Abstract
Background. The "Cell Cycle Hypothesis" suggests that the abnormal re-entry of neurons into the cell division cycle leads to neurodegeneration, a mechanism supported by in vitro studies on neuronal-like cells treated with the hyperphosphorylating agent forskolin. Pterostilbene, a bioavailable compound found in foods such as blueberries and grapes, may exert neuroprotective effects and could serve as a potential adjunct therapy for neurodegenerative diseases. Methods. In this study, we investigated the effects of pterostilbene on neuronal-like cells derived from the human neuroblastoma SK-N-BE cell line, where cell cycle reactivation was induced by forskolin treatment. We analyzed molecular endpoints associated with differentiated versus replicative cell states, specifically the following: (a) the expression of cyclin CCND1, (b) the Ki67 cell proliferation marker, (c) the AT8 nuclear tau epitope, and (d) genome-wide DNA methylation changes. Results. Our findings indicate that pterostilbene exerts distinct effects on the cell division cycle depending on the cellular state, with neuroprotective benefits observed in differentiated neuronal-like cells, but not in cells undergoing induced division. Additionally, pterostilbene alters DNA methylation patterns. Conclusion. These results suggest that pterostilbene may offer neuroprotective advantages for differentiated neuronal-like cells. However, further studies are required to confirm these effects in vivo by examining specific biomarkers in human populations consuming pterostilbene-containing foods.