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Natural C20 Carotenoids Protect dPC12 Cells from Aβ-Induced Cell Cycle Re-entry, Tau Phosphorylation, and Nrf2 Activation via the Akt/GSK-3β Pathway.

Parisa Gharedaghi,Nassim Faridi,Ping Wang,S. Bathaie

Published 2025 in Journal of Ethnopharmacology

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE Saffron has been known to improve mood and memory since ancient times. Crocin and Crocetin, bioactive C20 carotenoids, were isolated from saffron stigma and demonstrated multiple biological and pharmacological effects. AIM OF THE STUDY We recently demonstrated the effect of Crocin/Crocetin on apoptosis inhibition in an amyloid beta oligomer (AβO)-induced Alzheimer's disease (AD) model using neuronally differentiated PC12 (dPC12) cells. This study investigates their neuroprotective effects on the Akt/GSK-3β pathway in these cells, focusing on NRF2 activity, NQO1 expression, and Tau phosphorylation. METHODS dPC12 cells were exposed to AβO to mimic the AD condition. The cells were treated with Crocin/Crocetin before and after to produce preventive and therapeutic modalities. The expression of key pathway markers was evaluated using Western blot and immunocytochemistry. Flow cytometry was employed to assess cell cycle arrest and apoptosis. RESULTS Crocin/Crocetin significantly attenuated AβO-induced toxicity in dPC12 cells in both modalities mentioned. The named carotenoids significantly suppressed GSK3β kinase activity and reduced Tau phosphorylation (p-Thr231). Furthermore, they increased AKT phosphorylation, promoted NRF2 translocation into the nucleus, and induced NQO1 expression. These effects were observed in a time-dependent manner. Flow cytometry analyses revealed the involvement of both cell cycle arrest and apoptosis in response to AβO treatment. Crocin and Crocetin inhibited this response. CONCLUSIONS Collectively, Crocin/Crocetin effectively mitigated AβO-induced injury in dPC12 cells. Although Crocetin was more effective than Crocin and improved at lower concentrations, both carotenoids exhibited neuroprotective effects against AβO toxicity in preventive and therapeutic modalities via activating the Akt/GSK-3β signaling pathway.

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