Phytoestrogen β-Ecdysterone Protects PC12 Cells Against MPP+-Induced Neurotoxicity In Vitro: Involvement of PI3K-Nrf2-Regulated Pathway
Abstract
Epidemiological studies have strongly linked postmenopausal estrogens uptake with a reduced risk of developing Parkinson's disease (PD) in women. Estrogen replacement therapy may be beneficial in early PD. The aim of this study is to evaluate the hypothesis that the neuroprotective effects of phytoestrogen β-ecdysterone (β-Ecd) might mainly result from its antioxidant capability by the activation of the phosphoinositide-3-kinase (PI3K)-nuclear factor E2-related factor 2 (Nrf2)-regulated signaling pathway. We found that β-Ecd is able to protect MPP(+)-induced oxidative stress and apoptosis in PC12 cells in a concentration-dependent manner. β-Ecd increased the Akt kinase activity and the Akt signaling pathways, including glycogen synthase kinase 3-β inactivation, nuclear translocation of Nrf2, upregulation of HO-1 expression, but without affecting activity of both NF-κB and calpain. Enhancement of antioxidant response element (ARE) promoter-driven luciferase activity by β-Ecd correlated with the blockade of oxidative stress. Antioxidative effects of β-Ecd could be blocked by pharmacologic inhibition of the PI3K pathways with LY294002 or Nrf2 pathway with shRNA-mediated knockdown of Nrf2 but not by SP600125 (JNK inhibitor), SB203580 (p38-MAPK inhibitor), or PD98059 (ERK1/2 inhibitor). Together, our results indicate that the inducible effect of β-Ecd on HO-1 expression might be mediated, at least in part, by activating Akt kinase pathway and subsequent enhancement of Nrf2/ARE signaling pathway. In concert, these data suggest that β-Ecd may be a potential candidate for further preclinical study aimed at the treatment of PD.
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20E was protective against oxidative stress and apoptosis in PC12 cells treated with MPTP.
“In addition, 20E was also protective against oxidative stress and apoptosis in PC12 cells treated with MPTP, an inductor used in animal models of neurological disease like Parkinson [51].”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [51]
The activity of NF-κB and calpain was not affected in PC12 cells treated with MPTP.
“However, the activity of NF-κB and calpain was not affected.”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [51]
Akt signalling and nuclear translocation of Nrf2 and HO-1 expression were elevated as part of the anti-oxidant response.
“Akt signalling and nuclear translocation of Nrf2 and HO-1 (hemoxigenase-1) expression were elevated as a part of the anti-oxidant response.”
From Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound? (2025) · cites this paper as [51]
In vitro studies associate ecdysterone with endothelial dysfunction prevention, osteoporosis prevention, glucose regulation, cytotoxic effects, antibacterial properties, immunomodulatory effects, and anti-inflammatory activities.
“Moreover, the effects on cell lines are associated with endothelial dysfunction prevention, osteoporosis prevention, glucose regulation, cytotoxic effects, antibacterial properties, immunomodulatory effects, and anti-inflammatory activities [52,53,54,55,56,57,58,60,61,62,63,64,65,66,67,68,69,70,71,72,73].”
From Ecdysterone and Turkesterone—Compounds with Prominent Potential in Sport and Healthy Nutrition (2024) · cites this paper as [52]
Within the in vitro studies of ecdysterone, no serious effects were reported.
“Within these studies, no serious effects were reported [52,53,54,55,56,57,58,60,61,62,63,64,65,66,67,68,69,70,71,72,73].”
From Ecdysterone and Turkesterone—Compounds with Prominent Potential in Sport and Healthy Nutrition (2024) · cites this paper as [52]
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- Authors
- Zou, Y., Wang, R., Guo, H., & Dong, M.
- Affiliations
- Wangjing Hospital of China Academy of Chinese Medical Sciences (CN)
- Corresponding author
- Dong, Miaoxian
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-06-05
- Volume
- 147
- Issue
- 1
- Pages
- 28-38
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2134038831
- Cited by
- 36
- References
- 42
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 5
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- phytoestrogens, Parkinson's disease, MPP+ neurotoxicity, neuroprotection, PI3K signaling, Nrf2, Akt signaling, glycogen synthase kinase-3β, heme oxygenase-1, oxidative stress, apoptosis, antioxidant response element, PC12 cells
- MeSH terms
- Animals, Antioxidants, Calpain, Cell Survival, Ecdysterone, NF-kappa B, PC12 Cells, Reactive Oxygen Species, Oxidative Stress, Neuroprotective Agents, Phosphatidylinositol 3-Kinases, MPTP Poisoning, Phytoestrogens, Oncogene Protein v-akt, NF-E2-Related Factor 2, Rats, Heme Oxygenase-1, Antioxidant Response Elements
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