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Caffeic acid reduces A53T alpha-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson's disease

文献类型：期刊论文

作者Zhang, Yu1,2; Wu, Qimei1,2; Zhang, Lei1,2; Wang, Qing1,2; Yang, Zexian1,2; Liu, Jia3; Feng, Linyin1,2
刊名PHARMACOLOGICAL RESEARCH
出版日期2019-12-01
卷号150页码:14
ISSN号1043-6618
关键词Caffeic acid A53T Parkinson's disease Autophagy JNK
DOI10.1016/j.phrs.2019.104538
通讯作者Feng, Linyin(lyfeng@simm.ac.cn)
英文摘要The human A53T mutant of alpha-synuclein tends to aggregate and leads to neurotoxicity in familial Parkinson's disease (PD). The aggregation of alpha-synuclein is also found in sporadic PD. Thus, targeting alpha-synuclein clearance could be used as a drug-discovery strategy for PD treatment. Caffeic acid (CA) has shown neuroprotection in Alzheimer's disease or cerebral ischaemia; however, it is unclear whether CA confers neuroprotection in alpha-synuclein-induced PD models. Here we focus on whether and how A53T alpha-synuclein is affected by CA. We assessed the effect of CA on cell viability in SH-SY5Y cells overexpressing A53T alpha-synuclein. Pathway-related inhibitors were used to identify the autophagy mechanisms. Seven-month-old A53T alpha-synuclein transgenic mice (A53T Tg mice) received CA daily for eight consecutive weeks. Behaviour tests including the buried food pellet test, the pole test, the Rotarod test, open field analysis, and gait analysis were used to evaluate the neuroprotective effect of CA. Tyrosine hydroxylase and alpha-synuclein were assessed by immunohistochemistry or western blot in the substantia nigra (SN). We found that CA alleviated the cell damage induced by overexpressing A53T alpha-synuclein and that CA reduced A53T alpha-synuclein by activating the JNK/Bcl-2-mediated autophagy pathway. The efficacy of CA on A53T alpha-synuclein degradation was reversed by the autophagy inhibitor bafilomycin Al and the JNK inhibitor SP600125. In A53T Tg mice, CA improved behavioural impairments, attenuated loss of dopaminergic neurons, enhanced autophagy and reduced alpha-synuclein in the SN. Thus, the results provide scientific evidence for the neuroprotective effect of CA in PD. Our work lays the foundation for CA clinical trials to treat PD in the future.
WOS关键词REACTIVE OXYGEN ; UP-REGULATION ; CELL ; PATHOLOGY ; MUTANT ; CLEARANCE ; MUTATION ; DEFICITS ; SYSTEM ; TARGET
资助项目National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology[2018ZX09711002] ; Strategic Priority Reseach Program of the Chinese Academy of Sciences[XDA12040216] ; Foundation of Shanghai Science and Technology Committee[18DZ2290200]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
WOS记录号WOS:000527002800004
源URL[http://119.78.100.183/handle/2S10ELR8/280423]  
专题中国科学院上海药物研究所
通讯作者Feng, Linyin
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Neuropharmacol, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Yu,Wu, Qimei,Zhang, Lei,et al. Caffeic acid reduces A53T alpha-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson's disease[J]. PHARMACOLOGICAL RESEARCH,2019,150:14.
APA Zhang, Yu.,Wu, Qimei.,Zhang, Lei.,Wang, Qing.,Yang, Zexian.,...&Feng, Linyin.(2019).Caffeic acid reduces A53T alpha-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson's disease.PHARMACOLOGICAL RESEARCH,150,14.
MLA Zhang, Yu,et al."Caffeic acid reduces A53T alpha-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson's disease".PHARMACOLOGICAL RESEARCH 150(2019):14.

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来源：上海药物研究所

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