Abstract 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.
Martínez‐Ortega et al. (Mon,) studied this question.