Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells

被引：84

作者：

Kosaka, Kunio ^{[1
]}

Mimura, Junsei ^{[2
]}

Itoh, Ken ^{[2
]}

Satoh, Takumi ^{[3
]}

Shimojo, Yosuke ^{[1
]}

Kitajima, Chieko ^{[1
]}

Maruyama, Atsushi ^{[2
]}

Yamamoto, Masayuki ^{[4
]}

Shirasawa, Takuji ^{[5
]}

机构：

[1] Nagase & Co Ltd, Ctr Res & Dev, Kobe, Hyogo 6512241, Japan

[2] Hirosaki Univ, Grad Sch Med, Ctr Adv Med Res, Hirosaki, Aomori 0368562, Japan

[3] Iwate Univ, Dept Welf Engn, Fac Engn, Morioka, Iwate 0208551, Japan

[4] Tohoku Univ, Grad Sch Med, Dept Med Biochem, Sendai, Miyagi 9808575, Japan

[5] Juntendo Univ, Grad Sch Med, Dept Ageing Control, Tokyo 1138421, Japan

来源：

JOURNAL OF BIOCHEMISTRY | 2010年 / 147卷 / 01期

关键词：

carnosic acid; Nrf2; p62; PC12; rosemary; NERVE GROWTH-FACTOR; PROTEIN-KINASE-C; KAPPA-B ACTIVATION; TRANSCRIPTION FACTOR; INDUCED DIFFERENTIATION; KEAP1/NRF2; PATHWAY; NRF2-KEAP1; NEURONAL SURVIVAL; GENE; NGF;

D O I：

10.1093/jb/mvp149

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Neurotrophins such as NGF promote neuronal survival and differentiation via the cell surface TrkA neurotrophin receptor. Compounds with neurotrophic actions that are low in molecular weight and can permeate the blood-brain barrier are promising therapeutic agents against neurodegenerative diseases such as Alzheimer's disease. Carnosic acid (CA), an electrophilic compound in rosemary, activates antioxidant responsive element (ARE)-mediated transcription via activation of Nrf2. In the present study, we discovered that CA strongly promotes neurite outgrowth of PC12h cells. NGF as well as CA activated Nrf2, whereas CA and NGF-mediated neuronal differentiation was suppressed by Nrf2 knockdown. On the other hand, CA activated TrkA-downstream kinase Erk1/2 independently of Nrf2. CA-induced p62/ZIP expression in an Nrf2-dependent manner, while the CA-induced neural differentiation was suppressed by p62/ZIP knockdown. Furthermore, CA-induced ARE activation was attenuated both by p62/ZIP knockdown and a Trk signal inhibitor. These results suggest that the CA induction of p62/ZIP by Nrf2 enhances TrkA signaling which subsequently potentiates Nrf2 pathway. This is the first demonstration that activation of the Nrf2-p62/ZIP pathway by a low-molecular natural electrophilic compound plays important roles in TrkA-mediated neural differentiation and may represent the common molecular mechanism for neurotrophic activities of electrophilic compounds.

引用

页码：73 / 81

页数：9

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