Flavonoids from Seabuckthorn (Hippophae rhamnoides L.) mimic neurotrophic functions in inducing neurite outgrowth in cultured neurons: Signaling via PI3K/Akt and ERK pathways

Chen-Xi Xia; Alex Xiong Gao; Tina Ting-Xia Dong; Karl Wah-Keung Tsim

doi:10.1016/j.phymed.2023.154832

Flavonoids from Seabuckthorn (Hippophae rhamnoides L.) mimic neurotrophic functions in inducing neurite outgrowth in cultured neurons: Signaling via PI3K/Akt and ERK pathways

Phytomedicine. 2023 Jul:115:154832. doi: 10.1016/j.phymed.2023.154832. Epub 2023 Apr 18.

Authors

Chen-Xi Xia¹, Alex Xiong Gao¹, Tina Ting-Xia Dong¹, Karl Wah-Keung Tsim²

Affiliations

¹ Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518000, China; Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
² Shenzhen Key Laboratory of Edible and Medicinal Bioresources, HKUST Shenzhen Research Institute, Hi-Tech Park, Nanshan, Shenzhen 518000, China; Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China. Electronic address: botsim@ust.hk.

PMID: 37121059
DOI: 10.1016/j.phymed.2023.154832

Abstract

Background: Various brain disorders, including neurodegenerative diseases and major depressive disorders, threaten an increasing number of patients. Seabuckthorn, a fruit from Hippophae rhamnoides L., is an example of "medicine food homology". The fruit has enriched flavonoids that reported to have benefits in treating cognitive disorders. However, the studies on potential functions of Seabuckthorn and/or its flavonoid-enriched fraction in treating neurodegenerative disorders are limited.

Purpose: This study aimed to determine the ability and mechanism of the flavonoid-enriched fraction of Seabuckthorn (named as SBF) in mimicking the neurotrophic functions in inducing neurite outgrowth of cultured neurons.

Methods: Cultured PC12 cell line, SH-SY5Y cell line and primary neurons (cortical and hippocampal neurons isolated from E17-19 SD rat embryos) were the employed models to evaluate SBF in inducing neurite outgrowth by comparing to the effects of NGF and BDNF. Immuno-fluorescence staining was applied to identify the morphological change during the neuronal differentiation. Luciferase assay was utilized for analyzing the transcriptional regulation of neurofilaments and cAMP/CREB-mediated gene. Western blot assay was conducted to demonstrate the expressions of neurofilaments and phosphorylated proteins.

Results: The application of SBF induced neuronal cell differentiation, and this differentiating activation was blocked by the inhibitors of PI3K/Akt and ERK pathways. Additionally, SBF showed synergy with neurotrophic factors in stimulating the neurite outgrowth of cultured neurons. Moreover, the major flavonoids within SBF, i.e., isorhamnetin, quercetin and kaempferol, could account for the neurotrophic activities of SBF.

Conclusion: Seabuckthorn flavonoids mimicked neurotrophic functions in inducing neuronal cell differentiation via activating PI3K/Akt and ERK pathways. The results suggest the beneficial functions of Seabuckthorn as a potential health food supplement in treating various brain disorders, e.g., neurodegenerative diseases.

Keywords: Flavonoid; Hippophae rhamnoides L.; Neurite outgrowth; Neurodegenerative diseases.

MeSH terms

Animals
Depressive Disorder, Major* / metabolism
Flavonoids / pharmacology
Flavonoids / therapeutic use
Hippophae*
Humans
MAP Kinase Signaling System
Neurites / metabolism
Neuroblastoma* / metabolism
Neurodegenerative Diseases* / drug therapy
Neuronal Outgrowth
Neurons
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Sprague-Dawley

Substances

Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
Flavonoids