Neuroprotective Effect of Natural Alkaloid Fangchinoline Against Oxidative Glutamate Toxicity: Involvement of Keap1-Nrf2 Axis Regulation

doi:10.1007/s10571-019-00711-6

	Neuroprotective Effect of Natural Alkaloid Fangchinoline Against Oxidative Glutamate Toxicity: Involvement of Keap1-Nrf2 Axis Regulation
	Bao, Fengxia 1,2; Tao, Lingxue 2; Zhang, Haiyan 2,3
刊名	CELLULAR AND MOLECULAR NEUROBIOLOGY
	2019-11-01
卷号	39 期号:8 页码:1177-1186
关键词	Fangchinoline Keap1 Nrf2 Oxidative stress
ISSN号	0272-4340
DOI	10.1007/s10571-019-00711-6
通讯作者	Tao, Lingxue(lingxuetao@simm.ac.cn) ; Zhang, Haiyan(hzhang@simm.ac.cn)
英文摘要	Oxidative glutamate toxicity plays a vital role in the neurodegeneration diseases, including Alzheimer's diseases (AD). This study set out with the aim to investigate the beneficial effects of fangchinoline (FAN), a natural alkaloid, against glutamate-induced oxidative damage, and to clarify the underlying cellular and biochemical mechanisms. FAN prevented HT22 cells death from oxidative glutamate cytotoxicity in a dose-dependent manner, and significantly attenuated the overproduction of intracellular reactive oxygen species (ROS) and reversed the reduction of superoxide dismutase (SOD) activity induced by glutamate. Further investigations on the underlying mechanisms demonstrated that FAN potently up-regulated the protein level of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO-1), in glutamate-exposed HT22 cells. The protective effects of FAN were almost completely antagonized by inhibitor of Nrf2. Subsequent studies revealed that FAN could down-regulate Kelch-like ECH-associated protein 1 (Keap1) in both mRNA level and protein level. To sum up, our result demonstrated the protective effects of FAN against glutamate-induced oxidative neuronal damage, and for the first time clarified the anti-oxidative mechanisms of FAN involve activating endogenous antioxidant defense system including enhancing SOD activity and regulating Keap1/Nrf-2 antioxidation signaling through modulation of Keap1 expression. Above results shed more light on the molecular mechanisms of FAN's neuroprotective effects, and may provide important clues for the drug development in preventing oxidative stress-associated neurodegenerative diseases.
资助项目	National Natural Science Foundation of China[81872859] ; National Natural Science Foundation of China[81703507] ; National Natural Science Foundation of China[81522045]
WOS关键词	ALZHEIMERS-DISEASE ; CELL-DEATH ; STRESS ; NRF2 ; ACTIVATION ; INFLAMMATION ; INHIBITION ; MECHANISMS ; APOPTOSIS ; PATHWAY
WOS研究方向	Cell Biology ; Neurosciences & Neurology
语种	英语
出版者	SPRINGER/PLENUM PUBLISHERS
WOS记录号	WOS:000487899600009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/288548]
专题	中国科学院上海药物研究所
通讯作者	Tao, Lingxue; Zhang, Haiyan
作者单位	1.Shanghai Univ, Lab Neuropharmacol & Neurotoxicol, Shanghai 200444, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Shanghai Inst Mat Med, Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Bao, Fengxia,Tao, Lingxue,Zhang, Haiyan. Neuroprotective Effect of Natural Alkaloid Fangchinoline Against Oxidative Glutamate Toxicity: Involvement of Keap1-Nrf2 Axis Regulation[J]. CELLULAR AND MOLECULAR NEUROBIOLOGY,2019,39(8):1177-1186.
APA	Bao, Fengxia,Tao, Lingxue,&Zhang, Haiyan.(2019).Neuroprotective Effect of Natural Alkaloid Fangchinoline Against Oxidative Glutamate Toxicity: Involvement of Keap1-Nrf2 Axis Regulation.CELLULAR AND MOLECULAR NEUROBIOLOGY,39(8),1177-1186.
MLA	Bao, Fengxia,et al."Neuroprotective Effect of Natural Alkaloid Fangchinoline Against Oxidative Glutamate Toxicity: Involvement of Keap1-Nrf2 Axis Regulation".CELLULAR AND MOLECULAR NEUROBIOLOGY 39.8(2019):1177-1186.