中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (12): 1934-1935.doi: 10.4103/1673-5374.169618

• 观点:神经损伤修复保护与再生 • 上一篇    下一篇

核因子E2相关因子2释放可促进轴突生长

  

  • 收稿日期:2015-09-30 出版日期:2015-12-30 发布日期:2015-12-30

Releasing Nrf2 to promote neurite outgrowth

Chuanbin Yang, Yuanyuan Cheng, Jiao Zhao, Jianhui Rong*   

  1. School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
  • Received:2015-09-30 Online:2015-12-30 Published:2015-12-30
  • Contact: Jianhui Rong, Ph.D., jrong@hku.hk.
  • Supported by:

    This research was supported by the following grants to JHR: General Research Fund (GRF) (HKU 775812M) from the Research Grants Council of Hong Kong and the Seed Fund for Basic Research Program, The University of Hong Kong.

摘要:

转录因子核因子E2相关因子2是氧化应激细胞应答的重要调节器,是一种对氧化还原反应敏感的转录因子。越来越多的证据表明,核因子红细胞-2相关因子可能在损伤后的神经发生中发挥作用。天然产物儿茶酚部分(例如,咖啡酸衍生物)是核因子E2相关因子2通路的活化剂,在抗氧化、抗癌、抗发炎和神经保护中发挥作用。咖啡酸衍生物,N-二炔丙基咖啡酰胺不仅能够减轻6-羟基多巴胺的神经毒性,还能够增强多巴胺能PC12细胞和原代大鼠脑神经元中神经生长因子诱导的神经生长能力。重要的是他们发现了N-二炔丙基咖啡酰胺通过激活核因子E2相关因子2/血红素加氧酶-1途径,可增强神经生长因子诱导的神经突起生长。因此,这项研究不仅揭示了N-二炔丙基咖啡酰胺的神经生长活性的分子机制,也表现出中国传统药物对治疗神经退行性疾病的作用机制。

Abstract:

Transcriptional factor Nrf2 is widely recognized as an important regulator in the cellular response to oxidative stress. Increasing evidence suggests that Nrf2 may play a role in post-injury neurogenesis. Nrf2 thereby becomes a promising therapeutic target in drug discovery for the therapy of neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Natural products bearing catechol moiety (e.g., caffeic acid derivatives) have been evaluated as the activators of Nrf2 pathway in anti-oxidation, anti-cancer, anti-inflammation and neuroprotection. Our recent work demonstrated that ceffeic acid derivative, N-propargyl caffeate amide (PACA) not only attenuated 6-hydroxydopamine (6-OHDA) neurotoxicity but also potentiated NGF-induced neurite outgrowth in dopaminergic PC12 cells and primary rat midbrain neurons. To elucidate the neuritogenic mechanisms, we attempted to isolate the PACA-modified proteins by Click chemistry approach to cross-link Azido-biotin with alkyne group in PACA. As a result, Keap1 was identified a predominant PACA-modified protein. We subsequently confirmed that PACA activated Nrf2-Keap1 pathway and induced heme oxygenase-1 (HO-1) expression. Importantly, we found that PACA potentiated NGF-induced neurite outgrowth via activating Nrf2/HO-1 pathway. Thus, our study not only revealed the molecular mechanisms underlying the neuritogenic activity of PACA but also demonstrated a general strategy to characterize Chinese medicines in the treatment of neurodegenerative diseases.