Ginsenoside Re attenuates 8-OH-DPAT-induced serotonergic behaviors in mice via interactive modulation between PKCδ gene and Nrf2

Abstract

It has been recognized that serotonergic blocker showed serious side effects, and that ginsenoside modulated serotonergic system with the safety. However, the effects of ginsenoside on serotonergic impairments remain to be clarified. Thus, we investigated ginsenoside Re (GRe), a major bioactive component in the mountain-cultivated ginseng on (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a 5-HT_1A receptor agonist. In the present study, we observed that the treatment with GRe resulted in significant inhibition of protein kinase C δ (PKCδ) phosphorylation induced by the 5-HT_1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) in the hypothalamus of the wild-type (WT) mice. The inhibition of GRe was comparable with that of the PKCδ inhibitor rottlerin or the 5-HT_1A receptor antagonist WAY100635 (WAY). 8-OH-DPAT-induced significant reduction in nuclear factor erythroid-2-related factor 2 (Nrf2)-related system (i.e., Nrf2 DNA binding activity, γ-glutamylcysteine ligase modifier (GCLm) and γ-glutamylcysteine ligase catalytic (GCLc) mRNA expression, and glutathione (GSH)/oxidized glutathione (GSSG) ratio) was significantly attenuated by GRe, rottlerin, or WAY in WT mice. However, PKCδ gene knockout significantly protected the Nrf2-dependent system from 8-OH-DPAT insult in mice. Increases in 5-hydroxytryptophan (5-HT) turnover rate, overall serotonergic behavioral score, and hypothermia induced by 8-OH-DPAT were significantly attenuated by GRe, rottlerin, or WAY in WT mice. Consistently, PKCδ gene knockout significantly attenuated these parameters in mice. However, GRe or WAY did not provide any additional positive effects on the serotonergic protective potential mediated by PKCδ gene knockout in mice. Therefore, our results suggest that PKCδ is an important mediator for GRe-mediated protective activity against serotonergic impairments/oxidative burden caused by the 5-HT_1A receptor.

Graphical Abstract

Keywords:

• Mountain-cultivated ginseng
• ginsenoside Re
• hypothalamus
• 5-HT_1A receptor
• serotonin syndrome behavior
• Nrf2-dependent system
• protein kinase C δ knockout mice

Acknowledgements

The English in this document has been checked by a professional English editor (Editage by CACTUS Communications Inc., Seoul, Republic of Korea, www.editage.co.kr).

Authors contributions

Conceptualization: E.J.S., J.H.J., Y.L., and H.C.K. Methodology: E.J.S., B.T.N., N.S., and J.K.B. Validation: E.J.S., J.H.J., and H.C.K. Data collection: B.T.N., N.S., and E.J.S. Investigation, and interpretation of data: N.S., J.H.J., and H.C.K. Statistical analysis: E.J.S. Original draft preparation: H.C.K. Writing and editing: E.J.S. and H.C.K. Supervision: J.H.J. and H.C.K. Formal analysis: H.C.K., S.K.K., E.J.S., and J.H.J.

Disclosure statement

The authors report no conflict of interest.

Data availability statement

The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This study was carried out with the support of R&D Program for Forest Science Technology (Project No. 2020203C10-2122-BA01) provided by Korea Forest Service (Korea Forestry Promotion Institute).