Ginsenoside Re Mitigates 6-Hydroxydopamine-Induced Oxidative Stress through Upregulation of GPX4

Abstract

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.

Pharmacological Properties of Ginsenoside Re

“…The anti-oxidant mechanism of Re in PD remains unclear. In SH-SY5Y cells treated with 6-hydroxydopamine to induce oxidative stress, the Re compound (25 µM for 9 h) mediated its anti-oxidant effect by upregulating a key antioxidant gene GPX4 via PI3K/Akt and ERK cascades ( Lee et al, 2020 ).…”

Effects of Traditional Chinese Medication‐Based Bioactive Compounds on Cellular and Molecular Mechanisms of Oxidative Stress

“…Ginsenoside, a potential treatment candidate for the attenuation of aging-related disease [87], produces antidepressant-like effects on chronic unpredictable mild stress-exposed rats involving protection against oxidative stress and thus the neuronal deterioration resulting from inflammatory responses [88]. Ginsenoside not only upregulates GPX4 to reduce oxidative stress and thereby alleviates 6-hydroxydopamine-induced neuronal damage [89] but also effectively attenuates D-galactose-induced oxidative stress via restoring the upstream PI3K/AKT signaling pathway [90]. Besides, ginsenoside significantly ameliorates oxidative stress through regulating SIRT1 [91].…”

Ginsenoside Re exhibits neuroprotective effects by inhibiting neuroinflammation via CAMK/MAPK/NF‑κB signaling in microglia

“…Ginsenoside re (G-re) is a panaxatriol saponin and is one of the most extensively studied ginsenosides. G-Re exhibits diverse effects, including antioxidant (13)(14)(15)(16), anti-inflammatory (17)(18)(19) and angiogenic activities (20). Furthermore, G-Re has been reported to improve cardiac function (21,22) and exert antidiabetic effects (23)(24)(25)(26).…”