Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss associated with excitotoxicity, oxidative stress, neuroinflammation, and impaired neuroplasticity. Fisetin, a naturally occurring flavonoid, has emerged as a potential neuroprotective compound due to its antioxidant and anti-inflammatory properties. In this study, we investigated the effects of fisetin in cellular models of glutamate-induced excitotoxicity and neural progenitor differentiation. Differentiated PC-12 cells were exposed to 13 mM glutamate and treated with fisetin. Cell viability was assessed using the MTT assay, reactive oxygen species (ROS) production by dihydroethidium assay, and TNF-α levels by ELISA. In parallel, subventricular zone (SVZ)-derived neurosphere cultures were used to evaluate proliferation and differentiation. Fisetin significantly attenuated glutamate-induced cytotoxicity, reduced ROS production, and decreased TNF-α levels. In neurosphere cultures, fisetin reduced neurosphere size without altering neurosphere number, suggesting modulation of progenitor cell dynamics without affecting neural stem cell self-renewal. Moreover, fisetin increased β-III-tubulin-positive neuroblasts without affecting GFAP-positive glial cells. These findings support the pharmacological potential of fisetin in modulating key pathological features of NDs and encourage further in vivo validation and molecular pathway analysis.
