; Parkinson disease; Parkinson Disease - drug therapy; PC12 Cells; Proteome - metabolism; Proteomics; Rats; Transcription Factor RelA - metabolism; Zebrafish; Neuroprotection; Free radicals; Parkinson disease; 6-OHDA; HO-1; MTT; Anti-inflammation; PCA; LDH; NF-κB; ARE; NRF2; PD; TH; Proteomics; MPTP; DA
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2015.02.030

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-κB 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.
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•PCA and chrysin, extracted from Alpinia oxyphylla, efficiently treat in vivo and in vitro models of Parkinson disease.•The molecular mechanism for neuroprotection by PCA+chrysin in vitro involves modulation of the NRF2 and NF-κB pathways.•These results support the discovery and development of novel multiple-target therapeutics, especially natural medicines.