title: Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid.
abstract: Cyanide is a life-threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species. This may account for the fact that antioxidants prevent some aspects of cyanide-induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain barrier to up-regulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human-induced pluripotent stem cell-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino mouse model of cyanide poisoning that simulates damage observed in the human brain. Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2).
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nutter
authors.affiliation: Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Song
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Dolatabadi
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: James
authors.initials: J
authors.lastname: Parker
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Sanz-Blasco
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Traci
authors.initials: T
authors.lastname: Newmeyer
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ambasudhan
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.affiliation: Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.|Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D023482:Bioterrorism; D001921:Brain / Q000187:drug effects; D001930:Brain Injuries / Q000517:prevention & control*; D003486:Cyanides / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D045784:Abietanes; D000975:Antioxidants; D003486:Cyanides; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D010936:Plant Extracts; C018381:salvin
keywords: Nrf2; anti-oxidant response element; carnosic acid; cyanide poisoning; electrophilic compounds; human iPSC-derived neurons