Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia.
Many phytochemicals function as noxious agents that protect plants against insects and other damaging organisms. However, at subtoxic doses, the same phytochemicals may activate adaptive cellular stress response pathways that can protect cells against a variety of adverse conditions. We screened a panel of botanical pesticides using cultured human and rodent neuronal cell models, and identified plumbagin as a novel potent activator of the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. In vitro, plumbagin increases nuclear localization and transcriptional activity of Nrf2, and induces the expression of the Nrf2/ARE-dependent genes, such as heme oxygenase 1 in human neuroblastoma cells. Plumbagin specifically activates the Nrf2/ARE pathway in primary mixed cultures from ARE-human placental alkaline phosphatase reporter mice. Exposure of neuroblastoma cells and primary cortical neurons to plumbagin provides protection against subsequent oxidative and metabolic insults. The neuroprotective effects of plumbagin are abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo, administration of plumbagin significantly reduces the amount of brain damage and ameliorates-associated neurological deficits in a mouse model of focal ischemic stroke. Our findings establish precedence for the identification and characterization of neuroprotective phytochemicals based upon their ability to activate adaptive cellular stress response pathways.
Son
Tae Gen
TG
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
Camandola
Simonetta
S
Arumugam
Thiruma V
TV
Cutler
Roy G
RG
Telljohann
Richard S
RS
Mughal
Mohamed R
MR
Moore
Tyson A
TA
Luo
Weiming
W
Yu
Qian-Sheng
QS
Johnson
Delinda A
DA
Johnson
Jeffrey A
JA
Greig
Nigel H
NH
Mattson
Mark P
MP
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000172:deficiency; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009285:Naphthoquinones / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009447:Neuroblastoma; D009460:Neurologic Examination; D009474:Neurons; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
D051267:NF-E2-Related Factor 2; D009285:Naphthoquinones; D018696:Neuroprotective Agents; D018808:Transcription Factor AP-1; D051547:Heme Oxygenase-1; D005947:Glucose; C014758:plumbagin