Ginsenoside Re Inhibits ROS/ASK-1 Dependent Mitochondrial Apoptosis Pathway and Activation of Nrf2-Antioxidant Response in Beta-Amyloid-Challenged SH-SY5Y Cells

Abstract

Accumulation of amyloid-β (Aβ), which results in the formation of senile plaques that cause oxidative damage and neuronal cell death, has been accepted as the major pathological mechanism of Alzheimer’s disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis represents the effective strategies in combating AD. Ginsenoside Re (Re) has pharmacological effects against Aβ-induced neurotoxicity. However, its molecular mechanism remains elusive. The present study evaluated the effect of Re against Aβ-induced cytotoxicity and apoptosis in SH-SY5Y cells, and investigated the underlying mechanism. We demonstrate that Re inhibits the Aβ-triggered mitochondrial apoptotic pathway, as indicated by maintenance of mitochondrial functional, elevated Bcl-2/Bax ratio, reduced cytochrome c release, and inactivation of caspase-3/9. Re attenuated Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. ROS-scavenging abrogated the ability of Re to alter ASK-1 activation. Simultaneously, inhibition of JNK abolished Re-induced Bax downregulation in Aβ-challenged SH-SY5Y cells. In addition, Re enhanced activation of the nuclear factor-E2-related factor 2 (Nrf2) in Aβ-induced SH-SY5Y cells. Knockdown of Nrf2 by small interfering RNA targeting Nrf2 abolished the protective effect of Re. Our findings indicate that Re could be a potential therapeutic approach for the treatment of AD.

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

“…Bar, 25 μm in all images. Quantitation of the cytoplasmic SOD-1 and HO-1 fluorescent signals is shown in Additional file 3: Figure S3 alterations in mitochondrial respiration and ATP production both in neuronal cultures and transgenic mouse models [97][98][99][100][101][102]. In spite of their potential for the development of future therapeutic strategies, the consequences of the prolonged use of Nrf2 activators should be further explored, specially taking into consideration the reported association of Nrf2 exacerbated activation with certain types of cancer [103].…”

Pro-Resolving Effect of Ginsenosides as an Anti-Inflammatory Mechanism of Panax ginseng

“…Additionally, ginsenoside Rd was found to induce CD4 + Foxp3 + CD25 + regulatory T-cell (Treg) differentiation by upregulating Foxp3 expression, and it increased the generation of IL-10, TGF-β1, and IL-35, suggesting that ginsenoside Rd may have the potential to modulate M2 polarization [13]. Ginsenoside Re enhanced the activation of Nrf2 in Aβ-induced SH-SY5Y cells [76]. The activation of the Nrf2-HO-1 pathway for M2 macrophage polarization is also supported by the findings that a red ginseng-derived saponin fraction suppressed inflammatory responses via the Nrf2-HO-1 pathway in an adipocyte-macrophage co-culture system [42], and that saponins from Panax notoginseng acted as an extrinsic regulator that activates the Nrf2 antioxidant defense system and inhibits NF-κB inflammatory signaling to attenuate LPS-induced monocyte adhesion on cerebral endothelial cells [77].…”

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

“…Based on the antioxidant effects of multiple ginsenosides, we hypothesized that ginsenoside Re has a similar activity. However, the antioxidant mechanism of ginsenoside Re in the neuronal system has not been fully explored, although it was recently reported to have such an effect in Aβ-challenged SH-SY5Y through the Nrf2 signaling pathway [21]. Thus, we tested the effects of ginsenoside Re in an in vitro model of PD induced by 6-OHDA and explored the underlying mechanisms.…”