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.