N-Propargyl Caffeate Amide (PACA) Potentiates Nerve Growth Factor (NGF)-Induced Neurite Outgrowth and Attenuates 6-Hydroxydopamine (6-OHDA)-Induced Toxicity by Activating the Nrf2/HO-1 Pathway

Chuanbin YANG, Jia Zhao, Yuanyuan Cheng, X. Chris Le, Jianhui Rong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Insufficient production of neurotrophic factors is implicated in the pathogenesis of various neurodegenerative disorders. The aim of the present study was to evaluate the potential of N-propargyl caffeate amide (PACA) to enhance nerve growth factor (NGF)-induced neurite outgrowth and the underlying mechanisms. We discovered that PACA not only potentiated NGF-induced neurite outgrowth but also attenuated 6-hydroxydopamine (6-OHDA) neurotoxicity in dopaminergic PC12 cells and primary rat midbrain neurons. To identify the PACA-binding proteins, we introduced a biotin tag to the covalent PACA-protein adducts via "click chemistry" alkyne-azido cycloaddition. As a result, kelch-like ECH-associated protein 1 (Keap1) was isolated as the predominant protein from PACA treated PC12 cells. We demonstrated that the formation of PACA-Keap1 conjugates induced the nuclear translocation of transcription factor Nrf2 and the expression of antioxidant heme oxygenase-1 (HO-1). Importantly, specific HO-1 inhibitor SnPP diminished the neuroprotective and neuritogenic activities of PACA. Moreover, PACA attenuated 6-OHDA-induced production of neurotoxic reactive oxygen species and reactive nitrogen species. PACA also preserved mitochondrial membrane integrity and enhanced the cellular resistance against 6-OHDA neurotoxicity. These results suggest that PACA may exhibit neuroprotective and neuritogenic activities via activating the Nrf2/HO-1 antioxidant pathway.

Original languageEnglish
Pages (from-to)1560-1569
Number of pages10
JournalACS Chemical Neuroscience
Volume6
Issue number9
DOIs
Publication statusPublished - 6 Jul 2015

Scopus Subject Areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

User-Defined Keywords

  • N-Propargyl caffeate amide (PACA)
  • neuritogenic
  • neuroprotection
  • Nrf2/HO-1
  • Parkinson's disease

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