title: Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia.
abstract: 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.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Tae Gen
authors.initials: TG
authors.lastname: Son
authors.forename: Simonetta
authors.initials: S
authors.lastname: Camandola
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Roy G
authors.initials: RG
authors.lastname: Cutler
authors.forename: Richard S
authors.initials: RS
authors.lastname: Telljohann
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Mughal
authors.forename: Tyson A
authors.initials: TA
authors.lastname: Moore
authors.forename: Weiming
authors.initials: W
authors.lastname: Luo
authors.forename: Qian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: 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
chemical_list: D051267:NF-E2-Related Factor 2; D009285:Naphthoquinones; D018696:Neuroprotective Agents; D018808:Transcription Factor AP-1; D051547:Heme Oxygenase-1; D005947:Glucose; C014758:plumbagin