title: Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease.
abstract: 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.
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangdong, China; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong, China.
authors.forename: Samuel S W
authors.initials: SSW
authors.lastname: Szeto
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Cheong Meng
authors.initials: CM
authors.lastname: Chong
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Quan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangdong, China.
authors.forename: Baojian
authors.initials: B
authors.lastname: Guo
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, College of Pharmacy, Jinan University, Guangdong, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada.
authors.forename: K W
authors.initials: KW
authors.lastname: Michael Siu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China. Electronic address: simonlee@umac.mo.
authors.forename: Simon Ming
authors.initials: SM
authors.lastname: Yuen Lee
authors.affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong, China. Electronic address: ivankchu@hku.hk.
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Chu
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D051547:Heme Oxygenase-1 / Q000378:metabolism; D062385:Hydroxybenzoates / Q000494:pharmacology* / Q000627:therapeutic use; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D051381:Rats; D051996:Transcription Factor RelA / Q000378:metabolism; D015027:Zebrafish
chemical_list: D000978:Antiparkinson Agents; D005419:Flavonoids; D062385:Hydroxybenzoates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D020543:Proteome; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D009569:Nitric Oxide; C009091:protocatechuic acid; C043561:chrysin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051547:Heme Oxygenase-1
keywords: Anti-inflammation; Free radicals; NF-κB; NRF2; Neuroprotection; Parkinson disease; Proteomics