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Acteoside alleviates lipid peroxidation by enhancing Nrf2-mediated mitophagy to inhibit ferroptosis for neuroprotection in Parkinson's disease.
- Source :
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Free radical biology & medicine [Free Radic Biol Med] 2024 Oct; Vol. 223, pp. 493-505. Date of Electronic Publication: 2024 Jul 23. - Publication Year :
- 2024
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Abstract
- Increasing evidence underscores the pivotal role of ferroptosis in Parkinson's Disease (PD) pathogenesis. Acteoside (ACT) has been reported to possess neuroprotective properties. However, the effects of ACT on ferroptosis and its molecular mechanisms remain unknown. This study aimed to explore whether ACT can regulate ferroptosis in dopaminergic (DA) neurons within both in vitro and in vivo PD models and to elucidate the underlying regulatory mechanisms. PD models were established and treated with various concentrations of ACT. Cell viability assays, Western blot, lipid peroxidation assessments, immunohistochemistry, and transmission electron microscopy were employed to confirm ACT's inhibition of ferroptosis and its protective effect on DA neurons across PD models. Immunofluorescence staining, MitoSOX staining, and confocal laser scanning microscopy further validated ACT's regulation regulatory effects on ferroptosis via the Nrf2-mitophagy pathway. Four animal behavioral tests were used to assess behavioral improvements in PD animals. ACT inhibited ferroptosis in PD models in vitro, as evidenced by increased cell viability, the upregulation of GPX4 and SLC7A11, reduced lipid peroxides, and attenuation of mitochondrial morphological alterations typical of ferroptosis. By activating the Nrf2-mitophagy axis, ACT enhanced mitochondrial integrity and reduced lipid peroxidation, mitigating ferroptosis. These in vitro results were consistent with in vivo findings, where ACT treatment significantly preserved DA neurons, curbed ferroptosis in these cells, and alleviated cognitive and behavioral deficits. This study is the first demonstration of ACT's capability to inhibit neuronal ferroptosis and protect DA neurons, thus alleviating behavioral and cognitive impairments in both in vitro and in vivo PD models. Furthermore, The suppression of ferroptosis by ACT is achieved through the activation of the Nrf2-mitophagy signaling pathway. Our results show that ACT is beneficial for both treating and preventing PD. They also offer novel therapeutic options for treating PD and molecular targets for regulating ferroptosis.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Male
Disease Models, Animal
Humans
Cell Survival drug effects
Signal Transduction drug effects
Mitochondria metabolism
Mitochondria drug effects
Neuroprotection drug effects
Phospholipid Hydroperoxide Glutathione Peroxidase metabolism
Phospholipid Hydroperoxide Glutathione Peroxidase genetics
Polyphenols
Ferroptosis drug effects
NF-E2-Related Factor 2 metabolism
NF-E2-Related Factor 2 genetics
Lipid Peroxidation drug effects
Glucosides pharmacology
Parkinson Disease metabolism
Parkinson Disease drug therapy
Parkinson Disease pathology
Dopaminergic Neurons metabolism
Dopaminergic Neurons drug effects
Dopaminergic Neurons pathology
Neuroprotective Agents pharmacology
Mitophagy drug effects
Phenols pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 223
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 39048340
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2024.07.018