Ginsenosides are active components found abundantly in ginseng which has been used as a medicinal herb to modify disease status for thousands of years. However, the pharmacological activity of ginsenoside Re in the neuronal system remains to be elucidated. Neuroprotective activity of ginsenoside Re was investigated in SH-SY5Y cells exposed to 6-hydroxydopamine (6-OHDA) to induce cellular injury. Ginsenoside Re significantly inhibited 6-OHDA-triggered cellular damage as judged by analysis of tetrazolium dye reduction and lactose dehydrogenase release. In addition, ginsenoside Re induced the expression of the antioxidant protein glutathione peroxidase 4 (GPX4) but not catalase, glutathione peroxidase 1, glutathione reductase, or superoxide dismutase-1. Furthermore, upregulation of GPX4 by ginsenoside Re was mediated by phosphoinositide 3-kinase and extracellular signal-regulated kinase but not by p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. Ginsenoside Re also suppressed 6-OHDA-triggered cellular accumulation of reactive oxygen species and peroxidation of membrane lipids. The GPX4 inhibitor (1S,3R)-RSL3 reversed ginsenoside Re-mediated inhibition of cellular damage in SH-SY5Y cells exposed to 6-OHDA, indicating that the neuronal activity of ginsenoside Re is due to upregulation of GPX4. These findings suggest that ginsenoside Re-dependent upregulation of GPX4 reduces oxidative stress and thereby alleviates 6-OHDA-induced neuronal damage.

This study shows that taurine and ginsenoside Rf act synergistically to increase the expression of brain-derived neurotrophic factor (BDNF) in SH-SY5Y human neuroblastoma cells in a dose- and time-dependent manner. The increase of BDNF mRNA by taurine and ginsenoside Rf was markedly attenuated by inhibitors of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. In addition, taurine and ginsenoside Rf protected cells from corticosterone-induced BDNF suppression and reduced cell viability and lactate dehydrogenase release. The results from this study showed that combined treatment with both taurine and ginsenoside Rf enhanced BDNF expression and protected cells against corticosterone-induced damage.

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Intracellular iron accumulation in dopaminergic neurons contributes to neuronal cell death in progressive neurodegenerative disorders such as Parkinson’s disease. However, the mechanisms of iron homeostasis in this context remain incompletely understood. In the present study, we assessed the role of the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) in cellular iron homeostasis. We identified that PPARδ inhibited 6-hydroxydopamine (6-OHDA)-triggered neurotoxicity in SH-SY5Y neuroblastoma cells. PPARδ activation with GW501516, a specific PPARδ agonist, mitigated 6-OHDA-induced neuronal damage. Further, PPARδ activation also suppressed iron accumulation, which contributes to 6-OHDA-induced neuronal damage. PPARδ activation attenuated 6-OHDA-induced neuronal damage in a similar manner to that of the iron chelator deferoxamine. We further elucidated that PPARδ modulated cellular iron homeostasis by regulating expression of divalent metal transporter 1, ferroportin 1, and ferritin, but not transferrin receptor 1, through iron regulatory protein 1 in 6-OHDA-treated cells. Interestingly, PPARδ activation suppressed 6-OHDA-triggered generation of reactive oxygen species and lipid peroxides. The effects of GW501516 were abrogated by shRNA knockdown of PPARδ, indicating that the effects of GW501516 were PPARδ-dependent. Taken together, these findings suggest that PPARδ attenuates 6-OHDA-induced neurotoxicity by preventing intracellular iron accumulation, thereby suppressing iron overload-associated generation of reactive oxygen species and lipid peroxides, key mediators of ferroptotic cell death.

Peroxisome proliferator–activated receptor (PPAR)‐γ has been implicated as a key player in the regulation of adiponectin levels via both transcriptional and posttranscriptional mechanisms. Herein, we show that PPAR‐γ interacts with human antigen R (HuR) and that the PPAR‐γ–HuR complex dissociates following activation of PPAR‐γ by rosiglitazone, a specific ligand of PPAR‐γ. This rosiglitazone‐dependent dissociation of HuR from PPAR‐γ leads to nucleocytoplasmic shuttling of HuR and its binding to the 3′‐UTR of adiponectin mRNA. PPAR‐γ with H321A and H447A double mutation (PPAR‐γH321/447A), a mutant lacking ligand‐binding activity, impaired HuR dissociation from the PPAR‐γ–HuR complex, resulting in reduced nucleocytoplasmic shuttling, even in the presence of rosiglitazone. Consequently, rosiglitazone up‐regulated adiponectin levels by modulating the stability of adiponectin mRNA, whereas these effects were abolished by HuR ablation or blocked in cells expressing the PPAR‐γH321/447A mutant, indicating that the interaction of PPAR‐γ and HuR is a critical event during adiponectin expression. Taken together, the findings demonstrate a novel mechanism for regulating adiponectin expression at the posttranscriptional level and suggest that ligand‐mediated activation of PPAR‐γ to interfere with interaction of HuR could offer a therapeutic strategy for inflammation‐associated diseases that involve decreased adiponectin mRNA stability.—Hwang, J. S., Lee, W. J., Hur, J., Lee, H. G., Kim, E., Lee, G. H., Choi, M.‐J., Lim, D.‐S., Paek, K. S., Seo, H. G. Rosiglitazone‐dependent dissociation of HuR from PPAR‐γ regulates adiponectin expression at the posttranscriptional level. FASEB J. 33, 7707–7720 (2019). http://www.fasebj.org