β-Ecdysterone Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Apoptosis via Mitochondria-Dependent Mechanism: Involvement of p38MAPK–p53 Signaling Pathway
Abstract
Parkinson's disease (PD) is a neurological disorder pathologically characterized by loss of dopaminergic neurons in the substantia nigra. No curative therapy is available for PD. We recently found that phytoestrogen β-ecdysterone (β-Ecd) is able to reduce MPP(+)-induced apoptosis in PC12 cells. This study investigated the potential of β-Ecd to protect against SH-SY5Y cell apoptosis induced by the PD-related neurotoxin 6-hydroxydopamine (6-OHDA) and the underlying mechanism for this cytoprotection. In the present study, pretreatment with β-Ecd significantly reduced 6-OHDA-induced apoptosis of SH-SY5Y cells by a mitochondria-dependent pathway, as indicated by downregulation of Bax and PUMA (p53 upregulated modulator of apoptosis) expression, suppressing ΔΨm loss, inhibiting cytochrome c release, and attenuating caspase-9 activation. Furthermore, we showed that the inhibition of p38 mitogen-activated protein kinase (p38(MAPK))-dependent p53 promoter activity contributed to the protection of SH-SY5Y cells from apoptosis, which was validated by the use of SB203580 or p38β dominant negative (DN) mutants. Additionally, knock-down apoptosis signal-regulating kinase 1 (ASK1) by specific shRNA and blockade reactive oxygen species (ROS) by pharmacological inhibitor competently prevented β-Ecd-mediated inhibition of p38(MAPK) and ASK1 phosphorylation, respectively. These data provide the first evidence that β-Ecd protects SH-SY5Y cells against 6-OHDA-induced apoptosis, possibly through mitochondria protection and p53 modulation via ROS-dependent ASK1-p38(MAPK) pathways. The neuroprotective effects of β-Ecd make it a promising candidate as a therapeutic agent for PD.
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ShRNA inhibition of ASK1 and blockade of reactive oxygen species prevented the protection, indicating a mechanism for the anti-apoptotic effect.
“ShRNA inhibition of apoptosis silencing-regulating kinase (ASK1) and blockade of reactive oxygen species (ROS) prevented the protection, indicating a mechanism for the anti-apoptotic effect.”
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 [59]
The anti-apoptotic effect of 20E was observed in the human neuroblastoma cell line.
“The anti-apoptotic effect of 20E was also observed in the human neuroblastoma cell line [59].”
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 [59]
20E inhibited the p38MAPK-dependent promoter activity of p53.
“It also inhibited the p38MAPK-dependent promoter activity of p53 that contributed to cell protection.”
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 [59]
20E protected against apoptosis in a mitochondria-dependent manner; it downregulated Bax and PUMA, suppressed loss of mitochondrial membrane potential, and attenuated cytochrome C release and caspase 9 activity.
“In addition, 20E protected against apoptosis in a mitochondria-dependent manner; it downregulated Bax and PUMA (p53-upregulated modulator of apoptosis), suppressed the loss of mitochondrial membrane potential (ΔΨm), and attenuated cytochrome C release and caspase 9 activity.”
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 [59]
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- Authors
- Pan, Z., Niu, Y., Liang, Y., Zhang, X., & Dong, M.
- Affiliations
- Changchun University of Chinese Medicine (CN)
- Qiqihar Medical University (CN)
- Corresponding author
- Dong, Miaoxian
- Venue
- Neurotoxicity Research
- Published
- 2016-05-26
- Volume
- 30
- Issue
- 3
- Pages
- 453-466
- ISSN
- 1029-8428 (ISSN-L)
- 1476-3524
- OpenAlex
- W2405993884
- Cited by
- 21
- References
- 48
- Citations by year
- 2026: 3 · 2025: 2 · 2022: 2 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 3
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurotoxicity Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- The National Natural Science Foundation of China (81373629)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, 6-hydroxydopamine, neurotoxicity, apoptosis, SH-SY5Y cells, mitochondrial apoptosis, p38 MAPK, p53, ASK1, reactive oxygen species, cytochrome c release, caspase-9, Bax, PUMA, neuroprotection, phytoestrogens
- MeSH terms
- Antiparkinson Agents, Cell Survival, Drug Evaluation, Preclinical, Ecdysterone, Humans, Mitochondria, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Oxidopamine, Apoptosis, Reactive Oxygen Species, MAP Kinase Signaling System, Cytochromes c, Cell Line, Tumor, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinase 5, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein, Caspase 9
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