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Mech Ageing Dev. 2019 Apr 10;180:70-81. doi: 10.1016/j.mad.2019.04.002. [Epub ahead of print]

Astragaloside IV and ferulic acid synergistically promote neurite outgrowth through Nrf2 activation.

Author information

1
The Institute of Medicine, Qiqihar Medical University, Qiqihar 161006, China.
2
Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
3
The Institute of Medicine, Qiqihar Medical University, Qiqihar 161006, China. Electronic address: nyc1968@126.com.

Abstract

Recently, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have nuclear localization and nuclear exclusion signals and shuttle between the cytoplasm and the nucleus. Thus, we hypothesised that astragaloside IV (AS-IV) induction nuclear import of Nrf2 and ferulic acid (FA) inhibition nuclear export of Nrf2 contribute to synergistic antioxidant effects of combination of FA and AS-IV (FA/AS-IV). Here, we have demonstrated that FA/AS-IV enhances neurite outgrowth of PC12 cells challenged with lead acetate (PbAc) via antioxidant properties in a synergistic manner. Concomitantly, FA/AS-IV significantly promotes Nrf2 activation and induces "phase-II'' enzymes during PbAc toxicity, compared with either FA or AS-IV alone. Interestingly, FA but not AS-IV activates the extracellular signal-regulated kinases 1 and 2 (ERK1/2), leading to an increase in both de novo synthesis of Nrf2 and nuclear import of Nrf2. Simultaneously, AS-IV but not FA suppresses Fyn phosphorylation via Akt-mediated inhibition of GSK-3β, which inhibited nuclear export of Nrf2. Importantly, dual activation of both ERK1/2 and Akt by FA/AS-IV in PC12 cells challenged with PbAc is mediated by independent mechanisms, which are supported by pharmacological inhibitors. Collectively, these results support the notion that the FA/AS-IV may be promising in therapy for lead developmental neurotoxicity. This combination deserves further study in vivo.

KEYWORDS:

Astragaloside IV; Ferulic acid; Lead developmental neurotoxicity; Nuclear factor erythroid 2-related factor 2; Synergism

PMID:
30978363
DOI:
10.1016/j.mad.2019.04.002

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