Schisantherin A protects against 6-OHDA-induced dopaminergic neuron damage in zebrafish and cytotoxicity in SH-SY5Y cells through the ROS/NO and AKT/GSK3β pathways.
BACKGROUND
The fruit of Schisandra chinensis (Turcz.) Baill, has been traditionally used in management of liver diseases and ageing associated neurodegeneration. The bioactive compound from this medicinal plant would be valuable for its potential use in prevention and treatment of Parkinson׳s disease.


OBJECTIVE
The overall objective of the present study was to understand the neuroprotective effect of schisantherin A, a dibenzocyclooctadiene lignan from the fruit of S. chinensis (Turcz.) Baill, and to elucidate its underlying mechanism of action.


METHODS
This study investigated the protective effect of schisantherin A against selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced neural damage in human neuroblastoma SH-SY5Y cells and zebrafish models. Oxidative stress and related signaling pathways underlying the neuroprotective effect were determined by multiple biochemical assays and Western blot.


RESULTS
Pretreatment with schisantherin A offered neuroprotection against 6-OHDA-induced SH-SY5Y cytotoxicity. Moreover, schisantherin A could prevent 6-OHDA-stimulated dopaminergic neuron loss in zebrafish. Our mechanistic study showed that schisantherin A can regulate intracellular ROS accumulation, and inhibit NO overproduction by down-regulating the over-expression of iNOS in 6-OHDA treated SH-SY5Y cells. Schisantherin A also protects against 6-OHDA-mediated activation of MAPKs, PI3K/Akt and GSK3β.


CONCLUSIONS
These findings demonstrate that schisantherin A may have potential therapeutic value for neurodegenerative diseases associated with abnormal oxidative stress such as Parkinson׳s disease.
State Key Laboratory of Quality Research of Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Lun Qing
LQ
Zhang
State Key Laboratory of Quality Research of Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Fei
F
Sa
State Key Laboratory of Quality Research of Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Cheong Meng
CM
Chong
State Key Laboratory of Quality Research of Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Ying
Y
Wang
State Key Laboratory of Quality Research of Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Zhong Yan
ZY
Zhou
Laboratory of Neurodegenerative Diseases, LKS Faculty of Medicine, and State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China.
Raymond Chuen Chung
RC
Chang
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen, China.
Shun Wan
SW
Chan
State Key Laboratory of Quality Research of Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Pui Man
PM
Hoi
State Key Laboratory of Quality Research of Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: simonlee@umac.mo.
Simon Ming
SM
Yuen Lee
D000818:Animals; D000978:Antiparkinson Agents / Q000302:isolation & purification / Q000494:pharmacology; D045744:Cell Line, Tumor; D034242:Cyclooctanes / Q000302:isolation & purification / Q000494:pharmacology*; D004149:Dioxoles / Q000302:isolation & purification / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D032141:Schisandra / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish
D000978:Antiparkinson Agents; D034242:Cyclooctanes; D004149:Dioxoles; D017705:Lignans; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C034557:schizandrer A; D016627:Oxidopamine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
6-hydroxydopamine (6-OHDA); Oxidative stress; Parkinson׳s disease; Schisantherin A