This in vitro study shows resveratrol-loaded polymeric nanoparticles protect PC12 cells and astrocytes from rotenone-induced oxidative stress, mitochondrial dysfunction, and apoptosis while modulating NRF2/HMOX-1 expression.

By improving resveratrol delivery and implicating NRF2-mediated antioxidant defense, the work identifies a mechanistically actionable neuroprotective approach relevant to Parkinson's research, though it remains early-stage and requires in vivo and translational validation.

UNLABELLED: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited treatment options. Several natural compounds have been investigated, particularly resveratrol (RSV), which exhibits antioxidant and anti-inflammatory properties. However, its unfavorable pharmacokinetic profile limits its therapeutic application, making nanoencapsulation a promising strategy. This study evaluated the protective effects of resveratrol-loaded polymeric nanoparticles (NP RSV) and the involvement of the Keap1/NRF2/ARE pathway in a rotenone (ROT)-induced PD-like model in vitro. PC12 neuronal cells and astrocytes were pretreated with NP RSV, RSV, and dopamine for 1 h, followed by ROT exposure for 24 h. Cell viability was assessed by MTT, while cell death profile, reactive oxygen species production, and mitochondrial transmembrane potential (ΔΨm) were evaluated by flow cytometry. Morphological changes were evaluated by optical microscopy. Gene expression of NRF2 and heme oxygenase-1 (HMOX-1) was assessed by RT-qPCR. Pretreatment with NP RSV significantly protected cells by preserving viability, reducing reactive oxygen species, maintaining mitochondrial function, and decreasing apoptosis. Morphological analyses corroborated these results. Furthermore, NP RSV modulated ROT-induced NRF2 and HMOX-1 expression, suggesting involvement of the Keap1/NRF2/ARE pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11064-026-04749-z.