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.
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.
Satoh
Takumi
T
Department of Welfare Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate, Japan. tsatoh@iwate-u.ac.jp
Kosaka
Kunio
K
Itoh
Ken
K
Kobayashi
Akira
A
Yamamoto
Masayuki
M
Shimojo
Yosuke
Y
Kitajima
Chieko
C
Cui
Jiankun
J
Kamins
Joshua
J
Okamoto
Shu-ichi
S
Izumi
Masanori
M
Shirasawa
Takuji
T
Lipton
Stuart A
SA
D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D000478:Alkylation / Q000187:drug effects; D000818:Animals; D019556:COS Cells; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D016716:PC12 Cells; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027542:Rosmarinus; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D045784:Abietanes; D002396:Catechols; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D010936:Plant Extracts; D011506:Proteins; D003545:Cysteine; C034221:catechol; C018381:salvin