Senegenin Inhibits Aβ1-42-Induced PC12 Cells Apoptosis and Oxidative Stress via Activation of the PI3K/Akt Signaling Pathway

Abstract

Background/Aim Apoptosis and oxidative stress have been considered as key events in the pathogenesis of Alzheimer’s disease (AD). Senegenin (Sen), the major and most effective ingredient of Radix Polygalae , which has anti-apoptotic and anti-oxidative effects. The aim of this study was to investigate the anti-apoptotic and anti-oxidant effects of Sen on Aβ 1-42 -induced PC12 cells apoptosis and oxidative stress as well as its possible signaling pathway. Methods Rat pheochromocytoma (PC12) cells were treated by 20 μM Aβ 1-42 and then divided into 5 different treatment groups (Control; Aβ 1-42 20 μM; Aβ 1-42 20 μM + Sen 10 μM; Aβ 1-42 20 μM + Sen 30 μM; Aβ 1-42 20μM + Sen 60 μM). PC12 cells activity was detected by MTT assay. Colony formation assay was performed to assess the clonogenic ability of cells. The cell apoptosis was detected by Annexin-V/PI staining. The pro-apoptotic protein (Bax), anti-apoptotic protein (Bcl-2), anti-oxidative stress factor (HO-1, Nuclear Nrf2, Total Nrf2) and pathway-related protein (Akt, P-Akt, PI3K, P-PI3K) were tested by Western blot. The reactive oxygen species (ROS) level was assessed with a DCFH-DA probe. Results The results indicated that Sen dose-dependently increased cell viability and reduced the number of apoptotic cells. The ratio of P-PI3K/PI3K and P-Akt/Akt increased in a dose-dependent manner under the treatment of Sen, suggesting that Sen might activate the PI3K/Akt signaling pathway. Moreover, Sen upregulates the ratio of Bcl-2/Bax. Further study revealed that Sen can play an antioxidant role in enhancing HO-1, promoting Nrf2 nuclear translocation and reducing ROS accumulation to reduce oxidative stress. Conclusion Sen is effective in inhibiting apoptosis and oxidative stress in Aβ 1-42 -induced PC12 cells, which likely contribute to the development of novel therapies for AD.

Hyperoside prevent Aβ42-induced neurotoxicity in PC12 cells and Caenorhabditis elegans

“…In vitro, excessive ROS can cause oxidative stress and subsequent cell injury and apoptosis, which may be PC12 cells induced by exposure to Aβ42 [5]. The peroxidative damage of mitochondria is closely related to the high content of ROS, and MMP (ΔΨm) is an essential indicator of mitochondrial function and the apoptotic status [33].…”

“…Aβ induced neurotoxicity in neuronal cells has been considered as one of the crucial reasons in the development of AD [4]. The Aβ induced cytotoxicity could trigger redox impairment through producing reactive oxygen species (ROS), decreasing the mitochondrial membrane potential (ΔΨm), and inhibiting the activities of antioxidant enzymes [5,6].…”

Senegenin Rescues PC12 Cells with Oxidative Damage Through Inhibition of Ferroptosis

“…Sen shows unique pharmacological activity in promoting intelligence, anti-aging, antioxidant and other aspects, and also possesses cytoprotective properties in neurodegenerative disorders [12,13]. It has been previously reported that Sen was effective in inhibiting apoptosis and oxidative stress in Aβ 1−42 -induced PC12 cells [14]. Our previous study established that Sen could exert neuroprotection against H/R-induced injury via suppression apoptosis [15].…”

Neuroprotective Effects and Mechanisms of Senegenin, an Effective Compound Originated From the Roots of Polygala Tenuifolia

“…By activating the Keap-Nrf2-ARE pathway, senegenin can reduce ROS accumulation and up-regulate the expression of Nrf2 and HO-1 in a dose-dependent manner, which contributes to the reduction of oxidative stress ( Ren et al, 2022 ). In addition, senegenin can inhibit the production of PGE 2 and NO in RAW 264.7 macrophages induced by lipopolysaccharide (LPS) by suppressing MAPK/NF-κB and activating the Nrf2/HO-1 signaling pathway, and reduce inducible nitric oxide synthase (NOS) and Cyclooxygenase-2 (COX-2) gene expression ( Lv et al, 2016 ; Lu et al, 2017 ).…”

“…In addition, senegenin can also promote the phosphorylation of Akt ( Pi et al, 2016 ) It reveals that the PI3K/Akt signaling pathway may be involved in the neurotrophic effect of senegenin. In addition, through the PI3K/Akt signaling pathway, senegenin can also increase the ratio of P-PI3K/PI3K and P-Akt/Akt, increase cell survival in a dose-dependent manner, and reduce apoptosis ( Ren et al, 2022 ).…”