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

The overactive hypothalamic–pituitary–adrenal (HPA) axis is believed to trigger the overproduction of corticosterone, leading neurotoxicity in brain. Fisetin a flavonoid commonly found fruits and vegetables. It has been suggested possess various biological activities, including antioxidant, anti-inflammatory, neuroprotective effects. This study aims explore potential properties fisetin against corticosterone-induced cell death its underlying molecular mechanism PC12 cells. Our results indicate that fisetin, at concentrations ranging from 5 40 μM, significantly protected cells death. effectively reduced corticosterone-mediated generation reactive oxygen species (ROS) treatments also showed inhibiting apoptosis Moreover, inhibitors targeting MAPK/ERK kinase 1/2 (MEK1/2), p38 MAPK, phosphatidylinositol 3-kinase (PI3K) were block increase viability induced by corticosterone-treated Consistently, enhanced phosphorylation levels ERK, p38, Akt, c-AMP response element-binding protein (CREB) Additionally, it was diminished p-CREB p-ERK corticosterone can be restored treatment. Furthermore, investigation crosstalk between ERK CREB revealed activation occurred through ERK-independent pathway. we demonstrated counteracted nuclear accumulation FOXO3a, an apoptosis-triggering transcription factor, concurrently promoted FOXO3a subsequent cytoplasmic localization PI3K/Akt In conclusion, our findings exerts effect modulating PI3K/Akt/FOXO3a-dependent pathways emerges as promising phytochemical for neuroprotection.