Botanical Drug Puerarin Coordinates with Nerve Growth Factor in the Regulation of Neuronal Survival and Neuritogenesis via Activating ERK1/2 and PI3K/Akt Signaling Pathways in the Neurite Extension Process

• Published in: CNS neuroscience & therapeutics Vol. 21; no. 1; pp. 61 - 70
• Main Authors: Zhao, Jia, Cheng, Yuan‐Yuan, Fan, Wen, Yang, Chuan‐Bin, Ye, Shui‐Fen, Cui, Wei, Wei, Wei, Lao, Li‐Xing, Cai, Jing, Han, Yi‐Fan, Rong, Jian‐Hui
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-01-2015; John Wiley and Sons Inc
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cell Enlargement; Cell Survival - drug effects; ERK1/2; Heme Oxygenase-1 - metabolism; Isoflavones - pharmacology; Male; MAP Kinase Signaling System - physiology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Nerve Growth Factor - metabolism; Neurites - drug effects; Neurites - physiology; Neuritogenesis; Neurogenesis - drug effects; Neurogenesis - physiology; Neurons - drug effects; Neurons - physiology; Neuroprotective Agents - pharmacology; Nrf2/heme oxygenase‐1; Original; PC12 Cells; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt; Puerarin; Random Allocation; Rats; Rodents; Studies; ERK1/2; Neuritogenesis; Puerarin; Nrf2/heme oxygenase-1; PI3K/Akt
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12334

Summary
Aim
Nerve growth factor (NGF) regulates neuronal survival and differentiation by activating extracellular signal‐regulated‐kinases (ERK) 1/2 and phosphoinositide‐3‐kinase (PI3K)/Akt pathways in two distinct processes: latency process and neurite extension process. This study was designed to investigate whether botanical drug C‐glucosylated isoflavone puerarin coordinates with NGF to regulate neuritogenesis via activating ERK1/2 and PI3K/Akt in neurite extension process.
Methods
We investigated the neuroprotective and neurotrophic activities of puerarin in MPTP‐lesioned mice and dopaminergic PC12 cells. The effects of puerarin on ERK1/2, Akt, Nrf2, and HO‐1 were assessed by Western blotting. The neurite outgrowth was assayed by neurite outgrowth staining kit.
Results
Puerarin protected dopaminergic cells and ameliorated the behavioral impairments in MPTP‐lesioned mice. Puerarin potentiated the effect of NGF on neuritogenesis in PC12 cells by >10‐fold. Mechanistic studies revealed: (1) puerarin rapidly activated ERK1/2 and Akt, leading to the activation of Nrf2/heme oxygenase‐1 (HO‐1) pathways; (2) ERK1/2, PI3K/Akt, and HO‐1 inhibitors attenuated the neuritogenic activity of puerarin. Notably, puerarin enhanced NGF‐induced neuritogenesis in a timing‐dependent manner.
Conclusion
Puerarin effectively coordinated with NGF to stimulate neuritogenesis via activating ERK1/2 and PI3K/Akt pathways in neurite extension process. These results demonstrated a general mechanism supporting the therapeutic application of puerarin‐related compounds in neurodegenerative diseases.