Bibliographic Details
| Title: |
The Neuroprotective Effects of Flavonoid Fisetin against Corticosterone-Induced Cell Death through Modulation of ERK, p38, and PI3K/Akt/FOXO3a-Dependent Pathways in PC12 Cells |
| Authors: |
Pei-Rong Chang, Je-Wen Liou, Pei-Yi Chen, Wan-Yun Gao, Chia-Ling Wu, Ming-Jiuan Wu, Jui-Hung Yen |
| Source: |
Pharmaceutics, Vol 15, Iss 10, p 2376 (2023) |
| Publisher Information: |
MDPI AG, 2023. |
| Publication Year: |
2023 |
| Collection: |
LCC:Pharmacy and materia medica |
| Subject Terms: |
hypothalamic–pituitary–adrenal axis, corticosterone, fisetin, ERK, PI3K/Akt, FOXO3a, Pharmacy and materia medica, RS1-441 |
| More Details: |
The overactive hypothalamic–pituitary–adrenal (HPA) axis is believed to trigger the overproduction of corticosterone, leading to neurotoxicity in the brain. Fisetin is a flavonoid commonly found in fruits and vegetables. It has been suggested to possess various biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. This study aims to explore the potential neuroprotective properties of fisetin against corticosterone-induced cell death and its underlying molecular mechanism in PC12 cells. Our results indicate that fisetin, at concentrations ranging from 5 to 40 μM, significantly protected PC12 cells against corticosterone-induced cell death. Fisetin effectively reduced the corticosterone-mediated generation of reactive oxygen species (ROS) in PC12 cells. Fisetin treatments also showed potential in inhibiting the corticosterone-induced apoptosis of PC12 cells. Moreover, inhibitors targeting MAPK/ERK kinase 1/2 (MEK1/2), p38 MAPK, and phosphatidylinositol 3-kinase (PI3K) were found to significantly block the increase in cell viability induced by fisetin in corticosterone-treated cells. Consistently, fisetin enhanced the phosphorylation levels of ERK, p38, Akt, and c-AMP response element-binding protein (CREB) in PC12 cells. Additionally, it was found that the diminished levels of p-CREB and p-ERK by corticosterone can be restored by fisetin treatment. Furthermore, the investigation of crosstalk between ERK and CREB revealed that p-CREB activation by fisetin occurred through the ERK-independent pathway. Moreover, we demonstrated that fisetin effectively counteracted the corticosterone-induced nuclear accumulation of FOXO3a, an apoptosis-triggering transcription factor, and concurrently promoted FOXO3a phosphorylation and its subsequent cytoplasmic localization through the PI3K/Akt pathway. In conclusion, our findings indicate that fisetin exerts its neuroprotective effect against corticosterone-induced cell death by modulating ERK, p38, and the PI3K/Akt/FOXO3a-dependent pathways in PC12 cells. Fisetin emerges as a promising phytochemical for neuroprotection. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1999-4923 |
| Relation: |
https://www.mdpi.com/1999-4923/15/10/2376; https://doaj.org/toc/1999-4923 |
| DOI: |
10.3390/pharmaceutics15102376 |
| Access URL: |
https://doaj.org/article/83b4ce27d6704a77af93b35e3f562ad2 |
| Accession Number: |
edsdoj.83b4ce27d6704a77af93b35e3f562ad2 |
| Database: |
Directory of Open Access Journals |
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