Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways.
Berberine (BBR) is a renowned natural compound that exhibits potent neuroprotective activities. However, the cellular and molecular mechanisms are still unclear. Hormesis is an adaptive mechanism generally activated by mild oxidative stress to protect the cells from further damage. Many phytochemicals have been shown to induce hormesis. This study aims to investigate whether the neuroprotective activity of BBR is mediated by hormesis and the related signaling pathways in 6-OHDA-induced PC12 cells and zebrafish neurotoxic models. Our results demonstrated that BBR induced a typical hormetic response in PC12 cells, i.e. low dose BBR significantly increased the cell viability, while high dose BBR inhibited the cell viability. Moreover, low dose BBR protected the PC12 cells from 6-OHDA-induced cytotoxicity and apoptosis, whereas relatively high dose BBR did not show neuroprotective activity. The hormetic and neuroprotective effects of BBR were confirmed to be mediated by up-regulated PI3K/AKT/Bcl-2 cell survival and Nrf2/HO-1 antioxidative signaling pathways. In addition, low dose BBR markedly mitigated the 6-OHDA-induced dopaminergic neuron loss and behavior movement deficiency in zebrafish, while high dose BBR only slightly exhibited neuroprotective activities. These results strongly suggested that the neuroprotection of BBR were attributable to the hormetic mechanisms via activating cell survival and antioxidative signaling pathways.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Chao
C
Zhang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Chuwen
C
Li
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China; Lee's Pharmaceutical (Hong Kong) Ltd., Shatin, Hong Kong 999077, China.
Shenghui
S
Chen
Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Shandong Provincial Key Laboratory for Biosensor, Biology Institute of Shandong Academy of Sciences, Jinan 250014, China.
Zhiping
Z
Li
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Xuejing
X
Jia
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Kai
K
Wang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Jiaolin
J
Bao
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Yeer
Y
Liang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Xiaotong
X
Wang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Meiwan
M
Chen
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Peng
P
Li
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Huanxing
H
Su
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Jian-Bo
JB
Wan
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
Simon Ming Yuen
SMY
Lee
Key Laboratory for Drug Screening Technology of Shandong Academy of Sciences, Shandong Provincial Key Laboratory for Biosensor, Biology Institute of Shandong Academy of Sciences, Jinan 250014, China. Electronic address: hliukch@sdas.org.
Kechun
K
Liu
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China. Electronic address: chengweihe@umac.mo.
Chengwei
C
He
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001599:Berberine / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000235:genetics; D059165:Hormesis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051058:Oncogene Protein v-akt / Q000235:genetics; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D001599:Berberine; D016627:Oxidopamine; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt
Berberine; Hormesis; Neuroprotection; PC12 cells; Zebrafish