Journal
JOURNAL OF NEUROCHEMISTRY
Volume 133, Issue 6, Pages 898-908Publisher
WILEY
DOI: 10.1111/jnc.13074
Keywords
anti-oxidant response element; carnosic acid; cyanide poisoning; electrophilic compounds; human iPSC-derived neurons; Nrf2
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Funding
- NIH [R21 NS080799, R01 NS086890, R01 ES017462, P01 HD29587]
- La Jolla Interdisciplinary Neuroscience Center Core Grant [P30 NS076411]
- Michael J. Fox Foundation
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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 invitro, and invivo in various brain areas of a non-Swiss albino mouse model of cyanide poisoning that simulates damage observed in the human brain.
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