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

doi:10.3390/pharmaceutics15102376

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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:	Chang, Pei-Rong Liou, Je-Wen Chen, Pei-Yi Gao, Wan-Yun Wu, Chia-Ling Wu, Ming-Jiuan Yen, Jui-Hung
Contributors:	Tzu Chi Univ, Dept Mol Biol & Human Genet Tzu Chi Univ, Sch Med, Dept Biochem Buddhist Tzu Chi Med Fdn, Hualien Tzu Chi Hosp, Genet Counseling Ctr, Lab Med Genet Tzu Chi Univ, Inst Med Sci Chia Nan Univ Pharm & Sci, Dept Biotechnol
Keywords:	hypothalamic-pituitary-adrenal axis corticosterone fisetin ERK PI3K/Akt FOXO3a
Date:	2023
Issue Date:	2024-12-25 11:04:00 (UTC+8)
Publisher:	MDPI
Abstract:	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 mu M, 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.
Relation:	Pharmaceutics, v.15, n.10, Article 2376
Appears in Collections:	[Offices] 456

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