Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1

Takumi Satoh, Kunio Kosaka, Ken Itoh, Akira Kobayashi, Masayuki Yamamoto, Yosuke Shimojo, Chieko Kitajima, Jiankun Cui, Joshua Kamins, Shu Ichi Okamoto, Masanori Izumi, Takuji Shirasawa, Stuart A. Lipton

Research output: Contribution to journalArticlepeer-review

288 Citations (Scopus)

Abstract

Electrophilic compounds are a newly recognized class of redox-active neuroprotective compounds with electron deficient, electrophilic carbon centers that react with specific cysteine residues on targeted proteins via thiol (S-)alkylation. Although plants produce a variety of physiologically active electrophilic compounds, the detailed mechanism of action of these compounds remains unknown. Catechol ring-containing compounds have attracted attention because they become electrophilic quinones upon oxidation, although they are not themselves electrophilic. In this study, we focused on the neuroprotective effects of one such compound, carnosic acid (CA), found in the herb rosemary obtained from Rosmarinus officinalis. We found that CA activates the Keap1/Nrf2 transcriptional pathway by binding to specific Keap1 cysteine residues, thus protecting neurons from oxidative stress and excitotoxicity. In cerebrocortical cultures, CA-biotin accumulates in non-neuronal cells at low concentrations and in neurons at higher concentrations. We present evidence that both the neuronal and non-neuronal distribution of CA may contribute to its neuroprotective effect. Furthermore, CA translocates into the brain, increases the level of reduced glutathione in vivo, and protects the brain against middle cerebral artery ischemia/reperfusion, suggesting that CA may represent a new type of neuroprotective electrophilic compound.

Original languageEnglish
Pages (from-to)1116-1131
Number of pages16
JournalJournal of Neurochemistry
Volume104
Issue number4
DOIs
Publication statusPublished - 2008 Feb

Keywords

  • Carnosic acid
  • Cysteine thiol
  • Keap1
  • Neurite outgrowth-promoting prostaglandin 11
  • Nrf2
  • S-alkylation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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