title: 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.
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.
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong , 10 Sassoon Road, Pokfulam, Hong Kong, China.
authors.forename: Chuanbin
authors.initials: C
authors.lastname: Yang
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong , 10 Sassoon Road, Pokfulam, Hong Kong, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong , 10 Sassoon Road, Pokfulam, Hong Kong, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta , 10-102 Clinical Sciences Building, Edmonton, Alberta T6G 2G3, Canada.
authors.forename: X Chris
authors.initials: XC
authors.lastname: Le
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong , 10 Sassoon Road, Pokfulam, Hong Kong, China.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Rong
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008636:Mesencephalon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D051381:Rats; D013481:Superoxides / Q000378:metabolism
chemical_list: D002109:Caffeic Acids; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; C000608216:N-propargyl caffeate amide; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D013481:Superoxides; D009569:Nitric Oxide; D016627:Oxidopamine; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D004298:Dopamine
keywords: N-Propargyl caffeate amide (PACA); Nrf2/HO-1; Parkinson’s disease; neuritogenic; neuroprotection