Exploring the Dual Role of Resveratrol in N2a Neuronal Cells: Mechanisms, Benefits, and Future Directions

Resveratrol (trans-resveratrol, RSV) is a naturally occurring polyphenol that has numerous biological properties, including neuroprotective, anti-inflammatory, and antioxidant effects. However, its effects are concentration-dependent, with both beneficial and detrimental outcomes in different cell types. This study investigates the dose-dependent prooxidant and proapoptotic mechanisms of RSV in murine neuro-2a neuroblastoma cells. We assessed the dose-dependent effects of RSV on cell viability, cytotoxicity, oxidative stress, and apoptosis. At low concentrations (≤6.25 μM), RSV was noncytotoxic, while higher concentrations (12.5 to 30 μM) markedly reduced cell viability and increased lactate dehydrogenase release, indicating cytotoxicity. This cytotoxic threshold was accompanied by a pronounced prooxidant shift, characterized by a dose-dependent increase in reactive oxygen species and nitric oxide, alongside a significant suppression of key antioxidant enzymes (superoxide dismutase, catalase, and peroxidase). Furthermore, high-dose RSV markedly up-regulated the expression of the proapoptotic gene caspase-3 and increased caspase-3 protein levels, as determined by caspase quantification assay. Our findings reveal a complex dose-dependent response, suggesting a threshold at which RSV loses its neuroprotective properties and becomes neurotoxic. A key novel finding was the rapid biotransformation of RSV, as revealed by high-performance liquid chromatography analysis. Resveratrol-3-sulfate was identified as the primary metabolite, detectable as early as 30 min posttreatment, suggesting that active cellular metabolism is associated with RSV bioactivity. This early metabolic conversion has not been previously reported in neuronal cells and may provide a mechanistic link to its concentration-dependent effects. This study highlights that understanding this precise concentration-dependent duality is essential for developing targeted RSV-based therapies for neurodegenerative diseases, where avoiding prooxidant effects is critical, and for neuroblastoma, where exploiting these effects could be therapeutically advantageous.