Theacrine, a purine alkaloid from kucha, protects against Parkinson's disease through SIRT3 activation

Duan，Wen Jun1,2,3; Liang，Lei1,2,3; Pan，Ming Hai1,2,3; Lu，Dan Hua1,2,3; Wang，Ting Mei1,2,3; Li，Shan Bing1,2,3; Zhong，Han Bing4; Yang，Xuan Jun4,5; Cheng，Yan6; Liu，Bo7; Li，Wei Xi8; Kurihara，Hiroshi1,2,3; Bi，Wei9; Li，Yi Fang1,2,3; He，Rong Rong1,2,3

2020-10-01

10.1016/j.phymed.2020.153281

PHYTOMEDICINE   影响因子和分区

0944-7113

1618-095X

Background: Oxidative damage of dopaminergic neurons is the fundamental causes of Parkinson's disease (PD) that has no standard cure at present. Theacrine, a purine alkaloid from Chinese tea Kucha, has been speculated to benefit the neurodegeneration in PD, through similar actions to its chemical analogue caffeine, albeit excluding side effects. Theacrine has nowadays gained a lot of interest for its multiple benefits, while the investigations are weak and insufficient. Hypothesis/Purpose: It is well-known that tea has a wide range of functions, especially in the prevention and treatment of neurodegenerative diseases. Theacrine is an active monomer compound in Camellia assamica var. kucha Hung T. Chang & H.S.Wang (Kucha), which appears to be effective and safe in PD therapy. The aim of this study is to examine its actions in diverse PD models and explore the mechanisms. Study Design: For determination of theacrine's effects, we employed diverse oxidative damage-associated PD models, including 6-OHDA-treated rats, MPTP-treated mice/zebrafish and MPP-treated SH-SY5Y cells, and using caffeine, selegiline and depranyl as positve control. For investigation and verification of the mechanisms, we utilized approaches testing mitochondrial function-related parameters and enzyme activity as well as applied gene knockdown and overexpression. Methods: We employed behavioral tests including spontaneous activity, pole, swimming, rotarod and gait, immunohistochemistry, HPLC, flow cytometry, immunohistochemistry, Western blot, gene knockdown by siRNA and overexpression by plasmid in this study. Results: Theacrine is demonstrated to retrieve the loss of dopaminergic neurons and the damages of behavioral performance in multiple animal models of PD (6-OHDA-treated rats and in MPTP-treated mice and zebrafish). The followed data of MPP-treated SH-SY5Y cells indicate that theacrine relieves apoptosis resulted from oxidative damage and mitochondrial dysfunction. Further investigations illustrate that theacrine activates SIRT3 directly. It is of advantage to prevent apoptosis through SIRT3-mediated SOD2 deacetylation that reduces ROS accumulation and restores mitochondrial function. This concept is elaborated by 3TYP that inhibits SIRT3 enzyme activity and knockdown/overexpression of SIRT3 gene, demonstrating a crucial role of SIRT3 in theacrine-benefited dopaminergic neurons. Conclusion: Theacrine prevents apoptosis of dopaminergic neurons through directly activating SIRT3 which deacetylating SOD2 and restoring mitochondrial functions.

Dopaminergic neurons Mitochondrial dysfunction Oxidative damage Parkinson's disease SIRT3 Theacrine

SCI

英语

其他

National Key Research and Development Program of China[2017YFC1700400][2017YFC1700404] ; Natural Science Foundation of China[81873209][81903821][81973718][U1801284] ; Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program[2017BT01Y036] ; Guangdong Science and Technology Foundation for Distinguished Young Scholars[2017A030306004] ; Natural Science Foundation of Guangdong[2019A1515010909] ; Science and Technology Program of Guangzhou[201903010062]

Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine

Plant Sciences ; Chemistry, Medicinal ; Integrative & Complementary Medicine ; Pharmacology & Pharmacy

WOS:000566511300015

ELSEVIER GMBH

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85088127095

Scopus

1.Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility,Jinan University,Guangzhou,510632,China
2.International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE),College of Pharmacy,Jinan University,Guangzhou,510632,China
3.Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou,510632,China
4.Department of Biology,Southern University of Science and Technology,Shenzhen,518055,China
5.Institute of Chinese Medical Sciences,University of Macau,Macau,China
6.Xiangya School of Pharmaceutical Sciences,Central South University,Changsha,410008,China
7.State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Chengdu,610041,China
8.School of Traditional Chinese Medicine,Yunnan University of Traditional Chinese Medicine,Kunming,650500,China
9.Department of Neurology,The First Affiliated Hospital of Jinan University,Guangzhou,510630,China

Duan，Wen Jun,Liang，Lei,Pan，Ming Hai,et al. Theacrine, a purine alkaloid from kucha, protects against Parkinson's disease through SIRT3 activation[J]. PHYTOMEDICINE,2020,77.

Duan，Wen Jun.,Liang，Lei.,Pan，Ming Hai.,Lu，Dan Hua.,Wang，Ting Mei.,...&He，Rong Rong.(2020).Theacrine, a purine alkaloid from kucha, protects against Parkinson's disease through SIRT3 activation.PHYTOMEDICINE,77.

Duan，Wen Jun,et al."Theacrine, a purine alkaloid from kucha, protects against Parkinson's disease through SIRT3 activation".PHYTOMEDICINE 77(2020).