title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Chinese Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhao
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Cheng
authors.forename: Wen
authors.initials: W
authors.lastname: Fan
authors.forename: Chuan-Bin
authors.initials: CB
authors.lastname: Yang
authors.forename: Shui-Fen
authors.initials: SF
authors.lastname: Ye
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Li-Xing
authors.initials: LX
authors.lastname: Lao
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Han
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Rong
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D049108:Cell Enlargement; D002470:Cell Survival / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011897:Random Allocation; D051381:Rats
chemical_list: D007529:Isoflavones; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D020932:Nerve Growth Factor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C033607:puerarin
keywords: ERK1/2; Neuritogenesis; Nrf2/heme oxygenase-1; PI3K/Akt; Puerarin