Fisetin Augments OEC Neuroprotection Through Modulating Neurotrophin/Cytokine Signaling and Activating PI3K/Akt/CREB...

The persistence of deleterious substances at lesion sites severely impedes neuronal survival and axonal regeneration following central nervous system (CNS) injury or in neurodegenerative disorders. Therefore, clearing these harmful components and establishing a regeneration-permissive microenvironment are crucial for functional recovery. In this study, primary olfactory ensheathing cells (OECs) isolated from adult SD rats were pharmacologically treated with fisetin, a pharmacological agent. To model CNS injury conditions, neural debris was generated through mechanical disruption of primary neural cells. Neurons exposed to this hostile environment were then treated with conditioned medium from fisetin-activated OECs. Subsequent assessments using qRT-PCR, Western blot, CCK-8 assays, immunofluorescence, and ELISA revealed that fisetin significantly enhanced OEC activation, increasing proliferation and viability. Critically, fisetin-treated OECs markedly mitigated debris-induced neurotoxicity, thereby promoting neuronal survival and neurite outgrowth, which was associated with the upregulated anti-inflammatory cytokines (IL-4, IL-10, TGF-β) and neurotrophic factors (BDNF, GDNF, NGF). Mechanistically, fisetin-activated OECs facilitated neuronal growth via the PI3K/Akt/CREB pathway, suggesting that fisetin potentiates OEC-mediated neuroprotection and neurite regeneration in degenerative environments. These findings may highlight the therapeutic potential of combining OECs therapy with fisetin for CNS injuries and neurodegenerative diseases.