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

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.